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Introduction In subjects with nonalcoholic fatty liver disease (NAFLD), advanced fibrosis (AF) carries the highest risk of adverse liver-related events. To reduce the number of unnecessary biopsies, several noninvasive tools (NITs) for the risk stratification of fibrosis have been developed. We conducted this meta-analysis to assess the performance of the fibrosis-4 index (FIB-4) and NAFLD fibrosis scores (NFS), the 2 most common NITs, for the appropriate selection of subjects with AF for biopsy. Methods Four databases were searched until December 2020 (CRD42021224766). Original articles reporting data on the performance of FIB-4 and NFS, interpreted according to standard cutoffs in subjects with biopsy-proven NAFLD, were included. Separate data extractions were performed according to the lower cutoff, the higher cutoff, and the dual threshold approach. The numbers of subjects classified as true-negative, true-positive, false-negative, and false-positive were extracted. Summary operating points were estimated using a random-effects model. Results Eighteen studies evaluating 12,604 subjects were included. Participants were adult outpatients with biopsy-proven NAFLD or nonalcoholic steatohepatitis. Overall, a weak-to-moderate performance was found for both scores. The head-to-head comparison showed FIB-4 to be associated with a higher performance in ruling in and NFS in ruling out AF in the single threshold approach, whereas, with the dual threshold approach, a lower prevalence of indeterminate findings was found for FIB-4. Discussion This meta-analysis suggested that currently available NITs have a limited performance in identifying AF among subjects with NAFLD. Further studies are needed to optimize existing thresholds or develop new NITs.

Background Age-related hearing loss (ARHL) and retinal vessel changes have both been associated to neurodegeneration/dementia, suggesting a possible link between these 2 conditions in older age. We aimed to determine whether superficial and deep vascular density (SVD and DVD) of the capillary plexi of macular vasculature can be associated with peripheral ARHL and age-related central auditory central processing (CAPD). Method We analyzed data on 886 older participants (65 years+, age range: 65–92 years) in the cross-sectional population-based Salus in Apulia Study. Optical coherence tomography angiography was used to measure SVD and DVD of the capillary plexi of the macula at the 3-mm circle area centered on the fovea (whole retina), the parafoveal quadrant, and foveal quadrant. Disabling peripheral ARHL was defined as >40 dB hearing level of pure tone average on the frequencies from 0.5, 1, 2, and 4 KHz in the better ear, and age-related CAPD as Results DVD at the whole retina and at the parafoveal quadrant were inversely associated only with age-related CAPD (odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88–0.96 and OR: 0.94, 95 CI: 0.90–0.99, respectively). No further associations with peripheral ARHL were evident. Conclusions Retinal vasculature is associated with central auditory processing pathology, possibly playing an important role in early detection and intervention. The association of retinal vascular density with age-related CAPD may bring us a further step forward in understanding the biological mechanisms underlying the links between neurodegeneration/dementia and ARHL.

Group B Coxsackieviruses (CVB) include six serotypes (B1-6) responsible for a wide range of clinical diseases. Since no recent seroepidemiologic data are available in Italy, the study aim was to investigate CVB seroprevalence in a wide Italian population. The study retrospectively included 2459 subjects referring to a large academic hospital in Rome (Italy) in the period 2004-2016. Seroprevalence rates and neutralizing antibodies (nAb) titers were evaluated in relation to years of observation and subjects' characteristics. Positivity for at least one serotype was detected in 69.1% of individuals. Overall, the prevalent serotype was B4, followed by B3 (33.3%), B5 (26.2%), B1 (12.7%), B2 (11.0%), and B6 (1.7%). For B2, a significant decrease in seroprevalence over years was observed. Positivity to at least one virus was 25.2% in children aged 0 to 2 years, but significantly increased in preschool (3-5 years) (50.3%) and school (6-10 years) children (70.4%). Higher nAb responses for B3 and B4 were observed in children aged 3 to 5 years. A high overall CVB prevalence was found. Type-specific variations in prevalence over time probably reflect the fluctuations in circulation typical of Enteroviruses. Children are at greater risk for CVB infection given the high number of seronegative subjects aged 0 to 10 years.

Age is a major contributor to the liver fibrosis rate and its adverse health-related outcomes, including mortality, but older populations are still under-explored. We investigated multimorbidity and inflammatory biomarkers in relation to the increasing liver fibrosis risk to delineate 8-year all-cause mortality trajectories in 1929 older adults from the population-based Salus in Apulia Study. Liver fibrosis risk was assumed using the fibrosis-4 (FIB-4) score, assigned to three liver fibrosis risk groups (low, intermediate, high). In the secondary analyses, the APRI score was also calculated to allow for comparisons. Male subjects (prevalence difference: −13.49, 95% confidence interval (CI): −18.96 to −8.03), a higher multimorbidity burden (effect size, ES: −0.14, 95% CI: −0.26 to −0.02), a higher prevalence of physical frailty (ES: 6.77, 95% CI: 0.07 to 13.47), and a more pronounced inflammatory pattern as indicated by tumor growth factor-α circulating levels (ES: −0.12, 95% CI: −0.23 to −0.01) were significantly more common in the highest-risk FIB-4 score group. Liver function characterized by lipid profile and platelet levels worsened with increasing FIB-4 risk score. The 8-year risk of death was nearly double in subjects in the highest-risk FIB-4 score group, even after controlling for possible confounders. Furthermore, a steeper mortality curve was clearly observed for FIB-4 scores as compared with the APRI scoring system with respect to liver fibrosis risk. In conclusion, using a scoring tool based on simple routine biomarkers to detect liver fibrosis risk may enhance biological knowledge of age-related outcomes of chronic liver disease and be helpful in the clinical setting to identify subjects at risk for adverse health-related outcomes, including mortality.

Background. Hepatocellular carcinoma (HCC) is most commonly considered as a complication of cirrhosis. However, an increasing number of HCC in subjects with non-alcoholic fatty liver disease (NAFLD) without cirrhosis is being reported. We conducted a meta-analysis to assess the prevalence of the absence of cirrhosis in NAFLD-associated HCC. Methods. Four databases were searched until March 2021 (CRD42021242969). The original articles included were those reporting data on the presence or absence of cirrhosis among at least 50 subjects with NAFLD-associated HCC. The number of subjects with absent cirrhosis in each study was extracted. For statistical pooling of data, a random-effects model was used. Subgroup analyses according to the continent, target condition and reference standard for the diagnosis of cirrhosis were conducted. Results. Thirty studies were included, evaluating 13,371 subjects with NAFLD-associated HCC. The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). A higher prevalence was reported in Asia versus Europe, North America and South America (45, 36, 37 and 22%, respectively) as well as in studies adopting histology only as the reference standard for the diagnosis of cirrhosis versus histology and other modalities (e.g., radiology, endoscopy, biochemistry or overt clinical findings) (53 and 27%, respectively). No difference was found between studies including subjects with non-alcoholic steatohepatitis (NASH) only, versus NAFLD with or without NASH (p = 0.385). One in three subjects with NAFLD-associated HCC presented without cirrhosis. This should be reflected in future guidelines and surveillance programs adapted to allow for the early detection of these cancers too.

The liver contribution to the biological network underlying physical frailty in aging is underestimated. How best to measure this contribution magnitude and impact on health risk trajectories in frail individuals is not yet entirely clear. We analyzed the association of a novel liver frailty phenotype with the risk of death in older participants of the Salus in Apulia Study cohort. Clinical and physical examination, routine biomarkers, medical history, and anthropometry were analyzed in 1929 older adults (65 +). Physical frailty was classified by Cardiovascular Health Study criteria, and liver fibrosis risk by fibrosis-4 (FIB-4). The liver frailty phenotype was defined as physical frailty plus high-risk liver fibrosis (score > 2.67). Physical frailty, high-risk liver fibrosis, and liver frailty subjects were compared to subjects without these conditions (non-frail). Proportional Cox regression tested the adjusted association between liver frailty and all-cause mortality for each category. The liver frailty prevalence was relatively low (3.8%), but higher in men (58.1%). Compared to non-frail older subjects, liver frailty subjects were significantly older (effect size (ES) − 1.11, 95% confidence interval (CI) − 1.35 to − 0.87), with a lower education (ES 0.48, 95%CI 0.24 to 0.71) and higher multimorbidity (ES 15.81, 95%CI 4.20 to 27.41). Cox multivariate analyses showed a two-fold increased risk of overall mortality (hazard ratio 2.09, 95%CI 1.16–3.74) even after the adjustment for age, sex, education, and alcohol consumption. The liver frailty phenotype runs twice the risk of overall mortality compared with the non-frail population. This clinical tool, validated in a Southern Italian population, is based on simple sets of measures that can conveniently be assessed also in the primary care setting. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00434-x.

Importance: The association between age-related hearing loss (ARHL) and physical or cognitive frailty has been poorly explored. These associations could define new perspectives for delaying frailty-related processes in older age. Objective: To examine whether peripheral ARHL and age-related central auditory processing disorder (CAPD) are independently associated with physical or cognitive frailty. Design, Setting, and Participants: This cross-sectional study analyzed registry data from December 31, 2014, on 1929 older (≥65 years) participants of the Salus in Apulia Study (Southern Italy) who underwent audiologic, physical, and neuropsychological assessment. Data analysis was performed from December 12, 2019, to January 4, 2020. Main Outcomes and Measures: Prevalence of peripheral ARHL in older individuals with physical and/or cognitive frailty and those without frailty assessed using the Fried criteria (physical) and the Mini-Mental State Examination (cognitive). Multivariable logistic regression models were used to assess associations of audiologic variables with frailty phenotype. Results: Data from 1929 participants (mean [SD] age, 73.6 [6.3] years; 974 male [50.5%]) were eligible for the analyses. The prevalence of peripheral ARHL was higher in the physical frailty group (96 [26.6%]) than in the nonfrail group (329 [21.0%]) (difference, 5.61 percentage points; 95% CI, 0.63-10.59 percentage points) and in the cognitive frailty group (40 [38.8%]) than in the nonfrail group (385 [21.1%]) (difference, 17.75 percentage points; 95% CI, 8.2-27.3 percentage points). Age-related CAPD was more prevalent in the physical frailty group (62 [17.2%]) than in the nonfrail group (219 [14.0%]) (difference, 3.21 percentage points; 95% CI, -1.04 to 7.46 percentage points) and in the cognitive frailty group (28 [27.2%]) than in the nonfrail group (253 [13.9%]) (difference, 13.33 percentage points; 95% CI, 4.10-22.21 percentage points). In the multivariable models, age-related CAPD was associated with cognitive frailty in the fully adjusted model (odds ratio [OR], 1.889; 95% CI, 1.094-3.311). There was also an inverse association between the unitary increase in Synthetic Sentence Identification With the Ipsilateral Competitive Message scores, indicating a lower likelihood of this disorder, and cognitive frailty (OR, 0.989; 95% CI, 0.988-0.999). Peripheral ARHL was associated with cognitive frailty only in the partially adjusted model (OR, 1.725; 95% CI, 1.008-2.937). Conclusions and Relevance: In this cross-sectional study of 1929 participants, age-related CAPD was independently associated with cognitive frailty. Whether the management of ARHL may help prevent the development of different frailty phenotypes or improve their clinical consequences should be addressed in longitudinal studies and, eventually, well-designed randomized clinical trials..

Aging is often associated with a decline in physical function that eventually leads to loss of autonomy in activities of daily living (ADL). Walking is a very common ADL, important for main determinants of quality of life in older age, and it requires the integration of many physiological systems. Gait speed has been described as the ‘sixth vital sign’ because it is a core indicator of health and function in aging and disease. We reviewed original studies up to June 2020 that assessed frailty in both longitudinal and cross‐sectional observational studies, paying particular attention to how gait is measured in older population and how the gait parameter adopted may influence the estimated frailty models and the health‐related outcomes of the various studies (i.e. clinical, cognitive, physical, and nutritional outcomes). Eighty‐five studies met the search strategy and were included in the present systematic review. According to the frailty tools, more than 60% of the studies used the physical phenotype model proposed by Fried and colleagues, while one‐third referred to multi‐domain indexes or models and only 5% referred to other single‐domain frailty models (social or cognitive). The great heterogeneity observed in gait measurements and protocols limited the possibility to directly compare the results of the studies and it could represent an important issue causing variability in the different outcome measures in both clinical‐and population‐based settings. Gait appeared to be an indicator of health and function also in frail older adults, and different gait parameters appeared to predict adverse health‐related outcomes in clinical, cognitive, and physical domains and, to a lesser extent, in nutritional domain. Gait has the potential to elucidate the common basic mechanisms of cognitive and motor decline. Advances in technology may extend the validity of gait in different clinical settings also in frail older adults, and technology‐based assessment should be encouraged. Combining various gait parameters may enhance frailty prediction and classification of different frailty phenotypes.

COVID-19 (Coronavirus disease-19) may present with neurological signs, but whether people already affected by neurological conditions are at a higher risk of contracting COVID-19 is still not known. We, therefore, aimed to investigate the association of previously diagnosed neurological conditions with COVID-19. 502,536 community-dwelling UK Biobank participants (54.4% male, mean age 56.6 ± 10.3 years) were included. Among these, 57,463 participants had a diagnosis of neurological conditions (11.43%) and a total of 1326 COVID-19-positive cases were identified (0.26%). Neurological conditions were identified through medical history and linkage to data on hospital admissions (ICD-10 code G00–G99). COVID-19 presence was diagnosed using the data provided by Public Health England. The association of previous diagnosis of neurological conditions with COVID-19 was evaluated through logistic regressions, adjusted for potential confounders, reported as odds ratios (ORs) with their 95% confidence intervals (CIs). Nerve, nerve root and plexus disorders (G50–G59) were the most common conditions identified. The presence of COVID-19 was almost doubled in neurological conditions compared to the general population (0.45 vs. 0.24%, p

Thyroid hormones control both metabolic pathways and body composition, whereas little knowledge is available about the possible influence of skeletal muscle mass (MM) on thyroid hormone metabolism and circulating levels. This was a cross-sectional study conducted at the Population Health Unit of the National Institute of Gastroenterology IRCCS "S. de Bellis" (Italy) and investigating the extent to which skeletal MM affects thyroid function in obesity. Two hundred twenty-seven consecutive healthy volunteers (155 women and 72 men) with overweight and obesity (BMI ≥ 25 kg/m2) and taking no medication or supplement were assessed for hormone, metabolic and routine laboratory parameters. Body composition parameters were collected by using bioelectrical impedance analysis (BIA). MM was directly related to the body mass index (BMI), waist circumference (WC), insulin, triglycerides, uric acid and free-triiodothyronine (FT3) serum levels, FT3 to the free-thyroxine (FT4) ratio, and insulin-resistance (HOMA-IR), and inversely related to age, total, and HDL-cholesterol serum levels. Multiple regression models confirmed the relationship between MM and the FT3 to FT4 ratio, independently of age, BMI, TSH, triglycerides, and insulin serum levels. The same analyses run by gender showed that this relationship maintained significance only in men. Increased skeletal MM in obesity results in improved thyroid activity mediated by increased T4 conversion to T3, and higher FT3 circulating levels, particularly in men. In conclusion, preserving a greater skeletal MM in obesity helps to enhance thyroid activity. Clinical trial registration ClinicalTrials.gov, identifier NCT04327375.

The world is currently struggling to face the coronavirus pandemic (COVID-19), and many countries have imposed lockdowns and recommended quarantine to limit both the spread of the virus and overwhelming demands for medical care. Direct implications include the disruption of work routines, boredom, depression, increased calorie consumption, and other similar harmful effects. The present narrative review article briefly analyzes the preliminary effects of the quarantine lifestyle from the standpoint of dietary habits. In six different databases, we searched for original articles up to 10 August 2020, assessing eating habits among populations during the COVID-19 pandemic, and recorded any change in the intake of major food categories, as well as changes in body weight. The research strategy yielded 364 articles, from which we selected 12 articles that fitted our goal. Our preliminary findings revealed a sharp rise of carbohydrates sources consumption, especially those with a high glycemic index (i.e., homemade pizza, bread, cake, and pastries), as well as more frequent snacks. A high consumption of fruits and vegetables, and protein sources, particularly pulses, was also recorded, although there was no clear peak of increase in the latter. Data concerning the consumption of junk foods lacked consistency, while there was a decreased alcohol intake and fresh fish/seafood consumption. As a possible connection, people gained body weight. Therefore, in the realistic perspective of a continuing global health emergency situation, timely preventive measures are needed to counteract obesity-related behaviors in the long-term, so as to prevent further health complications.

Self-report questionnaires are a valuable method of physical activity measurement in public health research, however, accuracy is often lacking. Resolving the differences between self-reported and objectively measured physical activity is an important surveillance challenge currently facing population health experts. The present work aims at providing the relationship between activity energy expenditure estimated from wrist-worn accelerometers and intensity of self-reported physical activity (InCHIANTI structured interview questionnaire) in a sub-cohort of a population-based study on aging in Southern Italy. Linear regression was used to test the association between measured and reported physical activity. We found that activity energy expenditure predicted clinical average levels of PA assessed through InCHIANTI classification.

Once the WHO declared the Sars-CoV-2 pandemic, the world had to reprogram numerous clinical activities, particularly those related to highly disabling diseases such as inflammatory bowel diseases (IBDs). In this study, 1083 IBD patients were assessed, affected by Crohn’s Disease (CD) and Ulcerative Colitis (UC), and subdivided into two groups. The first group included patients who needed treatment in person at the outpatients clinic, while the second group could be tele-monitored because they were able to self-administer therapy. The tele-monitoring was based on telecommunication applications via smartphone, driven by a dedicated clinical control room in the IBD Clinic. The aim of this study was to assess the quality of life (using IBDQ32) of UC patients and tele-monitored CD patients (tele-monitoring group) as compared to those patients who underwent assessment in person in the outpatients clinic (control group). Despite observing a lower number of relapses in the control group than the tele-monitoring group, there were no statistically significant differences between the groups in terms of the IBD32Q scores. Tele-monitoring of patients who are able to self-administer the IBD therapy can be an effective vicarious system as compared to the clinical evaluation in person, that could lead to important changes to avoid the overcrowding of the IBD outpatients clinic, especially during public health crises like the present pandemic.

Context Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the bariatric procedures most commonly used for the management of obesity. Whether one or the other is associated with a higher chance of remission of type 2 diabetes (T2D) is unclear. Objective This work aims to compare the efficacy of RYGB and SG for T2D remission at 1, 3, and 5 years after surgery. Data Sources Four databases were searched until January 2020. Study Selection Randomized controlled studies with at least 12 months of follow-up of patients with T2D allocated to RYGB or SG were selected. Data Extraction To ensure uniformity, broad and narrow criteria for T2D remission were defined. The number of patients achieving remission of T2D at each assessment was extracted. Data were pooled using a random-effects model. Data Synthesis Ten studies were included, evaluating 778 patients. The overall prevalence of achievement of broad and narrow criteria for T2D remission was 73% and 53% at the 1-year, 60% and 48% at the 3-year, and 51% and 43% at the 5-year assessment. Compared to SG, RYGB was associated with a higher chance of achieving broad and narrow criteria for remission at 1 year after surgery (risk ratio [RR] = 1.34 vs RR = 1.22) and broad criteria for remission at 5 years (RR = 1.18). No other differences were found. Conclusions The present meta-analysis suggests a more favorable effect of RYGB than SG on achieving T2D remission in the short-term only, although the evidence currently available does not clarify whether differences in this outcome are confirmed long term or fade thereafter.

The association between late-life depression (LLD) and age-related hearing loss (ARHL) was suggested by preliminary studies, but reliance on LLD subtypes may introduce significant bias. We examined the association between ARHL and LLD according to the age of onset (early-onset depression (EOD) and late-onset depression (LOD)). We investigated the association between ARHL and LLD diagnosed according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR in 1749 Italian community-dwelling older subjects from the population-based GreatAGE Study, Southern Italy. Peripheral ARHL was assessed as a pure tone average (PTA) threshold > 40 dB hearing level in the better ear- and age-related CAPD as a score of

We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study).Cross-sectional data from a population-based study.Castellana Grotte, Bari, Italy.Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and50% score on the SSI-ICM test [Synthetic Sentence Identification-Ipsilateral Competing Message]), neurologic and neuropsychological examinations, and serum metabolic biomarkers assays were investigated on 1647 healthy volunteers aged65 years.The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers.The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients.

IntroductionInsulin is the most effective antihyperglycemic treatment and basal insulin is the preferred initial formulation in patients with type 2 diabetes. However, its effects are dose-dependent, so adequate titration is necessary to reach targets. We performed a meta-analysis to compare the efficacy and safety of patient-led versus physician-led titration of basal insulin in patients with uncontrolled type 2 diabetes.Research design and methodsFour databases were searched from database inception through March 2020. Randomized controlled studies with at least 12 weeks of follow-up of patients with type 2 diabetes allocated to patient-led versus physician-led titration of basal insulin were selected. Data on glycemic endpoints (hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), hypoglycemia) and other outcomes (insulin dose, body weight, patient-reported outcomes, adverse events, rescue medication, discontinuation) were extracted. Data were pooled using a random-effects model.ResultsSix studies evaluating 12 409 patients were finally included. Compared with the physician-led performance, patient-led titration was associated with a statistically significant higher basal insulin dose (+6 IU/day), leading to benefits on HbA1c (−0.1%) and FPG (−5 mg/dL), despite a higher risk of any level hypoglycemia (relative risk=1.1) and a slight increase in body weight (+0.2 kg). No difference was found for the other outcomes.ConclusionsThe present study showed that patient-led titration of basal insulin was not inferior to physician-led titration in patients with uncontrolled type 2 diabetes. Therefore, diabetes self-management education and support programs on basal insulin should be widely adopted in clinical practice and patients provided with tools to self-adjust their dose when necessary.

