bluuebunny/crossref_metadata_2025 huggingface dataset:
Overview of Modern Management of Patients with Critical Injury and Severe Sepsis
Authors: Streat Stephen J. , Plank Lindsay D. , Hill Graham L.
Published: August 2002

Over the last 10 years there have been substantial changes in the issues confronting intensivists and surgeons caring for critically ill patients. A substantial increase in the number of elderly patients with surgical illness and complex co‐morbidity has accompanied the increase in the proportion of elderly in populations in the developed world. This phenomenon has been seen particularly with sepsis. Incidence rates for blunt trauma have declined overall, but the problems of the elderly trauma patient have become more evident. Major elective surgery remains a common indication for short‐term intensive care in many countries, but the need for cost‐containment has led to increased use of high‐dependency care for many such patients. Expectations of both society and clinicians have increased, and this has been reflected in the increased demand for complex procedures (e.g., liver transplantation, cerebral artery aneurysm clipping, aortic aneurysm repair) in patients previously considered at too high risk. Along with these expectations have come pressures on clinicians to reduce costs at the same time as improving clinical outcomes. Despite many advances in the care of critically ill patients with injury or sepsis, mortality, morbidity, and cost remain high; and nutritional support is frequently required. The duration and extent of the metabolic changes seen in response to critical surgical illness and intensive care treatments have become better characterized. Although some of the changes in body water and fat are modifiable, loss of large amounts of (functional) protein has been resistant to various strategies so far studied.
Factors affecting female‐biased sex ratio in a trap‐nesting wasp, Trypoxylon malaisei
Authors: Oku S. , Nishida Takayoshi
Published: August 2002

We examined the female‐biased sex ratio of a trap‐nesting wasp Trypoxylon malaisei considering the following factors: (1) local mate competition (LMC), (2) resource quality, (3) partial bivoltinism, and (4) presence of constrained females. The sex ratio (expressed as male ratio) at emergence was strongly female biased, i.e., 0.30 and 0.19, in terms of the number and investment, respectively. To evaluate the primary sex ratio, we analyzed the data from nests where all the offspring successfully emerged, excluding nests composed of single‐sex offspring. The primary sex ratio was also female biased, at 0.33 and 0.21, in terms of the number and investment, respectively. LMC was highly responsible for the female‐biased sex ratio because both the nonrandom oviposition sequence [females at inner cells and male(s) at outer cells] and earlier emergence of males allowed sib‐matings to occur. In contrast, the other three factors little affected the female‐biased sex ratio: the sex ratio was fairly constant when resource quality (nest size) varied, partial bivoltinism was extremely rare or absent, and constrained females were absent or did not reproduce at all.
Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse
Authors: Sasaki Motoko , Van De Water Judy , Kenny Thomas P. , Gallo Michael L. , Leung Patrick S. C. , Nakanuma Yasuni , Ansari Aftab A. , Coppel Ross L. , Neuberger James , Gershwin Eric M.
Published: August 2002

The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). The nature of the clonal selection process is unclear, and to address this issue, we took advantage of a transgenic technology, XenoMouse, that contains 80% of the human immunoglobulin (Ig) variable gene repertoire and can produce high-affinity human antibodies to virtually any immunogen without evidence of clonal bias. We immunized mice with PDC-E2 to obtain 13 HmAbs, including 4 IgG2 and 9 IgM isotypes. Immunoglobulin gene analysis was unique and demonstrated a clonal bias; the immunoglobulin gene usage was considerably different from other antibody responses analyzed in XenoMouse systems. Four of the 13 mAbs recognized the inner lipoyl domain of PDC-E2, 2 of 13 recognized the entire PDC-E2 molecule, 4 of 13 recognized PDC-E2 and OGDC-E2, 1 of 13 recognized OGDC only, 1 recognized BCOADC-E2 only, and 1 recognized an unidentified 100-kd mitochondrial protein. Immunohistochemical staining using these HmAbs produced mitochondrial staining of septal bile ducts in both PBC and control livers. Ig gene analysis showed that 7 of 13 HmAbs used the VH3 and 4 of 13 used VH4 gene repertoire, respectively. Three of 7 VH3 antibodies used the same Ig VH3-21 gene family found in human AMA from patients with PBC. The CDRs of these autoantibodies were slightly mutated when compared with the sequences present within the Ig germline genes. In conclusion, the XenoMouse not only recapitulates the unique specificity and restriction of PBC patients, but indicates that the autoantibodies are derived from a restricted clonal selection process. Such data suggest that the original immunogen leads to somatic mutation without subsequent development of determinant spreading. (Hepatology 2001;34:631-637.)
Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy
Authors: Yuen Man-Fung , Sablon Erwin , Hui Chee-Kin , Yuan He-Jun , Decraemer Hilde , Lai Ching-Lung
Published: August 2002

Factors associated with hepatitis B virus (HBV) DNA breakthrough and the significance of YMDD variants without the presence of wild-type YMDD during prolonged lamivudine treatment are unknown. We studied the amino acid sequence of codon 552 (YMDD motif) and codon 528 by means of a line probe assay in 159 chronic HBV patients (median follow-up 29.6 months). Pretreatment HBV DNA levels and alanine transaminase (ALT) levels correlated inversely with the time to HBV DNA breakthrough with YMDD variants (r = −0.46, P = .001; r = −0.45, P = .001 respectively). Patients harboring YMDD variants 3 months before HBV DNA breakthroughs had higher HBV DNA breakthrough levels compared with those without YMDD variants 3 months before HBV DNA breakthroughs (18.9 × 106 vs. 5.4 × 106 copies/mL, P = .007). Patients with HBV DNA breakthroughs had higher percentages of YMDD variants without the presence of wild-type YMDD compared with patients without HBV DNA breakthrough (25.6% vs. 9%, P = .007 for single M552I variant; 20.9% vs. 8.1%, P = .026 for single M552V variant; 30.2% vs. 9.9%, P = .004 for M552I/M552V variants). Patients with HBV DNA levels of more than 103 copies/mL after 6 months of lamivudine therapy had a 63.2% chance of subsequently developing YMDD variants. HBeAg seroconversion occurred in 2 patients after the emergence of YMDD variants. Only one patient developed YMDD variant after HBeAg seroconversion. There was no increase in the rate of development of YMDD variants or L528M mutation in patients receiving lamivudine 25 mg daily or famciclovir 500 mg 3 times a day before being given lamivudine 100 mg daily.
Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats
Authors: Hernández-Muñoz Rolando , Díaz-Muñoz Mauricio , Suárez-Cuenca Juan A. , Trejo-Solís Cristina , López Verónica , Sánchez-Sevilla Lourdes , Yáñez Lucía , De Sánchez Victoria Chagoya
Published: August 2002

Cirrhosis is one of the most common causes of mortality worldwide, because hepatic dysfunction constitutes a potentially lethal condition. Having demonstrated the hepatoprotective effect of adenosine against CCl4-induced cirrhosis, the present study was aimed at assessing adenosine's effect on an already-established micronodular cirrhosis. Chronic administration of CCl4 (10 weeks) induced a cirrhotic state, characterized by increased liver fibronectin and collagen types I and III content, enhanced expression of α-1 (I) collagen mRNA, portal hypertension, and liver dysfunction. After CCl4 discontinuation (5 weeks), increased persitance of α-1 (I) collagen mRNA expression and deposition, enhanced proline incorporation into collagen and prolyl hydroxylase activity evidenced active fibrogenesis. Several weeks after CCl4 withdrawal, deposited collagen showed an enhanced type I/III ratio, which was associated with deficient collagenolytic activity in cirrhotic livers. Liver expression of some metalloproteinases (MMPs) and of tissue inhibitors of MMPs (TIMPs) also indicated decreased collagen breakdown in cirrhotic livers. Parameters indicative of oxidative stress (mainly protein oxidation) were persistently augmented. These events were coincident with diminished regenerative capacity of the cirrhotic liver. Intraperitoneal adenosine administration to CCl4-induced cirrhotic rats blocked active fibrogenesis and increased the collagen degradation (most probably by decreasing liver TIMPs levels), normalizing collagen-type ratios. In addition, the nucleoside promoted an effective hepatocyte's proliferation in the cirrhotic liver and accelerated normalization of parameters indicative of liver function and oxidative stress. Thus, adenosine readily reversed an experimental cirrhosis through stimulating liver collagenolytic and proliferative capacities, as well as by accelerating functional recovery.
Nuclear factor-κB in the liver of patients with chronic hepatitis C: Decreased RelA expression is associated with enhanced fibrosis progression
Authors: Boya Patricia , Larrea Esther , Sola Iosu , Majano Pedro-Lorenzo , Jiménez Carlos , Civeira María-Pilar , Prieto Jesús
Published: August 2002

