Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy.

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of tnfaip2 deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, tnfaip2 deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both in vitro and in vivo and exacerbated by tnfaip2 deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by tnfaip2 deletion, TNT inhibition, and donor cell lysosome damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target.Abbreviations: AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.

Blood pressure and sodium intake from snacks in adolescents.

BACKGROUND/OBJECTIVES: The relationship between sodium intake and arterial blood pressure (BP) values in adolescence is still controversial. The intake of high-sodium processed foods as snacks has gone up worldwide. The purpose of the present cross-sectional study was to analyze the association between BP values and sodium intake from snacks. SUBJECTS/METHODS: The mean weekly consumption of snacks was evaluated in 1200 randomly selected adolescents aged 11-13 years by a food-frequency questionnaire; their anthropometric and BP values were measured by trained researchers. A dietary 24-h food-recall questionnaire was randomly given to 400 of the 1200 adolescents. RESULTS: Mean sodium intake from snacks was 1.4 g/day. Systolic and diastolic BP (SBP and DBP, respectively) significantly increased from the lower to the higher tertile of sodium from snacks and with increasing frequency of salty snacks consumption. In a multiple logistic regression model, both being in the highest SBP quartile and in the highest DBP quartile were significantly associated with the intake of sodium from snacks (odds ratio (OR)=1.48; 95% confidence interval (CI) 1.14-1.91 and OR=2.17; 95% CI 1.68-2.79, respectively), the consumption of >2/day salty snacks (OR=1.86; 95% CI 1.32-2.63 and OR=2.38; 95% CI 1.69-3.37, respectively) and body mass index (OR=1.26; 95% CI 1.22-1.31 and OR=1.14; 95% CI 1.10-1.18, respectively) but not with age, sex or exercise levels. In the 400 individuals, the average total sodium intake was 3.1 g/day and was significantly higher in individuals belonging to the highest quartile of SBP and DBP. CONCLUSIONS: Sodium intake from snacks was almost half of the average daily sodium consumption and was significantly associated with BP values in adolescents.

High-normal blood pressure and impaired renal function. A prospective study in a population-based cohort.

AIM: The association between high-normal blood pressure and the impairment of renal function is highly controversial. We analysed the contribution of high-normal blood pressure on incident impaired renal function. METHODS: The study was performed in a population-based cohort of 1307 subjects free of diabetes, cardiovascular and renal disease at baseline, who attended both at baseline and after 6-year follow-up a metabolic screening. The outcome was incident impaired renal function, defined as a glomerular filtration rate <60 mL/min/1.73 m2. RESULTS: Incidence of impaired renal function was 2.5%, 4.5%, 8.7% and 10.8% in optimal, normal, high-normal blood pressure and hypertension, respectively. Adjusted relative odds ratio (OR) of impaired renal function were modelled using logistic regression analyses including multiple confounders. The adjusted OR were 1.6 (95% CI 0.5-5.0) for normal blood pressure, 3.4 (1.2-10.3) for high-normal blood pressure and 3.7 (1.3-10.7) for hypertension. Results were similar after excluding overweight or obese patients. CONCLUSION: High-normal blood pressure is an independent predictor of impaired renal function. Trials are warranted to test if therapeutic intervention on blood pressure is justified also in subjects with high-normal blood pressure to preserve renal function.

Long-term outcome of hepatitis B virus-related Chronic Hepatitis under protracted nucleos(t)ide analogues.

