Secondary bile acids and the biliary epithelia: The good and the bad

The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.

Moving forward in the treatment of cholangiocarcinoma

Despite being the second most frequent primary liver tumor in humans,early diagnosis and treatment of cholangiocarcinoma(CCA)are still unsatisfactory.In fact,survival after 5 years is expected in less than one fourth of patients diagnosed with this disease.Rare incidence,late appearance of symptoms and heterogeneous biology are all factors contributing to our limited knowledge of this cancer and determining its poor prognosis in the clinical setting.Several efforts have been made in the last decades in order to achieve an improved classification/understanding with regard to the diverse CCA forms.Location within the biliary tree has helped to distinguish between intrahepatic,perihilar and distal CCA types.Sequence analysis contributed to identifying several characteristic genetic aberrations in CCA that may also serve as possible targets for therapy.Novel findings are expected to significantly improve the management of this malignancy in the near future.In this changing scenario our review focuses on the current and future strategies for CCA treatment.Both systemic and surgical treatments are discussed in detail.The results of the main studies in this field are reported,together with the ongoing trials.The current findings suggest that an integrated multidisciplinary approach to this malignancy would be helpful to improve its outcome.

Inverse full state hybrid projective synchronization for chaotic maps with different dimensions

A new synchronization scheme for chaotic(hyperchaotic) maps with different dimensions is presented.Specifically,given a drive system map with dimension n and a response system with dimension m,the proposed approach enables each drive system state to be synchronized with a linear response combination of the response system states.The method,based on the Lyapunov stability theory and the pole placement technique,presents some useful features:(i) it enables synchronization to be achieved for both cases of n < m and n > m;(ii) it is rigorous,being based on theorems;(iii) it can be readily applied to any chaotic(hyperchaotic) maps defined to date.Finally,the capability of the approach is illustrated by synchronization examples between the two-dimensional H′enon map(as the drive system) and the three-dimensional hyperchaotic Wang map(as the response system),and the three-dimensional H′enon-like map(as the drive system) and the two-dimensional Lorenz discrete-time system(as the response system).

Chronic rejection after liver transplantation:Opening the Pandora’s box

Chronic rejection(CR)of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation.Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy,CR still represents an important cause of graft injury,which might be irreversible,leading to graft loss requiring re-transplantation.To date,we still do not fully appreciate the mechanisms underlying this process.In addition to T cell-mediated CR,which was initially the only recognized type of CR,recently a new form of liver allograft CR,antibody-mediated CR,has been identified.This has indeed opened an era of thriving research and renewed interest in the field.Liver biopsy is needed for a definitive diagnosis of CR,but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation.Moreover,the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury,which should not be disregarded.Therapies for CR may only be effective in the“early”phases,and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage.Herein,we provide an overview of the current knowledge and research on CR,focusing on early detection,identification of non-invasive biomarkers,immunosuppressive management,re-transplantation and future perspectives of CR.

Continuous-time chaotic systems: Arbitrary full-state hybrid projective synchronization via a scalar signal

Referring to continuous-time chaotic systems, this paper presents a new projective synchronization scheme, which enables each drive system state to be synchronized with a linear combination of response system states for any arbitrary scaling matrix. The proposed method, based on a structural condition related to the uncontrollable eigenvalues of the error system, can be applied to a wide class of continuous-time chaotic (hyperchaotic) systems and represents a general framework that includes any type of synchronization defined to date. An example involving a hyperchaotic oscillator is reported, with the aim of showing how a response system attractor is arbitrarily shaped using a scalar synchronizing signal only. Finally, it is shown that the recently introduced dislocated synchronization can be readily achieved using the conceived scheme.

Novel four-wing and eight-wing attractors using coupled chaotic Lorenz systems

This paper presents the problem of generating four-wing (eight-wing) chaotic attractors.The adopted method consists in suitably coupling two (three) identical Lorenz systems.In analogy with the original Lorenz system,where the two wings of the butterfly attractor are located around the two equilibria with the unstable pair of complex-conjugate eigenvalues,this paper shows that the four wings (eight wings) of these novel attractors are located around the four (eight) equilibria with two (three) pairs of unstable complex-conjugate eigenvalues.

COVID-19 in normal,diseased and transplanted liver

Starting from December 2019 the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has extended in the entire world giving origin to a pandemic.Although the respiratory system is the main apparatus involved by the infection,several other organs may suffer coronavirus disease 2019(COVID-19)-related injuries.The human tissues expressing angiotensin-converting enzyme 2(ACE2)are all possible targets of viral damage.In fact myocarditis,meningo-encephalitis,acute kidney injury and other complications have been described with regard to SARS-CoV-2 infection.The liver has a central role in the body homeostasis contributing to detoxification,catabolism and also synthesis of important factor such as plasma proteins.ACE2 is significantly expressed just by cholangiocytes within the liver,however transaminases are increased in more than one third of COVID-19 patients,at hospital admission.The reasons for liver impairment in the course of this infection are not completely clear at present and multiple factors such as:Direct viral effect,release of cytokines,ischemic damage,use of hepatotoxic drugs,sepsis,and others,may contribute to damage.While COVID-19 seems to elicit just a transient alteration of liver function tests in subjects with normal hepatic function,of concern,more severe sequelae are frequently observed in patients with a reduced hepatic reserve.In this review we report data regarding SARS-CoV-2 infection in subjects with normal or diseased liver.In addition the risks of COVID-19 in immunosuppressed patients(either transplanted or suffering for autoimmune liver diseases)are also described.

