Osteoporosis in rheumatoid arthritis: role of the vitamin D/parathyroid hormone system

AbstractOsteoporosis is a well-established extra-articular feature of rheumatoid arthritis (RA). Systemic inflammation seems to play a crucial role in causing an alteration of multiple homeostatic systems implied in bone health, such as the RANK/RANKL/Osteoprotegerin and Wnt/β catenin pathways; several other causal factors have been called into question, including the chronic use of corticosteroids. Since vitamin D exerts important immune-regulatory roles, it has been claimed that derangement of the vitamin D/parathyroid hormone (PTH) system, a well-known determinant of bone health, may play a pathogenic role in autoimmunity; animal models and clinical data support this hypothesis. Furthermore, RA patients seem to be relatively refractory to vitamin D-induced PTH suppression. Therefore, the link between RA and osteoporosis might in part be due to alterations in the vitamin D/PTH system. A better understanding of the pathophysiology of this system may be crucial to prevent and cure osteoporosis in patients with inflammatory/autoimmune diseases. A major clinical correlate of the strict cooperation and interdependence between vitamin D and PTH is that correction of the vitamin D deficiency, at least in autoimmune diseases, should be targeted to PTH suppression

Synthesis and D₂-like binding affinity of new derivatives of N3-[(1- ethyltetrahydro-1H-2-pyrrolyl)methyl]-4,5-dihydrobenzo[g]indole-3- carboxamide and related compounds

In previous papers 4a,b we have reported the syntheses and structure-activity relationships of a series of 5-phenyl-3-pyrrole carboxamide and related 4,5-dihydrobenzo[g]indole-3-carboxamide analogues whose most representative terms were 1a and 2a respectively. Encouraged by these results we carried out several modifications of 2a

Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review

Repair of sustained liver injury results in fibrosis (i.e. the accumulation of extracellular matrix proteins), and ultimately the complete distortion of parenchymal architecture of the liver, which we call cirrhosis. Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases, since many clinically relevant decisions, such as starting treatment and/or monitoring for complications including hepatocellular carcinoma, may depend on it. The gold standard for fibrosis staging is liver biopsy, the role of which, however, is questioned nowadays because of cost, hazards and poor acceptance by patients. On the other hand, imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy. Making progress in this field is now more crucial than ever, since treatments for established fibrosis appear on the horizon. Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis, such as growth arrest-specific6, Mac-2-binding protein, osteopontin, placental growth factor, growth/differentiation factor 15 and hepatocyte growth factor. All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases. Here, we review the pros and cons for their use in this setting

17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle

Rationale & Aim: Estrogen and estrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of HCV life cycle is/are affected by estrogens. Methods: Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate IC50 values. To dissect how 17β-estradiol interferes with phases of HCV life cycle, its effects were measured on the HCV pseudo-particle system (viral entry), the sub-genomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. Results: Progesterone and testosterone showed no inhibitory effect on HCV; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β-estradiol inhibited infection by 64-67% (IC50 values 140 to 160 nM). Fulvestrant reverted the inhibition by 17β-estradiol in a dose-dependent manner. 17β-estradiol exerted only a slight inhibition (<20%) on HCV pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant IC50 decline occurred between primary (134 nM) and secondary (100 nM) infections (p=0.02), with extracellular HCV RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. Conclusions: 17β-estradiol inhibits HCV acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the HCV life cycle

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

Background The joint effect of the interaction of alcohol intake, hepatitis B virus (HBV) and hepatitis C virus (HCV) on the risk of cirrhosis is still unexplored because a large sample size is required for this investigation. Objective Evaluation of interaction of HBV, HCV and alcohol abuse on the risk of cirrhosis. Design We analysed 12,262 consecutive patients with chronic liver disease of various aetiologies referring to 95 Italian liver units in 2001 or 2014. To evaluate the interaction between alcohol abuse, HBV infection, and HCV infection, patients unexposed to either factors were used as reference category. Adjustment for BMI and age was done by multiple logistic regression analysis. Results Females were older than males (p<0.01) and less frequently showed HBV and alcoholic aetiology (p<0.01). In both sexes, an overtime increasing age and an increasing proportion of subjects with liver cirrhosis was observed, reflecting a better survival (0.01).An additive interaction is observed in females: the O.R. generated by the simultaneous presence of HBV, HCV, and alcohol (5.09; 95% C.I. 1.06–24.56) exceeds the sum (4.14) of the O.R. generated by a single exposure (O.R. = 0.72 for HBsAg positivity, OR = 1.34 for antiHCV positivity, and O.R. = 2.08 for alcohol intake). No interaction is observed in male sex. Conclusions The observed gender difference suggests that the simultaneous presence of HBV/HCV coinfection and risky alcohol intake enhances the mechanism of liver damage to a greater extent in females than in males