Long-term outcome of patients with chronic hepatitis B virus (HBV) infection under continuous nucleos(t)ide analogues (NUCs) has been poorly elucidated. We enrolled 121 anti-HBe-positive patients into a prospective surveillance programme while on (>36 months) NUCs therapy. HBV-DNA clearance, add-on therapy and safety were evaluated. Development of cirrhosis, events of liver decompensation and hepatocellular carcinoma (HCC) during the follow-up were the main endpoints, as the complication-free survival. At baseline, 74 patients (61%) had chronic hepatitis, the remainders a cirrhotic liver. HBV-DNA levels >38 000 IU/mL were discovered in 103 patients. At enrolment, 79 patients were naïve to NUCs treatment. Lamivudine monotherapy (n = 70) or a different NUC (n = 51) was administered. At month 6 of therapy, HBV-DNA clearance was documented in 88 patients (73%). Treatment schedule was modified in 52 patients due to breakthrough or suboptimal response. During a mean follow-up of 6 ± 3 years, viral clearance was achieved in the majority of patients. Ten of 74 patients (13.5%) with chronic hepatitis progressed to cirrhosis, 1 patient developed a HCC. In the 47 patients with cirrhosis at presentation, HCC occurred in 14 (30%) and liver decompensation in 5 (11%). The 5 and 10-year event-free survivals were, respectively, 89.3% (95% CI, 81.7 -96.9) and 75.6% (95% CI, 61.5 -89.7) for patients with chronic hepatitis, and 70.2% (95% CI, 56.3 -84.1) and 40.4% (95% CI, 16.9 -63.9) for those with cirrhosis. Protracted, effective treatment with oral NUCs affects the natural history of chronic HBV infection by reducing the incidence of cirrhosis and risk of complications, but does not guarantee against the development of HCC in cirrhosis at presentation.

Variations of serum levels of adiponectin and resistin in chronic viral hepatitis.

BACKGROUND AND AIMS: Several studies investigated the possible role of adipokines during chronic viral hepatitis, not producing defined results neither clearly establishing their behavior in course of anti-viral treatment. Our study evaluated blood concentrations of adiponectin and resistin in patients with chronic hepatitis C (CHC), B (CHB), and D (CHD) receiving anti-viral treatment, at baseline and after therapy. METHODS: We examined 122 subjects, divided into two groups: 64 patients with chronic hepatitis C virus (HCV) infection (38 males and 26 females, mean age 47.25 yr) and 58 patients including 39 ones with chronic hepatitis B virus (HBV) infection (26 males and 13 females, mean age 48.46 yr) and 19 ones with chronic HBV-hepatitis D virus (HDV) infection (15 males and 4 females, mean age 45.79 yr). Serum levels of adiponectin and resistin were assayed by enzyme-linked immunosorbent assay. RESULTS: In the group of CHC patients we observed a significant decrease in resistin after therapy (p=0.006), while not a significant increase in adiponectin after treatment (p=0.32). Evaluation of changes in adiponectin and resistin levels after anti-viral treatment, both in responders and non-responders, revealed no significant variations. In the group of HBV+ and HBV-HDV+ patients, we found a decrease in resistin after therapy (p=0.0016) and a not significant reduction in adiponectin after treatment (p=0.13). Furthermore, we noticed a significant reduction of resistin (p=0.006) in the sub-group of responders. CONCLUSIONS: Our data suggested the possible marker role of adiponectin and resistin in the inflammatory process in course of chronic viral hepatitis.

Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial.

OBJECTIVE: Smokers are characterized by a low-grade systemic inflammatory state and an oxidant-antioxidant imbalance. Few human studies were conducted on the effects of resveratrol, a natural compound with anti-inflammatory and antioxidant properties, and no trial on smokers has been performed to date. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers. METHODS AND RESULTS: A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to "resveratrol-first" (30-days: 500mg resveratrol/day, 30-days wash-out, 30-days placebo) and 25 to "placebo-first" (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol/day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. After analyzing data with general linear models to assess period and carry-over effects, the ratios of the values after resveratrol to those after placebo were respectively: 0.47 (95%CI 0.38-0.59) -CRP- and 0.71 (95%CI 0.65-0.78) -triglycerides-, while TAS increased by 74.2 µmol/L (95%CI 60.8-87.6). Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after resveratrol supplementation. CONCLUSIONS: Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.

Does use of metformin protect against cancer in Type 2 diabetes mellitus?

BACKGROUND: Type 2 diabetes mellitus has been associated with an increased cancer risk, which can be modified by specific hypoglycemic drugs. In particular, metformin, the most frequently prescribed biguanide, is now considered a protective agent against cancer incidence and mortality in Type 2 diabetic patients. AIMS: To review the potential associations between metformin use and cancer incidence and mortality and the possible biological links implicated in these associations. MATERIALS AND METHODS: We searched English-language original investigations published through September 2011. RESULTS: Metformin could block the mitogenic effects of insulin, but this effect does not entirely explain the reduction in cancer incidence. Metformin also plays a direct inhibition of cancer cell growth via the inhibitory effects of AMP-activated protein kinase on the mTOR pathway, which regulates cell growth and proliferation. Accordingly, many epidemiological studies have shown that metformin use is associated with a lower cancer incidence and mortality through a dose-response relationship, with greater exposure being associated with stronger risk reduction. Randomized clinical trials testing the effects of metformin on both recurrence and survival in early-stage breast cancer are on-going; these trials are based on pilot studies demonstrating an adjuvant effect of this drug in breast cancer. CONCLUSIONS: Metformin is an inexpensive and safe drug, that may modify the increased cancer risk of Type 2 diabetic patients. On-going clinical trials will show whether this drug can enhance the effect of chemotherapy in the treatment of cancer.

Is left ventricular hypertrophy a low-level inflammatory state? A population-based cohort study.

BACKGROUND AND AIMS: Cross-sectional studies have shown that chronic sub-clinical inflammation is associated with left ventricular hypertrophy (LVH), but results are conflicting. We investigated the association between baseline LVH and high-sensitivity C-reactive protein (CRP) values, both cross-sectionally and after a six-year-follow-up, in a population-based cohort (n = 1564) and a subgroup from this cohort (n = 515), without obesity, diabetes, metabolic syndrome or any drugs. METHODS AND RESULTS: ECG tracings at baseline were interpreted according to the Cornell voltage-duration product criteria: 166/1564 subjects (10.6%) showed LVH. Patients with baseline LVH showed increased BMI, waist circumference, blood pressure, and a worse metabolic pattern. Their CRP values both at baseline and at follow-up were almost two-fold higher than in patients without LVH. Similar results were found in the healthier sub-sample. In a multiple regression model, CRP at follow-up was directly associated with baseline LVH (expressed as Cornell voltage-duration product) in the whole cohort (ß = 0.0003; 95%CI 0.0002-0.0006; p < 0.001) and in the sub-sample (ß = 0.0003; 0.0002-0.0004; p < 0.001), after adjusting for age, sex, BMI, waist circumference, smoking, exercise levels, blood pressure and baseline CRP values. CONCLUSION: Baseline LVH, which is associated with systemic inflammation, predicts increased CRP values at follow-up, independently of cardiovascular and metabolic risk factors, both in a population-based cohort and a healthier sub-sample. The inflammatory consequences of LVH might be an intriguing subject for further researches.

The rs553668 polymorphism of the ADRA2A gene predicts the worsening of fasting glucose values in a cohort of subjects without diabetes. A population-based study.

AIMS: Single-nucleotide polymorphisms in the human ADRA2A gene have been associated with increased risk of Type 2 diabetes. The associations between the rs553668 polymorphism and fasting glucose concentrations both cross-sectionally and longitudinally after 6-year follow-up were evaluated in an adult Caucasian population-based cohort. METHODS: From a cohort of 1658 individuals, after excluding patients with diabetes, those who died and those whose blood samples were not available for genotyping, data of 1345 individuals were analysed. RESULTS: Subjects homozygous for the A allele showed significantly increased baseline fasting glucose values and a significant worsening of fasting glucose (ß = 0.48; 95% CI 0.10-0.86) and insulin secretion (ß =-20.75; -32.67 to -8.82 for homeostasis model assessment for ß-cell function) at follow-up by using generalized estimating equations. Incidence of impaired fasting glucose and diabetes was almost twofold higher in subjects homozygous for the A allele (respectively: incident impaired fasting glucose 7.6-8.2, 16.1%, incident diabetes 1.7-2.3, 3.2% in GG, AG, AA carriers). CONCLUSIONS: Our results suggested that the rs553668 polymorphism is associated with glucose worsening in subjects without diabetes at baseline.

Contributors to the obesity and hyperglycemia epidemics. A prospective study in a population-based cohort.