Vitamin D improves bone density and latest studies show adherence to Med-Diet as protective on osteoporosis. This observational study aimed at investigating the relationship between 25(OH)D levels and adherence to Med-Diet. Body weight, BMI, WC, glucose, insulin, 25(OH)D, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine serum levels and insulin resistance were determined in 284 overweight/obese subjects not taking medications or supplements. Adherence to Med-Diet was evaluated by using PREDIMED score. High-level of adherence stood out. 25(OH)D was inversely related to BMI, WC, HOMA-IR, serum insulin and triglycerides, while directly to PREDIMED score. Two different regression models confirmed this positive correlation independently of gender and other parameters showing univariate relationship with 25(OH)D. This study argues that a closer adherence to Med-Diet is independently associated with an increase of 25(OH)D suggesting that higher vitamin D levels may contribute to the protective effect of the Med-Diet on osteoporosis.

Background: Hypovitaminosis D and higher platelet numbers are emerging as cardiovascular risk factors, in particular in obese subjects. Methods: This observational study was aimed at investigating the relationship between platelet number and serum 25-hydroxyvitamin D (25(OH)D) levels in a cohort of individuals affected by overweight and obesity (body mass index (BMI) &ge, 25 Kg/m2). A sample of 341 subjects (248 women, 93 men), aged 18&ndash, 71 years, taking no medication, was examined. Anthropometric, hormone, metabolic and common routine hematochemical parameters were examined and evaluated in association with platelet count and serum 25(OH)D levels. Results: Platelet numbers were inversely related to age (p &lt, 0.04), 25(OH)D (p &lt, 0.05) and uric acid (p &lt, 0.04) levels, and directly associated with white blood cells (p &lt, 0.01), Thyroid Stimulating Hormone (TSH) (p &lt, 0.04), insulin levels (p &lt, 0.002) and Homeostasis Model Assessment &ndash, Insulin Resistance (HOMA-IR) (p &lt, 0.002). We applied statistical regression models to examine the relationship between platelet count (dependent variable) and parameters that had univariate associations with platelet numbers, showing that the association between platelet count and 25(OH)D was not confirmed. Moreover, vitamin D showed a negative independent association with BMI, diastolic blood pressure and serum insulin levels. Conclusions: This study indicates, for the first time, that vitamin D deficiency is associated with a parallel increase in platelet number, suggesting that higher platelet numbers may be one of the possible mechanisms leading to a greater cardiovascular risk in obese subjects. It also shows that vitamin D deficiency, a common condition in obesity, has independent associations with higher BMI, diastolic blood pressure and serum insulin levels.

Background Body fat distribution influences the risk of cardio-metabolic disease in people with overweight. This study was aimed at identifying the anthropometric parameters more strongly associated with the majority of cardio-metabolic risk factors. Methods This study included 1214 subjects (840 women), with a body-mass-index (BMI) ≥ 25 Kg/m2, aged 39.2 ± 13 years. Fasting blood glucose (FBG), triglycerides (TG), total, HDL- and LDL-cholesterol, uric acid, vitamin D, high-sensitive C-reactive protein (hs-CRP), white blood cells (WBC), platelets, insulin and insulin resistance (HOMA-IR), systolic (SBP) and diastolic blood pressure (DBP), smoking habit and snoring were evaluated as cardio-metabolic risk factors.We also included the Systematic COronary Risk Evaluation (SCORE) to estimate cardiovascular risk in our study population. BMI, waist circumference (WC), waist-to-height-ratio (WHtR) and neck circumference (NC) were evaluated as anthropometric parameters. Results All four anthropometric parameters were positively associated to SBP, DBP, TG, FBG, insulin, HOMA-IR, WBC, and snoring (pβ = 0.15; 95% CI 0.12 to 0.18; pβ = -0.18; 95% CI -0.22 to 0.14; pβ = 7.56; 95% CI 5.30 to 9.82; p Conclusions NC, combined with BMI and WC or WHtR could represent an essential tool for use in clinical practice to define the cardio-metabolic risk in individuals with excess body weight.

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

Background Several studies have suggested that higher consumption of dietary fiber is beneficial for a variety of health outcomes. However, many results have been inconclusive and, to our knowledge, there has been no attempt to systematically capture the breadth of outcomes associated with dietary fiber intake or to systematically assess the quality and the strength of the evidence on the associations of dietary fiber intake and different health outcomes or medical conditions. Objective The aim of this study was to describe the diverse health outcomes convincingly associated with dietary fiber consumption. Design This was an umbrella review of systematic reviews with meta-analysis of observational studies. For each association, random-effects summary effect size, 95% CIs, and 95% prediction intervals were estimated. We also assessed heterogeneity, evidence for small-study effect, and evidence for excess significance bias. We used these metrics to evaluate the credibility of the identified evidence. Results Our literature search identified 1351 abstracts. Of these, 18 meta-analyses including a total of 298 prospective observational studies and 21 outcomes were included. Outcomes studied included cancer and precancer lesions (n = 12), cardiovascular diseases (CVDs; n = 3), all-cause and specific-cause mortality (n = 4), type 2 diabetes (n = 1), and Crohn disease (n = 1). Overall, 6 (29%) of the 21 eligible outcomes reported highly significant summary results (P < 1 × 10 ' '6); these included CVD and CVD mortality, coronary artery disease, pancreatic cancer, and gastric cancer. Overall, 3 of 21 (14%) outcomes presented convincing evidence (pancreatic cancer, CVD mortality, and all-cause mortality), but only CVD and all-cause mortality were based on prospective studies. Two other outcomes (10%), CVD and coronary artery disease, presented highly suggestive evidence based on prospective studies. Conclusion Our results support dietary recommendations that promote higher fiber intake as part of a healthy diet. © 2018 American Society for Nutrition. All rights reserved.

// Anna Maria Valentini 1 , Federica Di Pinto 1 , Filomena Cariola 2 , Vito Guerra 3 , Gianluigi Giannelli 4 , Maria Lucia Caruso 1 and Michele Pirrelli 1 1 Department of Pathology, National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, Italy 2 Medical Genetic Unit, National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, Italy 3 Department of Epidemiology, National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, Italy 4 National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, Italy Correspondence to: Anna Maria Valentini, email: am.valentini@irccsdebellis.it Keywords: colorectal cancer; microsatellite instability; immunohistochemistry; PD-L1; PD-1 Received: September 24, 2017 Accepted : December 05, 2017 Published: January 12, 2018 ABSTRACT Objectives: We investigated the PD-L1 expression in colorectal cancer (CRC) and in its microenvironment. Results: PD-L1 was expressed in neoplastic cells (NCs) and tumor-infiltrating immune cells (IICs). All samples PD-L1+ on NCs were also on IICs. Three types of cancers could be grouped: group A(NCs-/ IICs-); group B (NCs-/ IICs+); group C (NCs+/IICs+). To group A belong tumors characterized by poorly immunogenic competence, poor immune response but massive granulocyte infiltrate, justifying the absence of PD-L1 as an immunoinhibitor receptor. To Group B probably belong more immunogenic CRCs, justifying the strong IICs-mediated immune response, and up-regulation of PD-L1 expression only on IICs. To group C belong CRCs probably characterized by a large amount of tumor neoantigens resulting in a marked infiltration of lymphocytes and PD-L1 upregulation also in NCs. Materials and Methods: Sixty-three colorectal cancer specimens from a cohort of 61 patients were retrospectively reviewed. Thirty-seven MSS and 26 MSI-H CRCs enrolled in this study. Immunohistochemical staining to PD-L1 was performed by using MAb E1L3N. Conclusions: Our study calls attention to the importance to assess PD-L1 expression in tumor microenvironment also evaluating type and density of infiltrating immune cells to better stratify CRCs with different immunological patterns.