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

Background The joint effect of the interaction of alcohol intake, hepatitis B virus (HBV) and hepatitis C virus (HCV) on the risk of cirrhosis is still unexplored because a large sample size is required for this investigation. Objective Evaluation of interaction of HBV, HCV and alcohol abuse on the risk of cirrhosis. Design We analysed 12,262 consecutive patients with chronic liver disease of various aetiologies referring to 95 Italian liver units in 2001 or 2014. To evaluate the interaction between alcohol abuse, HBV infection, and HCV infection, patients unexposed to either factors were used as reference category. Adjustment for BMI and age was done by multiple logistic regression analysis. Results Females were older than males (p<0.01) and less frequently showed HBV and alcoholic aetiology (p<0.01). In both sexes, an overtime increasing age and an increasing proportion of subjects with liver cirrhosis was observed, reflecting a better survival (0.01).An additive interaction is observed in females: the O.R. generated by the simultaneous presence of HBV, HCV, and alcohol (5.09; 95% C.I. 1.06–24.56) exceeds the sum (4.14) of the O.R. generated by a single exposure (O.R. = 0.72 for HBsAg positivity, OR = 1.34 for antiHCV positivity, and O.R. = 2.08 for alcohol intake). No interaction is observed in male sex. Conclusions The observed gender difference suggests that the simultaneous presence of HBV/HCV coinfection and risky alcohol intake enhances the mechanism of liver damage to a greater extent in females than in males

Acute decompensated heart failure in the emergency department: Identification of early predictors of outcome

Identification of clinical factors that can predict mortality and hospital early readmission in acute decompensated heart failure (ADHF) patients can help emergency department (ED) physician optimize the care-path and resource utilization.We conducted a retrospective observational study of 530 ADHF patients evaluated in the ED of an Italian academic hospital in 2013.Median age was 82 years, females were 55%; 31.1% of patients were discharged directly from the ED (12.5% after short staying in the observation unit), while 68.9% were admitted to a hospital ward (58.3% directly from the ED and 10.6% after a short observation). At 30 days, readmission rate was 17.7% while crude mortality rate was 9.4%; this latter was higher in patients admitted to a hospital ward in comparison to those who were discharged directly from the ED (12.6% vs. 2.4%, P\u200a 104\u200amm Hg, POS\u200a>\u200a94%, may guide the ED physician to identify low-risk patients who can be safely discharged directly from the emergency room or after observation unit stay

Pancreatobiliary Reflux Resulting in Pancreatic Ascites and Choleperitoneum after Gallbladder Perforation

A 65-year-old man with chronic hepatitis C and no history of alcohol abuse was admitted to our liver unit for the recent development of massive ascites and presumed hepatorenal syndrome. In the preceding two weeks, he had received medical treatment for acute pancreatitis and cholecystitis. Abdominal paracentesis demonstrated a cloudy, orange peritoneal fluid, with total protein concentration 3.6 g/dl, serum-ascites albumin gradient 1.0 g/dl, and ratios of ascites-serum bilirubin and amylase approximately 8:1. Diagnostic imaging demonstrated no pancreatic pseudocysts. Ten days later, at laparotomy, acalculous perforation of the gallbladder was identified. After cholecystectomy, amylase concentration in the ascitic fluid dropped within a few days to 40% of serum values; ascites disappeared within a few weeks. We conclude that in the presence of a perforated gallbladder, pancreatobiliary reflux was responsible for this unusual combination of choleperitoneum and pancreatic ascites, which we propose to call pancreatobiliary ascites

Prognostic sub-classification of intermediate-stage hepatocellular carcinoma: a multicenter cohort study with propensity score analysis

There is significant heterogeneity in the clini- copathological characteristics of intermediate hepatocellu- lar carcinoma (IHCC). This also translates to treatment as transarterial chemoembolization (TACE) is used as first- line therapy for patients with IHCC; however, in Asia liver resection (LR) is preferred. Prognostic tools are required to help guide clinicians in deciding treatment options. This study evaluates the prognostic impact of the Intermediate Stage Score (ISS) on overall survival (OS) in a large, multicenter cohort study of patients with IHCC treated with TACE or surgery LR. Consecutive patients from centers in Japan, Korea, Italy and the United Kingdom who under- went TACE or LR between 2001 and 2015 were enrolled. Propensity score (PS) adjustment was used to remove residual confounding and applied to LR (n=162) and TACE ( n = 449) to determine the prognostic significance of ISS. Among 611 patients, 75 % were men and 25 % women, with a mean age of 70 years. ISS is a valid prognostic tool in the BCLC-B population with a median OS ISS 1–51, 2–38.3, 3–24.3, 4–15.6, 5–16 months ( p \ 0.0001). ISS was analyzed within each treatment modality, and this was a valid prognostic score among those treated with TACE and LR ( p \ 0.001 vs. p = 0.008). In the PS-adjusted model, ISS retained its prognostic utility in TACE and LR groups (p\0.001 vs.p=0.007). ISS optimizes prognostic prediction in IHCC, reducing clinical heterogeneity, and is a useful tool for patients treated for TACE or LR

From MASH to HCC: the role of Gas6/TAM receptors

Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors