[Induced pluripotent stem cells. A new resource in modern medicine]. / Induzierte pluripotente Stammzellen. Eine neue Ressource in der modernen Medizin.

Pluripotent stem cells possess a remarkable unlimited self-renewal capacity and offer unparalleled in vitro differentiation potential. This provides a unique model system not only to study early human development but also gives renewed hope in terms of developing cell therapies and regenerative medicine. S. Yamanaka, a medical doctor and researcher, reported the possibility of reprogramming somatic cells to so-called induced pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc. This Nobel Prize winning work has since revolutionized stem cell research and paved the way for countless new avenues within regenerative medicine. This includes disease modeling in a patient-specific context with the ultimate aim of individually tailored pharmaceutical therapy. Additionally, genetic correction studies have rapidly increased in basic science and thus there is hope that these can be effectively and efficiently translated into clinical applications. Addressing the medical community this review gives a broad general overview about the state of the research field and possible clinical applications of pluripotent stem cells.

Intraoperative placement of external biliary drains for prevention and treatment of bile leaks after extended liver resection without bilioenteric anastomosis.

BACKGROUND: Improved surgical techniques, substantial preoperative diagnostics, and advanced perioperative management permit extensive and complex liver resection. Thus, hepatic malignancies that would have been considered inoperable some years ago may be curatively resected today. Despite all this progress, biliary leakage remains a clinically relevant issue, especially after extended liver resection. Intraoperative decompression of bile ducts by means of distinct biliary drains is controversial. Although drainage is rarely used as a routine procedure, it might be useful in selected patients at high risk for biliary leakage. METHODS: We describe surgical management of long-segment exposed or injured bile ducts after extended parenchymal resection with concomitant lymphadenectomy. Because blood supply to the bile duct may be impaired, the risk of biliary necrosis and/or leakage is significant. Internal splinting of the bile duct to ensure optimum decompression plus guidance might be helpful. Thus, in selected cases after trisectionectomy we inserted an external-internal or internal-external drain into long-segment exposed bile ducts. For internal-external drains the tube was diverted via the major duodenal papilla into the duodenum and then transfixed after the duodenojejunal flexure through the jejunal wall by means of a Witzel's channel. RESULTS: Because the entire bile duct is splinted, this technique is superior to bile duct decompression with a T-tube. This is supported by the course of a patient suffering biliary leakage after extended right-sided hepatectomy for colorectal metastasis. Initially, a T-tube was inserted for decompression, but biliary leakage persisted. After inserting transhepatic external-internal drainage, bile leakage stopped immediately. The patient's course was then uneventful. Five other patients (mostly with locally advanced hepatocellular or cholangiocellular carcinoma) treated similarly were discharged without complications. Drain removal 6 weeks postoperatively was uncomplicated in five of the 6 patients. In the sixth patient, external-internal drainage was replaced by a Yamakawa-type prosthesis for a biliary stricture. None of the patients suffered severe complications during long-term follow-up. CONCLUSIONS: The bile duct drainage technique presented in this study was useful for preventing and treating bile leakage after long-segment exposure of extrahepatic bile ducts during major hepatectomy. Transhepatic or internal-external drains are often used for bilioenteric anastomoses, but similar drainage techniques have not been reported for the native bile duct. T-tubes are generally used in this situation. In particular cases, however, inner splinting of the bile duct and appropriate movement of the bile via a tube can be helpful.

New insights into U(VI) sorption onto montmorillonite from batch sorption and spectroscopic studies at increased ionic strength.