Fractional-order systems without equilibria:The first example of hyperchaos and its application to synchronization

A challenging topic in nonlinear dynamics concerns the study of fractional-order systems without equilibrium points.In particular, no paper has been published to date regarding the presence of hyperchaos in these systems. This paper aims to bridge the gap by introducing a new example of fractional-order hyperchaotic system without equilibrium points. The conducted analysis shows that hyperchaos exists in the proposed system when its order is as low as 3.84. Moreover, an interesting application of hyperchaotic synchronization to the considered fractional-order system is provided.

Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger?

Hepatitis B virus(HBV) recurrence after liver transplantation(LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider,for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immunecompetent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a "mere nuisance".However, with regard to HBV and LT, outstanding issues are still on the table:(1)A standard HBV prophylaxis protocol after transplant has not yet been clearly defined;(2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs;and(3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.

Gastrointestinal endoscopy in cirrhotic patient:Issues on the table

Patients with liver cirrhosis are fragile and present specific clinical hallmarks.When undergoing to gastrointestinal(GI)endoscopy,these subjects require an individual pre evaluation,taking into account:Level of haemostasis impairment,the individual risk of infection,the impact of sedation on hepatic encephalopathy and other factors.The overall assessment of liver function,employing common scoring systems,should be also assessed in the preprocedural phase.Beside some common general problems,regarding GI endoscopy in cirrhotic subjects,also specific issues are present for some frequent indications or procedures.For instance,despite an increased incidence of adenomas in cirrhosis,colon cancer screening remains suboptimal in subjects with this disease.Several studies in fact demonstrated liver cirrhosis as a negative factor for an adequate colon cleansing before colonoscopy.On the other hand,also the routine assessment of gastroesophageal varices during upper GI endoscopy presents some concern,since important inter-observer variability or incomplete description of endoscopic findings has been reported in some studies.In this review we discussed in details the most relevant issues that may be considered while performing general GI endoscopic practice,in patient with cirrhosis.For most of these issues there are no guidelines or clear indications.Moreover until now,few studies focused on these aspects.We believe that targeting these issues with corrective measures may be helpful to develop a tailored endoscopic approach for cirrhosis,in the future.

Arbitrary full-state hybrid projective synchronization for chaotic discrete-time systems via a scalar signal

In this paper we present a new projective synchronization scheme,where two chaotic(hyperchaotic) discretetime systems synchronize for any arbitrary scaling matrix.Specifically,each drive system state synchronizes with a linear combination of response system states.The proposed observer-based approach presents some useful features:i) it enables exact synchronization to be achieved in finite time(i.e.,dead-beat synchronization);ii) it exploits a scalar synchronizing signal;iii) it can be applied to a wide class of discrete-time chaotic(hyperchaotic) systems;iv) it includes,as a particular case,most of the synchronization types defined so far.An example is reported,which shows in detail that exact synchronization is effectively achieved in finite time,using a scalar synchronizing signal only,for any arbitrary scaling matrix.

Natremia and liver transplantation:The right amount of salt for a good recipe

An adequate balance between electrolytes and clear water is of paramount importance to maintaining physiologic homeostasis.Natremia imbalance and,in particular,hyponatremia is the most frequent electrolyte abnormality observed in hospitalized subjects,involving approximately one-fourth of them.Pathological changes occurring during liver cirrhosis predispose patients to an increased risk of sodium imbalance,and hypervolemic hyponatremia has been reported in nearly 50%of subjects with severe liver disease and ascites.Splanchnic vasodilatation,portal-systemic collaterals’opening and increased excretion of vasoactive modulators are all factors impairing clear water handling during liver cirrhosis.Of concern,sodium imbalance has been consistently reported to be associated with increased risk of complications and reduced survival in liver disease patients.In the last decades clinical interest in sodium levels has been also extended in the field of liver transplantation.Evidence that[Na+]in blood is an independent risk factor for in-list mortality led to the incorporation of sodium value in prognostic scores employed for transplant priority,such as model for end-stage liver disease-Na and UKELD.On the other hand,severe hyponatremic cirrhotic patients are frequently delisted by transplant centers due to the elevated risk of mortality after grafting.In this review,we describe in detail the relationship between sodium imbalance and liver cirrhosis,focusing on its impact on peritransplant phases.The possible therapeutic approaches,in order to improve transplant outcome,are also discussed.