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During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

Different influences on internal exposure to platinum are investigated and for the first time weighted in environmentally exposed subjects as far as individual internal platinum concentrations are concerned. Detailed medical and environmental histories as well as oral cavity status were assessed in 84 dermatological patients, and internal platinum exposure was determined by analyzing platinum in urine using adsorptive voltammetry ( AV ). Platinum concentrations ranged from < 0.9 ( detection limit ) to 65.5 ng Pt / l urine. Influence of different types and age of alloy restorations and therefore relevance of the exposure pathway due to solubilization of platinum in saliva could be demonstrated. No platinum -related health effects ( contact stomatitis, asthma or kidney conditions ) were observed. Analysis of covariance showed the number of noble dental alloy restorations ( P < 0.0001 ) and to a lesser extent age ( P= 0.0017 ) to independently influence internal platinum exposure. Even though spread of environmental platinum has increased, internal platinum exposure is low in subjects without assessable medical or dental devices ( usually < 4.5 ng / l urine ) and not related to adverse health effects. For the first time, detailed individual information on possible exposure pathways to platinum were considered in an analysis of relevant influential factors: Car traffic exposure and dermatological condition showed no association with internal platinum exposure. Uptake from platinum containing noble metal dental alloy restorations ( NMDAR ) is of greatest relevance, surmounting the influence of each year of lifetime on platinum body load by more than 10 -fold.

We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.

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