The influence of ionic strength up to 3 mol kg-1 (background electrolytes NaCl or CaCl2) on U(VI) sorption onto montmorillonite was investigated as function of pHc in absence and presence of CO2. A multi-method approach combined batch sorption experiments with spectroscopic methods (time-resolved laser-induced fluorescence spectroscopy (TRLFS) and in situ attenuated total reflection Fourier-transform infrared spectroscopy (ATR FT-IR)). In the absence of atmospheric carbonate, U(VI) sorption was nearly 99% above pHc 6 in both NaCl and CaCl2 and no significant effect of ionic strength was found. At lower pH, cation exchange was strongly reduced with increasing ionic strength. In the presence of carbonate, U(VI) sorption was reduced above pHc 7.5 in NaCl and pHc 6 in CaCl2 system due to formation of aqueous UO2(CO3)x(2-2x) and Ca2UO2(CO3)3 complexes, respectively, as verified by TRLFS. A significant ionic strength effect was observed due to the formation of Ca2UO2(CO3)3(aq), which strongly decreases U(VI) sorption with increasing ionic strength. The joint analysis of determined sorption data together with literature data (giving a total of 213 experimental data points) allowed to derive a consistent set of surface complexation reactions and constants based on the 2SPNE SC/CE approach, yielding log K°≡SSOUO2+ = 2.42 ± 0.04, log K°≡SSOUO2OH = -4.49 ± 0.7, and log K°≡SSOUO2(OH)32- = -20.5 ± 0.4. Ternary uranyl carbonate surface complexes were not required to describe the data. With this reduced set of surface complexes, an improved robust sorption model was obtained covering a broad variety of geochemical settings over wide ranges of ionic strengths and groundwater compositions, which subsequently was validated by an independent original dataset. This model improves the understanding of U(VI) retention by clay minerals and enables now predictive modeling of U(VI) sorption processes in complex clay rich natural environments.

A comprehensive study of the sorption mechanism and thermodynamics of f-element sorption onto K-feldspar.

The mobility of heavy metal contaminants and radionuclides in the environment is directly controlled by their interactions with charged mineral surfaces, hence an assessment of their potential toxicity, e.g. in the context of radioactive waste disposal sites, requires understanding of sorption processes on the molecular level. Here, we investigate the sorption of a variety of rare earth elements (REE) and trivalent actinides (Am, Cm) on K-feldspar using batch sorption, time-resolved laser-induced fluorescence spectroscopy (TRLFS), and a surface complexation model. Initially, a reliable pKa for K-feldspar's surface deprotonation reaction was determined as 2.5 ± 0.02 by column titration experiments, in excellent agreement with a measured pHIEP of 2.8. Batch sorption experiments over a broad range of experimental conditions in terms of mineral grain size, pH, [M3+], ionic radius, solid/liquid ratio, ionic strength, and equilibration procedures were carried out to quantify macroscopic retention. The trivalent d-block element Y, early, mid, and late lanthanides (La, Eu, Nd, Lu), as well as two minor actinides (Am, Cm) were used for batch sorption experiments and showed similar pH dependent uptake behavior, underlining their chemical analogy. In parallel, spectroscopic investigations provided insight into surface speciation. Cm TRLFS spectra indicate the formation of three inner-sphere sorption complexes with increasing hydrolysis. Additionally, a ternary K-feldspar/Cm/silicate complex was found for pH > 10, and batch and spectroscopic data at low pH (<4) point to small amounts of outer sphere sorption complexes. Based on TRLFS data, batch sorption, and titration data, a generic geochemical sorption model was developed, that describes sorption edges for all investigated M3+/K-feldspar systems satisfactorily. The derived stability constants for the binary sorption complexes (logK1-4 = -3.6, -7.7, -11.5, and -17.4, respectively) could successfully be used to reproduce literature data. The stability constants obtained for the surface complexes were included into the database for the Smart Kd-concept, which will further improve the safety assessment of potential repositories for radioactive waste.

Liver volume measurement: reason of the difference between in vivo CT-volumetry and intraoperative ex vivo determination and how to cope it.

PURPOSE: Volumetric assessment of the liver regularly yields discrepant results between pre- and intraoperatively determined volumes. Nevertheless, the main factor responsible for this discrepancy remains still unclear. The aim of this study was to systematically determine the difference between in vivo CT-volumetry and ex vivo volumetry in a pig animal model. MATERIAL AND METHODS: Eleven pigs were studied. Liver density assessment, CT-volumetry and water displacement volumetry was performed after surgical removal of the complete liver. Known possible errors of volume determination like resection or segmentation borders were eliminated in this model. Regression analysis was performed and differences between CT-volumetry and water displacement determined. RESULTS: Median liver density was 1.07g/ml. Regression analysis showed a high correlation of r(2) = 0.985 between CT-volumetry and water displacement. CT-volumetry was found to be 13% higher than water displacement volumetry (p<0.0001). CONCLUSION: In this study the only relevant factor leading to the difference between in vivo CT-volumetry and ex vivo water displacement volumetry seems to be blood perfusion of the liver. The systematic difference of 13 percent has to be taken in account when dealing with those measures.

Advances in image guided conventional and minimal invasive liver surgery.

Technological developments, advances in perioperative medicine and ongoing scientific research have led to reduced rates of mortality and morbidity in patients undergoing major liver surgery. Under these conditions, the frontier of resectability is constantly in movement towards more complex cases with extended tumor spread and potentially minimized remnant liver volume. A promising technique to support oncological correct and safe liver surgery is the introduction of preoperative computer based planning models and intraoperative navigation systems. Whereas three-dimensional (3D) liver models are commercially available and have been clinically implemented, the use of navigation systems is currently under evaluation by different groups using a variety of techniques. This manuscript is meant to give the reader an overview on current developments, difficulties and future aspects of image guided liver surgery.

The costs of postoperative liver failure and the economic impact of liver function capacity after extended liver resection--a single-center experience.

PURPOSE: Postoperative liver failure (PLF) is a relatively frequent and life-threatening complication after extended liver resection. This study describes the economic burden of PLF from the hospitals' perspective and explores the role of liver function capacity. MATERIALS AND METHODS: Economic data of total costs and cost distribution were analyzed for 48 patients who had participated in a prospective study with the LiMAx test, a novel test for liver function capacity. For this population, detailed individual data were available. The economic data were analyzed and adjusted for relevant covariates. In addition, economic data of 916 patients who had undergone liver resection during 2005-2007 were retrieved from the hospitals' medical controlling office for comparison. RESULTS: A significant difference between the costs of patients with regular recovery (25,980 Euro [95% confidence interval (95%CI) = 9,559 to 42,401]) versus patients developing PLF (82,199 Euro [95%CI = 42,812 to 121,586]; p = 0.013) was observed. The mean additional costs of PLF were 56,219 Euro. An equivalent cost difference of mortality was obtained from the analysis of 916 patients. Patients developing PLF had a decreased LiMAx of 61 microg/kg/h compared to the regular group 122 microg/kg/h (p < 0.001) after surgery. Initial postoperative LiMAx and total costs revealed a linear correlation coefficient of r = -0.340 (p = 0.018). CONCLUSIONS: PLF is a very relevant medical and economic problem. Liver function capacity does not only predict PLF but also correlates with total costs in general.

Acute Graft Dysfunction 17 Years After Liver Transplant: A Challenging Clinical and Histologic Manifestation of Hepatitis E.

Acute hepatitis E virus infection after liver transplant is a challenging clinical phenomenon. Due to its unspecific clinical and histological presentation, the diagnosis of acute or chronic hepatitis E virus infection can be difficult in unclear cases of elevated liver enzymes. Here, we report the case of a 56-year-old male patient who presented to our center for 17-year follow-up after liver transplant with α1-antitrypsin deficiency. The patient was asymptomatic but had remarkably increased transaminases and cholestasis parameters. Blood levels for immunosuppressives were in the normal range, and cholestasis and deteriorated liver perfusion were excluded by ultrasonographic examination. A liver biopsy was performed that was histologically interpreted as acute cellular rejection grade I. Accordingly, the patient was treated with 5-day high-dose intravenous steroids and increased doses of the maintenance immunosuppressive agents, resulting in the slow normalization of the liver enzymes. Extended laboratory examinations revealed presence of acute hepatitis E virus infection, and a retrospectively immunohistologic staining of the liver biopsy was positive for hepatitis E virus antigen. Acute hepatitis E virus infection can be a reason for acute allograft dysfunction after liver transplant. This differential diagnosis should be kept in mind, especially when graft dysfunction occurs long after transplant.

Randomized clinical trial comparing liver resection with and without perioperative assessment of liver function.

BACKGROUND: Liver function tests may help to predict outcomes after liver surgery. The aim of this study was to evaluate the clinical impact on postoperative outcome and patient management of perioperative liver function testing using the LiMAx® test. METHODS: A multicentre RCT was conducted in six academic liver centres. Patients with intrahepatic tumours scheduled for open liver resection of at least one segment were eligible. Patients were randomized to undergo additional perioperative liver function tests (LiMAx® group) or standard care (control group). Patients in the intervention arm received two perioperative LiMAx® tests, one before the operation for surgical planning and another after surgery for postoperative management. The primary endpoint was the proportion of patients transferred directly to a general ward. Secondary endpoints were severe complications, length of hospital stay (LOS) and length of intermediate care/ICU (LOI) stay. RESULTS: Some 148 patients were randomized. Thirty-six of 58 patients (62 per cent) in the LiMAx® group were transferred directly to a general ward, compared with one of 60 (2 per cent) in the control group (P < 0·001). The rate of severe complications was significantly lower in the LiMAx® group (14 per cent versus 28 per cent in the control group; P = 0·022). LOS and LOI were significantly shorter in the LiMAx® group (LOS: 10·6 versus 13·3 days respectively, P = 0·012; LOI: 0·8 versus 3·0 days, P < 0·001). CONCLUSION: Perioperative use of the LiMAx® test improves postoperative management and reduces the incidence of severe complications after liver surgery. Registration number: NCT01785082 ( https://clinicaltrials.gov).

Smart Kd-values, their uncertainties and sensitivities - Applying a new approach for realistic distribution coefficients in geochemical modeling of complex systems.

One natural retardation process to be considered in risk assessment for contaminants in the environment is sorption on mineral surfaces. A realistic geochemical modeling is of high relevance in many application areas such as groundwater protection, environmental remediation, or disposal of hazardous waste. Most often concepts with constant distribution coefficients (Kd-values) are applied in geochemical modeling with the advantage to be simple and computationally fast, but not reflecting changes in geochemical conditions. In this paper, we describe an innovative and efficient method, where the smart Kd-concept, a mechanistic approach mainly based on surface complexation modeling, is used (and modified for complex geochemical models) to calculate and apply realistic distribution coefficients. Using the geochemical speciation code PHREEQC, multidimensional smart Kd-matrices are computed as a function of varying (or uncertain) environmental conditions. On the one hand, sensitivity and uncertainty statements for the distribution coefficients can be derived. On the other hand, smart Kd-matrices can be used in reactive transport (or migration) codes (not shown here). This strategy has various benefits: (1) rapid computation of Kd-values for large numbers of environmental parameter combinations; (2) variable geochemistry is taken into account more realistically; (3) efficiency in computing time is ensured, and (4) uncertainty and sensitivity analysis are accessible. Results are presented exemplarily for the sorption of uranium(VI) onto a natural sandy aquifer material and are compared to results based on the conventional Kd-concept. In general, the sorption behavior of U(VI) in dependence of changing geochemical conditions is described quite well.

Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. OBJECTIVE: To study fetuin A as predictor of NAFLD/NASH in preoperative patients. METHODS: 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. RESULTS: Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. CONCLUSION: Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.

No influence of immunosuppression on insulin sensitivity and beta-cell function in living donor liver transplantation.

In liver transplantation alterations of glucose metabolism are common but not well understood. Influence of immunosuppression is widely presumed but has not proven until now. Using a frequently sampled intravenous glucose tolerance test with a minimal modeling technique of glucose disappearance we analyzed insulin sensitivity (SI) and beta-cell function (first and second phase of pancreatic beta-cell secretion, Phi 1 and Phi 2) in living donor liver transplantation of the right lobe. Initial immunosuppression in recipients was done with tacrolimus, prednisolone, and basiliximab induction. Donors and recipients were investigated before and 10 days, 6 months, and 1 year after operation. Normal SI of controls (donors before operation) decreased markedly 10 days after right lobectomy to SI 2.22 +/- 0.35 x 10(-4) min(-1) x microU/mL (P < .001); Phi 2 was compensatory increased. All parameters normalized within 1 year. Recipients were insulin-resistant with hyperinsulinemia before transplantation. After transplantation no parameter was significantly different from donors; all normalized equally to donors over 1-year follow-up. Thus, immunosuppression in recipients has no influence on glucose metabolism because liver function itself seems to play a more pronounced role than known until now.