OBJECTIVE: Relatively unexplored contributors to the obesity and diabetes epidemics may include sleep restriction, increased house temperature (HT), television watching (TW), consumption of restaurant meals (RMs), use of air conditioning (AC) and use of antidepressant/antipsychotic drugs (ADs). DESIGN AND SUBJECTS: In a population-based cohort (n=1597), we investigated the possible association among these conditions, and obesity or hyperglycemia incidence at 6-year follow-up. Subjects with obesity (n=315) or hyperglycemia (n=618) at baseline were excluded, respectively, 1282 and 979 individuals were therefore analyzed. RESULTS: At follow-up, 103/1282 became obese; these subjects showed significantly higher body mass index, waist circumference, saturated fat intake, RM frequency, TW hours, HT, AC and AD use, and lower fiber intake, metabolic equivalent of activity in h per week (METS) and sleep hours at baseline. In a multiple logistic regression model, METS (odds ratio=0.94; 95% confidence interval (CI) 0.91-0.98), RMs (odds ratio=1.47 per meal per week; 1.21-1.79), being in the third tertile of HT (odds ratio=2.06; 1.02-4.16) and hours of sleep (odds ratio=0.70 per h; 0.57-0.86) were associated with incident obesity. Subjects who developed hyperglycemia (n=174/979; 17.8%) had higher saturated fat intake, RM frequency, TW hours, HT, AC and AD use at baseline and lower METS and fiber intake. In a multiple logistic regression model, fiber intake (odds ratio=0.97 for each g per day; 0.95-0.99), RM (1.49 per meal per week; 1.26-1.75) and being in the third tertile of HT (odds ratio=1.95; 1.17-3.26) were independently associated with incident hyperglycemia. CONCLUSIONS: Lifestyle contributors to the obesity and hyperglycemia epidemics may be regular consumption of RM, sleep restriction and higher HT, suggesting potential adjunctive non-pharmacological preventive strategies for the obesity and hyperglycemia epidemics.

Issues of internal medicine in psychiatric patients.

In opposition to opinions of a sectorialization of psychiatric illness, phenomena of comorbidity due to susceptibility of psychiatric patients to contract other diseases--whose co-presence is difficult to translate and treat--are more and more evident. In this review we have marked main issues of internal medicine in psychiatric patients. This review will discuss particularly main cardiovascular diseases (CAD, VTE), lung diseases (COPD,asthma, restrictive lung disease) gastroenterologic disease (IBS, coeliac disease, ulcerous rectocolitis), diabetes and metabolic syndrome, more likely infections verified in these patients (HIV, viral hepatitis), cancers considerably underlined (breast cancer, colon-rectal cancer and lung cancer), internistic issues in alcohol abuse which is a frequent state in these subjects. A special chapter is dedicated to antipsychotics. These drugs are characterized by a complex action modality and by frequent interactions with a large number of other drugs.

Male sexual disturbances in liver diseases: what do we know?

The alterations of sexual function known as the erectile dysfunction are quite frequent among patients affected by liver diseases and they tend to increase in advanced liver failure. This process is directly linked to cirrhosis or its treatments, such as liver transplantation, or to certain drugs (e.g. beta-blockers). Independent of cirrhosis, other factors may cause sexual problems in these patients. Alcohol itself seems to worsen sexual function in the absence of cirrhosis. Viral hepatitis has an uncertain influence on male gonadic function and even antiviral therapy itself can worsen some seminal and hormonal parameters, although it is reversible. Quality of life may be greatly decreased in cases of cirrhosis where these alterations are present, so it is important to value and care for them, if possible. This review investigates the major male sexual disturbances in liver diseases of various origins.

Characteristics of liver diseases in the elderly: a review.