Currently, the diagnosis of psychiatric illnesses is based upon DSM-5 criteria. Although endophenotype-specificity for a particular disorder is discussed, the identification of objective biomarkers is ongoing for aiding diagnosis, prognosis, or clinical response to treatment. We need to improve the understanding of the biological abnormalities in psychiatric illnesses across conventional diagnostic boundaries. The present review investigates the innovative post-genomic knowledge used for psychiatric illness diagnostics and treatment response, with a particular focus on proteomics. Areas covered: This review underlines the contribution that psychiatric innovative biomarkers have reached in relation to diagnosis and theragnosis of psychiatric illnesses. Furthermore, it encompasses a reliable representation of their involvement in disease through proteomics, metabolomics/pharmacometabolomics and lipidomics techniques, including the possible role that gut microbiota and CYP2D6 polimorphisms may play in psychiatric illnesses. Expert opinion: Etiologic heterogeneity, variable expressivity, and epigenetics may impact clinical manifestations, making it difficult for a single measurement to be pathognomonic for multifaceted psychiatric disorders. Academic, industry, or government's partnerships may successfully identify and validate new biomarkers so that unfailing clinical tests can be developed. Proteomics, metabolomics, and lipidomics techniques are considered to be helpful tools beyond neuroimaging and neuropsychology for the phenotypic characterization of brain diseases.

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

Background: Identifying predictive factors that contribute to changes in body weight may well be an interesting approach to the management of obesity. Objective: This study was firstly aimed at examining the effect of a one-year lifestyle program based on improvements in the habitual diet and increased levels of physical activity on weight loss. Secondly, it was focused on identifying anthropometric, and serum hormonal, metabolic and haematochemical factors which can be associated with the degree of weight loss in Kg. Methods: 488 overweight or obese subjects, 383 women and 105 men, aged 18-67 years, were enrolled in the study. Body mass index, waist circumference, serum blood glucose, lipids, uric acid, creatinine, insulin, TSH, FT3, FT4, and 24-h urine catecholamines were measured. Results: Weight loss was positively associated with BMI (P < 0.01), waist circumference (P < 0.01), uric acid (P < 0.01), creatinine (P < 0.05), smoking (P < 0.01), and negatively correlated with age (P < 0.01), total cholesterol (P < 0.05), LDL-cholesterol (P < 0.01), HDL cholesterol (P < 0.05). In a multiple regression model considering weight loss as a dependent variable, and smoking, age, BMI, uric acid, creatinine, total cholesterol, LDL-cholesterol and HDL cholesterol as independent variables, weight loss maintained a direct independent relationship with BMI (P < 0.001), uric acid (P < 0.05), LDL-cholesterol (P < 0.05), and HDL-cholesterol (P < 0.05), and an inverse independent association with cholesterol (P < 0.01). Conclusions: This study suggests that higher BMI and uric acid levels, and lower total cholesterol concentrations are associated with a greater potential to lose weight.

Background: Obesity and sleeping blood pressure (BP) abnormalities are well recognized as some of the main risk factors for hypertension and cardiovascular diseases (CVDs). The primary objective of this study was to evaluate the prevalence of hypertension and non-dipping profile in overweight/obese subjects. Methods: A sample of 100 consecutive healthy overweight/obese subjects, aged 20–69 years and never treated with antihypertensive drugs was examined. Ambulatory 24 h BP monitoring was performed to diagnose hypertension and a non-dipping profile. Anthropometric, metabolic and routine hematochemical parameters were assessed. All subjects underwent ultrasound measurement of common carotid intima–media thickness. Results: Hypertension was demonstrated in 69% (n = 69) and 27% of the sample (n = 27) had a non-dipping profile. Among the hematochemical variables, estimated glomerular filtration rate (eGFR) (p = 0.02) and FT4 (p = 0.01) serum levels were higher in the hypertensive group than in the normotensive group. Lower potassium and uric acid serum levels (p = 0.05) were independent predictive factors of a non-dipping BP profile. Conclusions: This study shows, for the first time, that 1) an unexpectedly high percentage (69%) of overweight/obese subjects is affected by hypertension, 2) early hypertensive subjects have an increased eGFR and higher FT4 serum levels, 3) lower potassium and uric acid levels are independent predictors of pathological nocturnal non-dipping.

We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.NCT01246986 at ClinicalTrials.gov.

Background and Aims:Hepatocellular carcinoma is associated with several chronic liver diseases, especially chronic hepatitis B virus, hepatitis C virus, and alcoholism. It is increasingly appreciated that obesity/metabolic syndrome is also associated with chronic liver disease and subsequent hepatocellular carcinoma.Methods:We retrospectively investigated the serum lipid profiles in a large hepatocellular carcinoma cohort, associated predominantly with the hepatitis B virus, hepatitis C virus, alcohol or nonalcoholic steatohepatitis. The cohort was examined both as a whole, as well as stratified by etiology.Results:We found significant associations between parameters of hepatocellular carcinoma biology such as maximum tumor diameter, portal vein thrombosis, tumor multifocality or alpha-fetoprotein levels and individual lipid components, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and body mass index. In a final multiple linear regression model considering all lipid variables together, only high-density lipoprotein cholesterol was significantly associated with the tumor Tumor Aggressiveness Index. High-density lipoprotein cholesterol was found to have a statistically higher hazard ratio for death than low high-density lipoprotein cholesterol levels (Cox). On examination by etiological group, alpha-fetoprotein levels were significantly higher in patients with hepatitis C virus compared to those with alcohol or nonalcoholic steatohepatitis, but maximum tumor diameter, tumor multifocality and portal vein thrombosis were similar across etiological groups. Nonalcoholic steatohepatitis patients had significantly less cirrhosis than other groups and hepatitis B virus patients had significantly higher cholesterol and low-density lipoprotein cholesterol levels than hepatitis C virus patients.Conclusions:This is the first report, to our knowledge, of a relationship between serum lipid parameters and indices of hepatocellular carcinoma growth, invasion and aggressiveness, as well as with survival.

Screening for non-alcoholic fatty liver disease (NAFLD) is key step for primary management of fatty liver in the clinical setting. Excess weight subjects carry a greater metabolic risk even before exhibiting pathological patterns, including diabetes. We characterized the cross-sectional relationship between routine circulating biomarkers and NAFLD in a large sample of diabetes-free subjects with overweight or obesity, to elucidate any independent relationship. A population sample of 1232 consecutive subjects with a body mass index of at least 25 kg/m2, not receiving any drug or supplemental therapy, was studied. Clinical data and routine biochemistry were analyzed. NAFLD was defined using the validated fatty liver index (FLI), classifying subjects with a score ≥ 60% as at high risk. Due to extreme skewing of variables of interest, resampling matching for age and sex was performed. Our study population was characterized by a majority of females (69.90%) and a prevalence of NAFLD in males (88.90%). As a first step, propensity score matching was explicitly performed to balance the two groups according to the FLI cut-off. Based on the resulting statistical trajectories, corroborated even after data matching, we built two logistic regression models on the matched population (N = 732) to verify any independent association. We found that each unit increase of FT3 implicated a 50% increased risk of NAFLD (OR 1.506, 95%CI 1.064 to 2.131). When including glycated haemoglobin (HbA1c) in the model, free-triiodothyronine (FT3) lost significance (OR 1.557, 95%CI 0.784 to 3.089) while each unit increase in HbA1c (%) indicated a significantly greater NAFLD risk, by almost two-fold (OR 2.32, 95%CI 1.193 to 4.512). Glucose metabolism dominates a key pathway along the hazard trajectories of NAFLD, turned out to be key biomarker in monitoring the risk of fatty liver in diabetes-free overweight subjects. Each unit increase in HbA1c (%) indicated a significantly greater NAFLD risk, by almost two-fold, in our study.

To evaluate whether progressively higher fasting plasma glucose (FPG) is associated to thickening of the interventricular septum (IVS) among non-diabetic subjects with obesity.We studied 227 consecutive non diabetic patients (155 women and 72 men, age range 18-72 years) with overweight or obesity (BMI ≥ 25 Kg/m2), taking no medication or supplement. Hormonal, metabolic and routine laboratory parameters were collected. Echocardiography and ultrasonography echo-color Doppler of intima-media thickness of the common carotid artery (IMT-CCA) were performed to evaluate intima-media thickness of the common carotid artery (IVST) and early signs of atherosclerosis, respectively, in all enrolled subjects.Of the 227 subjects, 48.9% had higher IVST values. Age (p 0.04), waist circumference (p 0.01), systolic (p 0.01) and diastolic blood pressure (p 0.01), FPG (p 0.01), insulin (p 0.04), HOMA IR (p = 0.01), uric acid (p 0.01) serum levels, IMT-CCA (p 0.01), and left atrial diameter (LAD) (p 0.01) were significantly higher in subjects with pathological IVST. Logistic regression models demonstrated an independent relation of FPG to IVST, both in semi and fully adjusted models (ORs 1.045 and 1.039, respectively). Moreover, graph presentation of the ORs and 95% CIs by FPG quintiles showed a positive risk trend for pathological IVST.Higher FPG levels represent an independent sensitive predictor of IVS thickening in subjects with obesity, even before overt diabetes. These results emphasize the importance of preventive management of the diabetes risk in obesity.

In patients with hepatocellular carcinoma (HCC) receiving sorafenib, drug resistance is common. HCC develops in a microenvironment enriched with extracellular matrix proteins including laminin (Ln)-332, produced by hepatic stellate cells (HSCs). Ln-332 is the ligand of α3β1 and α6β4 integrins, differently expressed on the HCC cell surface, that deliver intracellular pathways. The aim of this study was to investigate the effect of Ln-332 on sorafenib's effectiveness. HCC cells were challenged with sorafenib in the presence of Ln-332 and of HSC conditioned medium (CM). Sorafenib impaired HCC cell proliferation and induced apoptosis. HSC-CM or Ln-332 inhibited sorafenib's effectiveness in HCC cells expressing both α3β1 and α6β4. Inhibiting α3 but not α6 integrin subunit using blocking antibodies or small interfering RNA abrogated the protection induced by Ln-332 and HSC-CM. Hep3B cells expressing α6β4 but lacking the α3 integrin were insensitive to Ln-332 and HSC-CM protective effects. Hep3B α3-positive, but not wild-type and scramble transfected, cells acquired protection by sorafenib when plated on Ln-332-CM or HSCs. Sorafenib dephosphorylated focal adhesion kinase (FAK) and extracellular signal-regulated kinases 1/2, whereas Ln-332 and HSC-CM partially restored the pathways. Silencing FAK, but not extracellular signal-regulated kinases 1/2, abrogated the protection induced by Ln-332 and HSC-CM, suggesting a specific role for FAK. Sorafenib down-regulated total FAK, inducing its proteasomal degradation, while Ln-332 and HSC-CM promoted the escape of FAK from ubiquitination, probably inducing a preferential membrane localization. Conclusion This study unveils a novel mechanism of sorafenib resistance depending on the α3β1/Ln-332 axis and requiring FAK ubiquitination, providing new insights into personalizing therapy for patients with HCC. (Hepatology 2016;64:2103-2117).

The epithelial to mesenchymal transition (EMT) is a multistep biological process whereby epithelial cells change in plasticity by transient de-differentiation into a mesenchymal phenotype. EMT and its reversal, mesenchymal to epithelial transition (MET), essentially occur during embryogenetic morphogenesis and have been increasingly described in fibrosis and cancer during the last decade. In carcinoma progression, EMT plays a crucial role in early steps of metastasis when cells lose cell-cell contacts due to ablation of E-cadherin and acquire increased motility to spread into surrounding or distant tissues. Epithelial plasticity has become a hot issue in hepatocellular carcinoma (HCC), as strong inducers of EMT such as transforming growth factor-β are able to orchestrate both fibrogenesis and carcinogenesis, showing rising cytokine levels in cirrhosis and late stage HCC. In this review, we consider the significance of EMT-MET in malignant hepatocytes as well as changes in the plasticity of hepatic stellate cells for cellular heterogeneity of HCC, and further aim at explaining the current limiting insights into EMT by snapshot analyses of HCC tissues. Recent advances in the identification of clinically relevant mechanisms that impinge on important EMT-transcription factors, as well as on miRNAs causing EMT signatures and HCC progression are highlighted. In addition, we draw particular attention to framing EMT in the context of potential clinical relevance for HCC patients. We conclude that some aspects of EMT are still elusive and further studies are required to better link the clinical management of HCC with biomarkers and targeted therapies related to EMT.

Background: Irisin, a hormone-like myokine, regulates energy homeostasis and mediates the benefits of physical activity on health. Methods: To estimate the effect of different diets on irisin concentrations in subjects with the Metabolic Syndrome (MetS). Methods: Subjects with MetS were derived from a population survey, 163 subjects were enrolled and randomized to a: Low Glycaemic Index (LGID), Mediterranean (MD) or Low Glycaemic Index Mediterranean (LGIMD) Diet, and the groups were compared, also with 80 controls without MetS. Sociodemographic, medical and nutritional data were collected and fasting blood samples drawn. Subjects underwent LUS and bioimpedentiometry. Generalized Estimating Equations were performed. Results: At baseline, lower irisin concentrations were observed in MetS subjects. Mean irisin levels increased in all diet groups but only the LGID group reached statistical significance, as well as showing an interaction between LGID and time at the sixth month examination (4.57, 95% CI &minus, 1.27, 7.87). There was a positive effect of Vegetable Proteins (0.03, 95% CI &minus, 0.01,0.06) and Saturated Fatty Acids (0.04, 95% CI 0.01, 0.07) on irisin concentrations. In the LGIMD, a positive effect on Fat-Free Mass (0.38, 95% CI 0.19, 0.57) and a negative effect on the Body Mass Index (&minus, 0.75, 95% CI &minus, 1.30, &minus, 0.19) were observed. Conclusions: There seems to be a link between diet and muscle physiology. We showed that patients following a LGID had higher levels of irisin, a promising biomarker of muscle activity.

Pharmacotherapy for the treatment of depressive disorders in Alzheimer's Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8-12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects.The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine.The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.

Objective The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC.Design Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V-0 and V-1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model.Results Calculated tumour doubling times ranged from 30 to 621 days (mean, 107 +/- 91 days; median, 83 days) and were divided into quartiles: = 111 days (n= 19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p< 0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p< 0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p< 0.0001).Conclusions The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC.

Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis. Recently, olive oil has been demonstrated to modulate type-1 cannabinoid (CB1) receptor gene expression in both human colon cancer cells and rat colon. The aim of this study was to investigate a possible link between olive oil and ω-3 PUFAs effects and CB1 receptor expression in both intestinal and adipose tissue of ApcMin/+ mice. To confirm the role for the CB1 receptor as a negative modulator of cell proliferation in human colon cancer, CB1 receptor gene expression was also detected in tumor tissue and in surrounding normal mucosa of patients with colorectal cancer (CRC). Dietary ω-3 PUFAs significantly inhibited intestinal polyp growth in mice, correlating with CB1 receptor gene and protein expression induction. CB1 receptor gene up-regulation was also detected in adipose tissue, suggesting a close communication between cancer cells and the surrounding environment. Tissue CB1 receptor induction was associated with a concurrent inactivation of the Wnt/β-catenin pathway. Moreover, there was a significant reduction in CB1 receptor gene expression levels in cancer tissue compared to normal surrounding mucosa of patients with CRC, confirming that in cancer the “protective” action of the CB1 receptor is lost.

The combination of pegylated interferon (Peg-IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost-benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA-IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA-IC in 103 patients with HCV chronic infection. Serum HCV-RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow-up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA-IC levels were higher in responders (238 AU, interquartile difference 130-556 AU) and decreased significantly to 125 AU (70-290 AU). The mean baseline value in nonresponders was 149 AU (86.5-306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80-280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA-IC after 1 month (OR = 4.82; 95% CI 1.39-16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21-0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA-IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti-HCV positive patients undergoing antiviral therapy.

Omega-6 Polyunsaturated Fatty Acids (PUFAs), through the eicosanoids derived from arachidonic acid (AA), are able to modulate the inflammatory processes, whereas omega-3 PUFAs, such as eicosapentaenoic acid (EPA), exert anti-oxidant and anti-inflammatory effects. An unbalanced AA/EPA ratio in favor of AA leads to the development of different metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the effects of different diets, alone and in combination with two physical activity programs, on the AA/EPA ratio value in erythrocyte membranes of patients with NAFLD. One hundred forty-two subjects with NAFLD were enrolled in the study and randomized into six treatment groups. AA/EPA ratio was significantly reduced after 90 days of treatment with only a program of aerobic activity. However, it appears that the combination of physical activity and a Low Glycemic Index Mediterranean Diet (LGIMD) was more efficacious in reducing AA/EPA levels, at 45 days of treatment, even if this effect was not maintained over time. The combined effect of diet and physical activity reduced the AA/EPA ratio value improving the score of steatosis. Dietary intake of omega-3 PUFAs, in association with a healthy lifestyle, may be used in the prevention protocols for many chronic diseases, including NAFLD.

Background : Basiliximab (B), an anti-CD25 monoclonal antibody, may represent an alternative to steroids (S) in immunosuppression after liver transplantation (LTx). The aim of this prospective randomized clinical trial was to compare B with S in a cyclosporin A (CsA)-based immunosuppression regimen in primary LTx. Methods : Forty-seven adult recipients of LTx were randomly assigned to receive B or S. CsA was administered at the initial dose of 10 mg/kg/day and adjusted to the target C2 level of 800 to 1000 ng/mL by day 7. Clinically suspected acute cellular rejection (ACR) was histologically confirmed. Endpoints include ACR, survival, and disease-free survival. Results : In group B (26 patients), there were seven biopsy-confirmed ACR with an ACR rate of 15.4%; in group S (21 patients), 8 ACR with an ACR rate of 28.6% (P=n.s.). Cumulative survival at 36 months after transplantation was 84.3% for group B and 61.0% for group S. In hepatitis C virus patients (n=20: 12 in group B, 8 in group S), the ACR rate was 25% in group B and 50% in group S. The incidence of infection and other adverse events was similar in the two treatment groups. Conclusions : B may represent a valid alternative to S in the induction of immunosuppression in LTx. Further studies of basiliximab in a large cohort are needed.

Hepatocellular carcinoma (HCC) treatment is challenging because the mechanisms underlying tumor progression are still largely unknown. Transforming growth factor (TGF)–β1 is considered a crucial molecule in HCC tumorigenesis because increased levels of patients' serum and urine are associated with disease progression. The aim of the present study was to investigate the inhibition of TGF-β signaling and its impact on HCC progression. Human HCC cell lines were treated with a TGF-β receptor kinase inhibitor (LY2109761) whose selectivity was determined in a kinase assay. Exogenous TGF-β1 phosphorylates the TGF-β receptor, consequently activating Smad-2, whereas the drug selectively blocks this effect and dephosphorylates autocrine p-Smad-2 at concentrations ranging from 0.001 to 0.1 μM. A cytotoxic effect documented by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), trypan blue, and propidium iodide staining assays was observed at 10μM, whereas the drug inhibits (P < 0.001) the migration of HCC cells on fibronectin, laminin-5, and vitronectin and invasion through Matrigel (P < 0.001) at concentrations up to 0.1 μM. LY2109761 up-regulates (P < 0.001) E-cadherin mRNA and protein levels. This increase was localized at the cellular membrane where E-cadherin mediates anchorage that is cell–cell dependent. Consistently, a functional monoclonal antibody that inhibits E-cadherin–dependent cell–cell contact restores the migratory and invasive activity. Finally, nonmetastatic HCC tissues from 7 patients were cultured with TGF-β1 in the presence or absence of LY2109761. E-cadherin expression was reduced by TGF-β1 and was significantly (P < 0.0001) increased by LY2109761 treatment, measured by quantitative real-time PCR on microdissected tissues and by immunohistochemistry on serial sections. In 72 patients, E-cadherin tissue expression was more weakly expressed in metastatic than in nonmetastatic HCC (P < 0.0001). Conclusion: LY2109761 blocks migration and invasion of HCC cells by up-regulating E-cadherin, suggesting that there could be a mechanistic use for this molecule in clinical trials. (HEPATOLOGY 2008.)

Background. The optimal therapy for hepatocellular carcinoma (HCC) is transplantation. For all those patients not eligible for transplantation (or on the waiting list) among the treatments of choice used more frequently in recent years are resection (RES) and radiofrequency ablation (RFA). RFA is less efficacious for HCC ranging over 3cm. The aim of this study was to compare RFA to RES in a restricted cohort of patients with a single naive HCC ranging from 3 to 5cm in size and without end-stage liver disease. Patients and methods. A total of 102 patients who had never been treated before were enrolled. Those patients whose HCC position would have required too much parenchymal loss at RES (central or close to main vascular structures) were treated with RFA (n=60), and the others underwent RES (n=42). The two groups were similar for HCC size and liver disease status. The outcome was considered in terms of overall survival (OS) and disease-free survival (DFS) calculated by the Kaplan–Meier method. Differences among groups were validated by log-rank test. Results. The RES group seemed to present a better long-term OS (91%, 57%, and 43% vs 96%, 53%, and 32% at 1, 3, and 5 years, respectively) and DFS (74%, 35%, and 14% vs 68%, 18%, and 0%, respectively) but there was no statistical significance. Age, gender, virus etiology, HCC size and α-fetoprotein levels did not correlate with survival. Patients with recurrence within the first 12 months after treatment showed a worse long-term survival (p=0.011). Patients in Child-Pugh class B had poor prognoses compared with those in class A (p=0.047). Conclusion. Even if RES seemed to promise better long-term results, in the medium term this difference had no statistical significance. Survival in this series was more closely related to the stage of the underlying liver disease than to treatment (RES/RFA).

Hepatocellular carcinoma (HCC) growth severely affects prognosis. Ki-67, a known marker of cell proliferation, is a negative prognostic factor in HCC. Growth factors such as the epidermal growth factor (EGF) induce HCC cell proliferation but do not explain the great heterogeneity of HCC growth. Laminin-5 (Ln-5) is an extracellular matrix protein (ECM) present in the tissue microenvironment of HCC. The two main receptors for Ln-5, integrins α3β1 and α6β4, are expressed on the cell surface of HCC cells. The aim of this study is to investigate an alternative mechanism of HCC growth whereby Ln-5 promotes HCC cell proliferation through α3β1 and α6β4. HCC tissues containing Ln-5 display a larger diameter and higher number of positive cells for Ki-67, a well known proliferative index, as determined by double immunofluorescence staining and real-time PCR on microdissected tissues. In vitro, Ln-5, but not collagen I, collagen IV or fibronectin, induces proliferation as much as EGF does, via Erk phosphorylation as a consequence of β4 integrin phosphorylation. However, the two HCC cell lines do not proliferate in presence of Ln-5 despite β4 integrin and Erk1/2 activation. After transfection with α3 integrin, in the presence of Ln-5 one of these HCC cell lines acquires a proliferative activity whereas one of the proliferative HCC cell lines, knocked-down for α3 integrin, loses its proliferative activity. Conclusions: Our study suggests a new mechanism of HCC growth whereby Ln-5 stimulates proliferation via a different function of α6β4 and α3β1. (HEPATOLOGY 2007.)

Endometriosis is an estrogen-correlated benign disease characterized by a marked ability of endometrial-like cells to invade and proliferate outside uterine cavity, resembling for some invasive aspect the cancer growth. The molecular mechanisms regulating endometrial cell invasiveness are mostly unknown, although interactions between extracellular matrix (ECM) proteins and their transmembrane receptors, integrins, are likely to play a central role. In particular, laminin (Ln)-5 could be closely involved, as it is in cancer. We have investigated the expression of Ln-1, Ln-5, and collagen IV (Coll IV) ECM proteins and their receptors, alpha3beta1 and alpha6beta4 integrins, in atrophic, proliferative, and secretive endometrium and in endometriosis. The results show that Ln-5, but not Ln-I and Coll IV, is altered in secretive endometrium as well as in endometriosis tissues. No alterations are observed in atrophic or proliferative endometrium. Consistently, the polarization of both integrin subunits alpha3 and beta1, but not alpha6 and beta4, is altered in secretive endometrium and endometriosis tissues, but not in atrophic and proliferative endometrium. These results seem to suggest that Ln-5 and alpha3beta1 could be involved in the invasive mechanism of endometriosis. The altered expression of Ln-5, by upregulating matrix metalloproteases activity, suggest an invading process similar to that of many cancer processes.

Background & Aims Cancer stem cells (CSCs) are thought to be persistent in tumours due to their chemoresistance and to cause relapse and metastasis. Hepatic carcinomas displaying hepatic progenitor cell (HPC) features have been associated with a poor prognosis, though it remains unclear how CSCs relate to these different histological subtypes. Methods Candidate CSCs were isolated using the side population (SP) technique from primary tissue samples diagnosed as keratin(K)19-negative or -positive hepatocellular carcinoma (HCC) or as combined hepatocellular/cholangiocarcinoma and analysed for gene and protein expression. The effect of laminin-332 was analysed in vitro by using HCC cell lines and in vivo using a xenograft mouse model. Results The size of the SP correlated with the degree of HPC features found in human hepatic cancer, and also showed an elevated mRNA expression of biliary/HPC markers and the extracellular matrix marker LAMC2 , the gene encoding the laminin γ2-chain. Immunopositivity for the γ2-chain of laminin-332 was seen in the extracellular matrix surrounding small HPC-like tumour cells with a low proliferation rate. In vitro , laminin-332 increased K19 expression, phosphorylated mTOR and decreased phospho-histone H3 expression, indicating reduced cell mitosis. The effect of laminin-332 was enhanced upon mTORC1 inhibition and diminished when inhibiting mTORC1+C2. Resistance to doxorubicin and sorafenib treatment, and the SP fraction increased in the coated condition. In vivo , laminin-332 reduced tumour growth and sustained K19 expression. Conclusions In this study we identified a prominent role for laminin-332 as part of the specialised CSC niche in maintaining and supporting cell ‘stemness', which leads to chemoresistance and quiescence.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, burdened by a constantly increasing frequency. Therapy is currently restricted to invasive techniques but prognosis and survival are still unsatisfactory, mainly because of HCC recurrence and metastasis diffusion. This review will focus on the problem of tumor recurrence and/or metastasis, pointing out the role of the tissue microenvironment in affecting HCC behavior; new experimental findings will also be discussed in the light of their implications in medical care. Finally, new therapeutic approaches will be considered, paying particular attention to the tissue microenvironment as a potential target. In conclusion, this review will attempt to stimulate debate on translational research into HCC biology, in the field of clinical applications.

Background Matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metalloproteinases (TIMP), are involved in tissue inflammation and fibrotic processes. Treatment with bosentan has been shown to improve the clinical outcome of patients with pulmonary arterial hypertension (PAH) with and without association with systemic sclerosis (SSc), and also to modulate the serum levels of matrix metalloproteases-9. We measured TIMP-1 and TIMP-2 in the serum of patients with SSc with and without PAH treated with long-term bosentan compared with healthy donors (HD). Materials and methods Serum samples from HD (n = 16) and patients with SSc (n = 35), including patients with SSc without PAH (n = 23) and patients with PAH (n = 12), were analyzed using enzyme-linked immunosorbent assays (ELISAs) for total TIMP-1 andTIMP-2. Results Both mean TIMP-1 andTIMP-2 levels were significantly increased in patients with SSc compared with HD, but no differences were observed between patients with SSc with and without PAH. In the eight bosentan-treated patients, TIMP-1 and TIMP-2 levels did not change during 1 year of treatment, while bosentan increased the 6-min walking distance by 136 meters after 1 year, as well as clinical outcomes. Conclusions Increased levels of TIMP-1 and TIMP-2 in patients with SSc compared with HD suggest that the inhibition of proteolysis allows the accumulation of ECM proteins. As bosentan does not stimulate TIMPs, it appears to favour proteolytic imbalance and to increase the turnover of ECM proteins.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is alpha-fetoprotein (alpha-FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of alpha-FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of alpha-FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC.

The occurrence of metastasis severely affects prognosis and survival of breast cancer patients. In order to metastasize, breast cancer cells need to cross the basement membrane (BM) tissue boundaries. Matrix metalloproteases (MMPs) are enzymes with proteolytic activity towards extracellular matrix components (ECM) of the BM, that are blocked by physiological tissue inhibitors (TIMPs). Cancer metastasis occurs as a result of an imbalance between MMPs, in particular MMP-2 and MMP-9, and TIMPs, in particular TIMP-2 and TIMP-1. This is the first study to report that pro-MMP-9 and TIMP-1 serum concentrations are inversely correlated in breast cancer patients. In the same patients, we determined the pro-MMP-9, the TIMP-1, the pro-MMP-2 and TIMP-2 before and after surgical eradication of the breast cancer. Our results show that after surgery, when the breast cancer tissue was removed, pro-MMP-9 concentrations dramatically decreased and TIMP-1 concentrations strongly increased, with statistically significant differences, so that a new balance was established. No statistically significant differences were observed regarding pro-MMP-2 and TIMP-2. Also, no correlation was found between pro-MMP-2, pro-MMP-9, TIMP-1 and TIMP-2 and a number of clinical and pathological parameters. In conclusion, our study suggests that pro-MMP-9 and TIMP-1 could be used as markers of disease during the follow-up of breast cancer patients and possibly as prognostic markers, although more studies are needed to address this issue.