Spectroscopic evidence for selenium(IV) dimerization in aqueous solution.

The aqueous speciation of selenium(iv) was elucidated by a combined approach applying quantum chemical calculations, infrared (IR), Raman, and (77)Se NMR spectroscopy. The dimerization of hydrogen selenite (HSeO3(-)) was confirmed at concentrations above 10 mmol L(-1) by both IR and NMR spectroscopy. Quantum chemical calculations provided the assignment of vibrational bands observed to specific molecular modes of the (HSeO3)2(2-) ion. The results presented will provide a better understanding of the chemistry of aqueous Se(iv) which is of particular interest for processes occurring at mineral/water interfaces.

Duodenal biopsies of HIV-infected patients with diarrhoea exhibit epithelial barrier defects but no active secretion.

OBJECTIVES: To characterize diarrhoeal mechanisms in HIV-infected patients, epithelial transport and barrier function of the duodenal mucosa was investigated in vitro. PATIENTS: Twenty-one HIV-seropositive patients (13 asymptomatic and eight with diarrhoea) and 12 controls from an urban referral-based tertiary care centre in Berlin who underwent duodenoscopy. METHODS: A new miniaturized Ussing chamber allowed measurements on duodenal forceps biopsies. Epithelial barrier function was characterized by alternating current impedance analysis, which allows differentiation of epithelial and subepithelial resistance and by 3H-lactulose and 3H-mannitol flux measurements. Na+-glucose cotransport was quantified as phlorizin-sensitive short circuit current (Isc) and active ion secretion by baseline and bumetanide-sensitive Isc. RESULTS: Duodenal biopsies from asymptomatic HIV-infected patients were no different from controls, whereas biopsies from HIV-infected patients with diarrhoea showed a decrease in epithelial resistance from 21.2+/-1.9 to 12.9+/-1.3 omega cm2 (P<0.01). Concomitantly, mucosal-to-serosal lactulose flux increased from 0.29+/-0.02 to 0.40+/-0.03 micromol (hcm2) (P<0.01). Phlorizin-sensitive Isc indicating Na+-glucose cotransport, as well as baseline and bumetanide-sensitive Isc indicating active electrogenic chloride secretion were not different between the three groups. CONCLUSIONS: A miniaturized Ussing device was developed for electrophysiological investigations of duodenal forceps biopsies, which allowed characterization of active ion transport mechanisms and epithelial barrier function. Duodenum of HIV-infected patients with diarrhoea showed no evidence for active ion secretion or Na+-glucose malabsorption, but showed an impaired epithelial barrier function, which could contribute to diarrhoea by a leak flux mechanism.

Streptomycin biosynthesis and its regulation in Streptomycetes.

New insights into the gene orders, structures, evolution, and functions of streptomycin (Sm) biosynthetic genes (str) were gained via hybridization studies, determination of nucleotide sequences, and measurement of expression in the str gene clusters of Streptomyces griseus and S. glaucescens. Both str clusters showed considerable divergence in macro and micro structure. Genes putatively involved in pathways leading to the (dihydro-)streptose and N-methyl-L-glucosamine moieties of Sm were identified. Additional regulatory elements, such as gene strS and conserved TTA codons in the N-terminal sections of reading frames, are reported. Evidences for the involvement of physiological state, signal transduction, and activators in the control of Sm production are presented.

Two-quantum selective laser scission of polyadenilic acid in the complementary complex with a dansyl derivative of oligothymidilate.

Nonathymidilate was synthesized containing the chromophore (dansyl) group linked to its 5'-phosphate. In the presence of this compound the polyadenilic acid molecules are split by the radiation (power density J greater than or equal to 70 MW/cm2) of a nitrogen laser, while under the same conditions poly(C) and poly(U) are hardly affected. This selective optically non-linear effect was predicted and is explained in terms of radiativeless transfer of two-quantum excitation of the chromophore which is fixed on poly(A) molecule due to the formation of the complementary complex with nonathymidilate.

Mechanisms of epithelial barrier impairment in HIV infection.

Diarrhea and malabsorption due to intestinal dysfunction are common symptoms in HIV infection. The pathophysiologic mechanisms of these alterations are often not known, and the role of HIV per se is still controversially discussed. We measured the epithelial transport and barrier function by means of a miniaturized Ussing chamber system in the duodenum of HIV-infected patients in different disease stages, determined by the CD4 cell count in the serum as well as symptoms in patients with and without diarrhea. We could show that diarrhea induced by HIV per se is caused by a leak flux mechanism due to impaired epithelial barrier function. Antisecretory therapy does not seem to be useful in these patients, because we did not find increased active ion secretion. Along the course of the HIV infection, the epithelial transport and barrier function varies with HIV disease stage (expressed by CD4 cell status). In addition, an in vitro model was studied to characterize the effect of HIV-infected human immune cells on the epithelial barrier function using the human colonic epithelial cell line HT-29/B6. HIV infection of human immune cells induced an increase in cytokine release--for example, TNF-alpha, IL-1 beta, IFN-alpha, and IFN-gamma--downregulating the epithelial barrier function of the human colonic epithelial cell line HT-29/B6. Taken together we postulate a specific stage-dependent cytokine pattern released from HIV-infected immune cells in the mucosa, which, corresponding to the HIV disease stage, is responsible for the variation in epithelial function.

Gene probes for the detection of 6-deoxyhexose metabolism in secondary metabolite-producing streptomycetes.

DNA probes were designed from the streptomycin production genes strDELM of Streptomyces griseus involved in the biosynthesis of the 6-deoxyhexose (6DOH) dihydrostreptose which could detect the genomic fragments coding for 6DOH formation in other actinomycetes strains. In about 70% of the 43 strains tested at least one signal could be detected with strD-, strE- or strLM-specific probes. Evidence is presented that the hybridizing genes are mostly clustered and probably engaged in the formation of secondary metabolites. Because of the wide-spread use of 6DOH constituents in natural products these probes should allow to detect a vast array of different secondary metabolic gene clusters in actinomycetes.

Liver transplantation and diabetes mellitus.

Post-transplant diabetes mellitus (PTDM) is a common complication after orthotopic liver transplantation (oLT). In our study, we investigated the prevalence and risk factors one year after transplantation in 618 patients who underwent oLT between 1990 and 1996 in a single center. The influence of steroid medication and hepatitis B or C (HBV/HCV) was also studied. Before oLT 66 of the 618 patients were diabetic. After transplantation 37 of these 66 (56%) patients showed no further signs of DM. Of the 552 patients without DM before transplantation 39 (7.2%) developed new onset PTDM. There was no influence of steroid medication on the presence of PTDM (steroids 10.4% PTDM, no steroids 12.5% PTDM). In addition we found no influence of HBV or HCV-infection on PTDM development. Analysis for risk factors showed no significant influence of the diagnosis leading to oLT, of FK506 or Cyclosorin A medication, age, gender or Child-Pugh class. Five year patient survival was not influenced by the presence of PTDM, especially patients with a preexisting DM showed no reduced survival. However, a subgroup of patients with new onset insulin-requiring PTDM showed significantly reduced 5 year survival (p<0.05). In conclusion we found new onset PTDM in 7.2% of patients undergoing oLT one year after the operation. On the other hand in more than 50% of patients with preexisting DM, the disease was no longer present post-transplant. This could be an indication that DM is dependent on liver function in these patients. Patients with preexisting DM should not be excluded from transplantation if indicated. Development of new onset insulin-requiring PTDM could be an important prognostic factor for patient survival after oLT. Further investigations are necessary to evaluate the prognostic meaning of PTDM and the pathophysiologic mechanisms.