Chronic liver diseases are becoming more commonly diagnosed in the elderly, although they are not age-related. Most liver functions in advanced age appear to be well preserved, but some changes in liver morphology and physiology with aging may lead to several differences in clinical course and management of liver diseases in older patients compared to younger. A cautious individual evaluation is therefore required in aged patients, especially concerning reduced hepatic drug clearance and comorbidity. Many chronic liver diseases are characterized by a slow and indolent course with non-specific clinical presentation and this may lead a later diagnosis in the elderly. The presence of an advanced liver disease or cirrhosis is more frequent in old patients as the first clinical presentation. No significant differences in diagnostic investigations or treatment options occur between the elderly and the young. Hepatocellular carcinoma is an affliction of the old patients (mean age 65 age) and follow up with ultrasonography and alpha-fetoprotein is mandatory. Advanced age is not considered a contraindication to liver transplantation, but recipients older than 60 years with poor hepatic synthetic function and comorbidity show a worse prognosis with lower survival rates. This review focuses on new emerging conditions, clinical features and updated therapeutic approaches of the most common chronic liver diseases among the elderly.

What predicts the occurrence of the metabolic syndrome in a population-based cohort of adult healthy subjects?

BACKGROUND: Metabolic syndrome (MS), the concurrence of hyperglycaemia, dyslipidaemia, hypertension and visceral obesity, increases cardiovascular risk and mortality. Predictors of MS were previously evaluated in patients without the full syndrome, but with some of its traits. This might confound the resulting associations. METHODS: The relationship between baseline variables and MS development was evaluated in healthy middle-aged subjects without any MS component at baseline, over a 4.5-year follow-up. RESULTS: From a population-based cohort of 1658 subjects, 241 individuals showed no MS components and 201 (83.4%) of them participated in a follow-up screening. At baseline, patients who developed the MS (n = 28/201; 13.9%) showed significantly higher Homeostasis Model Assessment-Insulin Resistance score (HOMA-IR) and C-reactive protein (CRP) values, and lower exercise level than subjects who did not. In a multiple logistic regression analysis, after multiple adjustments, the only baseline variable significantly (p < 0.01) associated with the MS was CRP (OR = 4.05; 95% CI 2.23-7.38; p < 0.001). Results did not change after adjusting for weight gain. The area under the receiver-operating curve was 0.83 for CRP after multiple adjustments. The optimal cut-off point of baseline CRP values was 2.1 mg/L, with 86% (95% CI 81-90) sensitivity and 75% (69-81) specificity in predicting the MS. Baseline CRP resulted associated with after-study glucose values in a multiple regression model (beta = 0.14; 0.08-0.20; p < 0.001). CONCLUSIONS: Higher baseline CRP values confer a significant increased risk of developing the MS in healthy subjects, independently of weight gain.

Plasma visfatin concentrations after a lifestyle intervention were directly associated with inflammatory markers.

BACKGROUND AND AIMS: The biological activity and regulation of the novel adipokine visfatin are still largely unknown. Our aim was to evaluate if visfatin plasma concentrations may be influenced by a lifestyle intervention. METHODS AND RESULTS: Out of 335 dysmetabolic patients from a population-based cohort, randomized to receive a lifestyle intervention program (intervention group) or family physician usual care (controls), 20 patients per group were randomly selected for plasma visfatin determination. The before-after variation (Delta) in visfatin concentration at 1-year from randomization, and the correlations between (Delta)visfatin and intervention-induced changes in waist circumference, fasting glucose, markers of inflammation, and oxidative stress were evaluated. The intervention group showed a significant improvement in waist circumference, and many metabolic/inflammatory variables, while the controls worsened. Visfatin concentrations slightly decreased in the former and significantly increased in the controls ((Delta)visfatin=-2.4 vs 66.0 ng/ml, p<0.001). In robust regression models, the following variables resulted associated with (Delta)visfatin: (Delta)waist circumference, (Delta)fasting glucose, (Delta)hs-CRP (high-sensitivity C-reactive protein) and (Delta)TNFalpha (tumor necrosis factor-alpha). Significant effects on (Delta)visfatin of (Delta)TNFalpha (beta=16.8; 6.1-25.6; p=0.003) and, modified by group, of (Delta)hs-CRP (beta=29.8; 95% CI 15.4-44.2; p<0.001 and beta=4.2; 2.9-5.5; p<0.001 in the control and intervention group, respectively) were detected. By controlling for (Delta)waist, the effects of (Delta)TNFalpha and of (Delta)hs-CRP on (Delta)visfatin by group did not change, while (Delta)waist was no longer associated. The association between (Delta)visfatin and (Delta)glucose was no longer significant, after adjusting for (Delta)hs-CRP. CONCLUSION: Visfatin values increased with waist circumference and were associated with variations of inflammatory markers, suggesting participation in inflammatory mechanisms.

