Donor BMI >30 Is Not a Contraindication for Live Liver Donation.

The increased prevalence of obesity worldwide threatens the pool of living liver donors. Although the negative effects of graft steatosis on liver donation and transplantation are well known, the impact of obesity in the absence of hepatic steatosis on outcome of living donor liver transplantation (LDLT) is unknown. Consequently, we compared the outcome of LDLT using donors with BMI <30 versus donors with BMI ≥30. Between April 2000 and May 2014, 105 patients received a right-lobe liver graft from donors with BMI ≥30, whereas 364 recipients were transplanted with grafts from donors with BMI <30. Liver steatosis >10% was excluded in all donors with BMI >30 by imaging and liver biopsies. None of the donors had any other comorbidity. Donors with BMI <30 versus ≥30 had similar postoperative complication rates (Dindo-Clavien ≥3b: 2% vs. 3%; p = 0.71) and lengths of hospital stay (6 vs. 6 days; p = 0.13). Recipient graft function, assessed by posttransplant peak serum bilirubin and international normalized ratio was identical. Furthermore, no difference was observed in recipient complication rates (Dindo-Clavien ≥3b: 25% vs. 20%; p = 0.3) or lengths of hospital stay between groups. We concluded that donors with BMI ≥30, in the absence of graft steatosis, are not contraindicated for LDLT.

Chemical genetic approaches for the elucidation of signaling pathways.

New chemical methods that use small molecules to perturb cellular function in ways analogous to genetics have recently been developed. These approaches include both synthetic methods for discovering small molecules capable of acting like genetic mutations, and techniques that combine the advantages of genetics and chemistry to optimize the potency and specificity of small-molecule inhibitors. Both approaches have been used to study protein function in vivo and have provided insights into complex signaling cascades.

Risk factors in patients with rapid recurrent hepatitis C virus-related cirrhosis within 1 year after liver transplantation.

BACKGROUND: Recurrent cirrhosis (RC) due to pretransplant underlying disease leads to organ failure and subsequent death after orthotopic liver transplantation (OLT). RC occurs in up to 30% of patients with recurrent hepatitis C (HCV) within 5 years after OLT. We sought to identify early risk factors for rapid RC within the first year after OLT in HCV-positive patients. METHODS: Among 404 liver transplanted patients at the University of Mainz between 1998 and 2008, 90 were HCV-RNA positive. To identify predictive factors for rapid RC, we compared HCV-positive patients with advanced fibrosis stages within 1 year after OLT (n = 13) with these without RC at 5 years after OLT (n = 23). RESULTS: Overall, poorer patient survival was associated with advanced fibrosis scores in the 1-year protocol biopsy and nonresponse to interferon treatment before OLT. The strongest predictive factors for rapid RC were persistently high levels of alkaline phosphatase, bilirubin, viral load at 6 months after OLT, and multiple steroid pulse therapies. The CCR2-V64I polymorphism was not associated with rapid RC. CONCLUSION: We presented a group of patients with HCV-related rapid RC within the first year after OLT to identify predictive factors for rapid fibrosis progression.

Flow and pressure during liver preservation under ex situ and in situ perfusion with University of Wisconsin solution and histidine-tryptophan-ketoglutarate solution.

Effective preservation of liver grafts is the first essential step for successful liver transplantation. Insufficient perfusion leads to ischemic-type biliary lesions after transplantation. Perfusion of the graft can be performed either in situ or ex situ, with gravity flow or pressure-controlled. Mainly University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are used widespread in clinical liver transplantation. Due to a persistent lack of data, we performed this systematic investigation of in situ and ex situ perfusion of liver grafts with HTK (low-viscous) and UW (high-viscous) solutions at different pressure steps on the perfusion solution (gravity flow, 50, 100, 150, and 200 mm Hg). End points were perfusion flow and pressure in the hepatic artery. A pig model was used with n = 8 pigs randomized to each (HTK and UW) group. In situ perfusion was ineffective for both solutions at any pressure on the perfusate bag. Ex situ perfusion showed significantly improved flow and pressure in the hepatic artery and, therefore, was highly effective. No major differences between HTK and UW solutions could be detected. Therefore, an additional ex situ perfusion of the hepatic artery should be mandatory in every liver procurement.

Modulating pyridoxamine-mediated transamination through a betabeta alpha motif peptide scaffold.

A pyridoxamine coenzyme amino acid chimera (Pam) was incorporated into a designed betabeta alpha motif peptide to explore the ability of a small synthetic peptide scaffold to influence coenzyme mediated transamination. Structural characterization of this peptide by CD and NMR spectroscopy suggested that the pyridoxamine containing residue was accommodated into the sheet region of the motif without gross structural perturbations. To investigate the ability of the peptide architecture to influence the amount and distribution of transamination product in the conversion of pyruvic acid to alanine, a family of 18 related peptides, CBP01-CBP18, was rapidly synthesized and purified in parallel. These peptides were designed to generate different peptide environments for the pyridoxamine functionality within the context of the structured betabeta alpha peptide motif. Studies of peptide-mediated transamination revealed clear trends in stereospecific production of L-alanine as a function of substitutions at positions five and seven of the motif. Furthermore, new trends favoring the other enantiomeric product resulted from the addition of copper(II) ion, a known chelator of the transamination reaction intermediates. In the presence of copper(II) ion the amount of alanine product generated was increased by up to 32-fold relative to a pyridoxamine model compound in the presence of copper(II) ion. These functional results, accompanied by further CD and NMR spectroscopic analysis of CBP14, one of the CBP family of peptides, suggest that small synthetic betabeta alpha motif peptides can be used to influence the functional properties of coenzymes.

Low-dose cyclosporine therapy combined with standard immunosuppression in pediatric renal transplantation.

A new immunosuppressive regimen combining anti-lymphocyte globulin, azathioprine, prednisone, and low doses of cyclosporine was used in 28 children aged 9 months to 17 years (mean 5.8 years) who received primary renal allografts between July 1, 1984, and September 25, 1986. After a mean follow-up of 17.3 months, the patient and graft survival is 100% (18 of 18) for mismatched related kidneys, and 90% (nine of 10) for cadaver kidneys. The single graft failure was the result of a death from technical complications. Serum creatinine concentration after transplantation ranged from 0.3 to 1.7 mg/dL (mean 0.85 mg/dL). The probability of a rejection episode in the first year was 45% and 60% for mismatched-related and cadaver kidneys, respectively. Cyclosporine nephrotoxicity was recognized in only one (3.7%) of 27 children, and was rapidly reversed after cyclosporine was discontinued. An initial group of nine children was weaned from cyclosporine therapy 6 to 12 months after transplantation, but two (22%) had rejection episodes. Our preliminary experience suggests that the use of a quadruple immunosuppressive regimen for both living related and cadaver renal transplants in children is associated with an improved graft function rate and a low incidence of complications.

Recent advances in chemical approaches to the study of biological systems.

A number of novel chemical methods for studying biological systems have recently been developed that provide a means of addressing biological questions not easily studied with other techniques. In this review, examples that highlight the development and use of such chemical approaches are discussed. Specifically, strategies for modulating protein activity or protein-protein interactions using small molecules are presented. In addition, methods for generating and utilizing novel biomolecules (proteins, oligonucleotides, oligosaccharides, and second messengers) are examined.