Associations between serum uric acid and adipokines, markers of inflammation, and endothelial dysfunction.

AIM: Serum uric acid is associated with the metabolic syndrome and its components, while its relationship with cardiovascular disease is controversial. The aim of the study was to evaluate the association between uric acid and adipokines, markers of inflammation, oxidative stress, and endothelial dysfunction, which are all linked to cardiovascular disease. METHODS: The associations between uric acid and adiponectin, resistin, leptin, high-sensitivity-C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-alpha, nitrotyrosine, Total Antioxidant Status (TAS), E-selectin, vascular adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were cross-sectionally evaluated in a randomly collected sample of 100 men from a population-based cohort. RESULTS: Subjects within the highest uric acid quartile showed a worse metabolic pattern and a higher prevalence of the metabolic syndrome [odds ratio (OR)=3.6; 95% confidence interval (CI) 1.6-8.2; p<0.001 for each 50 micromol/l uric acid increment in a logistic regression model after multiple adjustments]. Nitrotyrosine and adiponectin were significantly lower, while TAS, hs-CRP, E-selectin, ICAM-1, and VCAM-1 were higher in the groups with increased uric acid levels. In a multiple regression model, after adjustments for multiple confounders, uric acid levels were inversely associated with nitrotyrosine (p<0.001) and adiponectin (p=0.02), and directly with TAS (p<0.001), and E-selectin (p=0.006). CONCLUSION: Serum uric acid showed opposite relationships, being associated with both beneficial (inverse association with nitrotyrosine, direct association with TAS) and detrimental (inverse association with adiponectin, direct association with E-selectin) markers, thus providing a possible explanation for the previously reported controversial and not linear association between uric acid and cardiovascular disease.

Gastrointestinal problems in the elderly.

Gastrointestinal (GI) disorders represent the third cause of consultations by general practitioners among subjects older than 65 years in Western countries. Although GI diseases in the elderly do not show peculiar characteristics, they often may present a more severe course, due to comorbidities and intake of many drugs. Moreover, several illnesses, such as neoplasias, are more frequent in the elderly. This review focuses on the epidemiological, physiopathological, and clinical aspects of GI diseases in advanced age. Some relevant issues are considered. It is advisable to avoid empirical approaches in the elderly and to choose endoscopic examinations because of the possibility to detect conditions such as already complicated gastroesophageal reflux disease or peptic ulcers as well as to diagnose precociously neoplastic formations in esophagus, stomach or colon. The monitoring of chronic liver disease is very important, mainly to prevent or detect hepatocellular carcinoma early. Idiopathic (or autoimmune) chronic pancreatitis in the elderly is more frequent than other forms of pancreatic diseases, like alcoholic pancreatitis.

Diagnostic and therapeutic questions in overlap syndromes of autoimmune hepatitis.

The term ''overlap syndromes of liver diseases'' includes coexistence of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC). Due to their unknown etiology, as well as their variable presentation with mixed clinical and biochemical features, these overlap syndromes are often a diagnostic and therapeutic challenge for hepatologists. The most frequent association reported occurs between AIH and PBC. More rare is the overlap between AIH and PSC, typical in young age and often concomitant with an inflammatory bowel disease as ulcerative colitis. The treatment of choice is based on ursodeoxycholic acid and immunosoppressive drugs, used at the same time or consecutively, according to the course of disease. Histological examination seems an important tool, but often does not help for a correct diagnosis due to lack of specificity. Two particular forms of variant syndrome are the so called outlier syndromes, without clear characteristics of overlap: the autoimmune cholangitis, probably a form of PBC anti-mitochondrial antibodies negative, and the hepatitis C virus related with stigmata of autoimmunity, such as nonspecific autoantibodies at low titer. The diagnostic score system elaborated in 1999 by the International AIH Group can help for diagnosis, even if its definite validity is lacking.