The mechanisms of liver damage in chronic hepatitis C virus (HCV) infection are poorly understood. The transcription factor, nuclear factor-κB (NF-κB), regulates the expression of genes involved in apoptosis, inflammation, and antiviral response. It plays a protective role in several forms of liver damage. In this study, we analyzed NF-κB by gel mobility shift assay and immunohistochemistry in liver biopsies from HCV-infected patients, and we have determined the hepatic levels of the components of the NF-κB system by semiquantitative polymerase chain reaction (PCR). We found that NF-κB was activated in the liver of patients with chronic hepatitis C. Neither NF-κB activity nor the RNA levels of NF-κB subunits showed correlation with liver inflammatory activity, viral load, or HCV genotype. By contrast, hepatic mRNA values of RelA, the main element of active NF-κB, correlated inversely with apoptosis (r = −.68; P < .05) and with the rate of fibrosis progression (r = −.51; P < .04). In intermediate/rapid fibrosers, RelA mRNA levels were significantly decreased as compared with slow fibrosers (P < .003) and with normal livers (P < .03). In conclusion, we found that NF-κB is activated in chronic HCV-infected livers, and that the expression of RelA is inversely correlated with liver cell apoptosis and with the rate of fibrosis progression. Our data thus suggest that RelA expression may protect against liver fibrosis and hepatocellular damage.
The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: A long-term retrospective cohort study
Authors: Di Martino Vincent , Rufat Pierre , Boyer Nathalie , Renard Philippe , Degos Françoise , Martinot-Peignoux Michèle , Matheron Sophie , Le Moing Vincent , Vachon François , Degott Claude , Valla Dominique , Marcellin Patrick
Published: August 2002

In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P = .012), higher total Knodell score (P = .011), and poorer sustained response to interferon therapy (P = .009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P = .001). Necroinflamatory score was higher in HIV-positive patients (P = .023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P = .011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P = .024) and in interferon-untreated patients (RR = 4.76, P = .001), independently of age at HCV infection (P = .001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P = .001) and in HIV-positive patients with CD4 cell count less than 200/mm3 (RR = 11.9, P = .007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.
Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18
Authors: Toivola Diana M. , Nieminen Mikko I. , Hesse Michael , He Tao , Baribault Hélène , Magin Thomas M. , Omary Bishr M. , Eriksson John E.
Published: August 2002

Simple epithelial tissues such as liver and pancreas express keratins 8 (K8) and 18 (K18) as their major intermediate filament proteins. K8 and K1 null mice and transgenic mice that express mutant K18 (K18C) manifest several hepatocyte abnormalities and demonstrate that K8/18 are important in maintaining liver tissue and cell integrity, although other potential functions remain uncharacterized. Here, we report an additional abnormal liver phenotype, which is similar in K8 null, K18 null, and K18C mouse models. Liver histologic examination showed large polynuclear areas that lacked cell membranes, desmosomal structures, and filamentous actin. Similar, but less prominent, areas were observed in the pancreas. The parenchyma outside the polynuclear areas displayed irregular sinusoidal structures and markedly enlarged nuclei. Most K8 null hepatocytes were positive for the proliferating cell nuclear antigen (PCNA) with a doubled DNA content in comparison with the predominantly PCNA-negative wild-type hepatocytes. The distribution of the 14-3-3ζ protein was also altered in K8 null mice. Taken together, our results indicate that absence of keratin filaments causes disturbances in cell-cycle regulation, driving cells into the S-G2 phase and causing aberrant cytokinesis. These effects could stem from disturbed functions of K8/18-dependent cell-cycle regulators, such as the signaling integrator, 14-3-3.
Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver
Authors: Ross Mark A. , Sander Christina M. , Kleeb Talia B. , Watkins Simon C. , Stolz Donna Beer
Published: August 2002

Regenerating liver was evaluated for the spatiotemporal expression of angiogenic growth factor receptors on endothelial cell (EC) membranes during revascularization resulting from 70% partial hepatectomy (PHx). Fractions enriched in EC membranes were examined by Western blot for angiogenic growth factor receptor expression from 1 to 14 days after PHx. Increases in vascular endothelial growth factor (VEGF) receptors Flt-1 and Flk-1/KDR, angiopoietin receptors Tie-1, Tie-2, and platelet-derived growth factor receptor beta (PDGF-Rβ), modest increases in epidermal growth factor receptor (EGF-R), and no increase in hepatocyte growth factor receptor (c-Met) or fibroblast growth factor receptors (FGF-R) were observed in isolated membranes during EC proliferation. All receptors were tyrosine phosphorylated, and therefore activated, during peak expression. Immunofluorescence staining of regenerating liver identified populations with increased receptor expression, indicating cells receptive to ligand signaling. EGF-R was upregulated evenly throughout the sinusoidal membrane, whereas c-Met was observed on hepatocyte canaliculae, bile duct epithelium, and large vessel EC. Tie-2 and PDGF-Rβ were increased on sinusoidal and large vessel EC, whereas Tie-1 was expressed in EC surrounding avascular hepatic islands. Flk-1/KDR was increased on large vessels with slight increases on sinusoidal EC, whereas Flt-1 was increased in arterioles, sinusoidal EC as well as in hepatocytes. Although Flt-1 was phosphorylated on isolated hepatocytes, vascular endothelial growth factor165 (VEGF165) did not induce a proliferative or motogenic response. Proliferation assays on isolated EC indicated responsiveness to VEGF165, but synergism among several growth factors including PDGF-BB was also observed. The data identify novel autocrine and paracrine interactions and indicate that each growth factor acts on a specific set of EC at specific times during revascularization of regenerating liver.
TIPS is a useful long-term derivative therapy for patients with Budd-Chiari syndrome uncontrolled by medical therapy
Authors: Perelló Antonia , García-Pagán Juan Carlos , Gilabert Rosa , Suárez Yanette , Moitinho Eduardo , Cervantes Francisco , Reverter Juan Carlos , Escorsell Angels , Bosch Jaume , Rodés Juan
Published: August 2002

Patients with Budd-Chiari syndrome (BCS) may require treatment with portal decompressive surgery or liver transplantation. Transjugular intrahepatic portosystemic shunt (TIPS) represents a new treatment alternative, but its long-term effect on BCS outcome has not been evaluated. Twenty-one patients with BCS consecutively admitted to our unit were evaluated. The mean follow-up was 4 ± 3 years. Seven patients had nonprogressive forms and were successfully controlled with medical therapy; 1 case, with a short-length hepatic vein stenosis was successfully treated by angioplasty. All 8 patients are alive and asymptomatic. The remaining 13 patients, had a TIPS because of clinical deterioration (in one of them, because early TIPS thrombosis a successful side-to-side portacaval shunt [SSPCS] was performed) followed by an improvement in clinical condition. However, a patient with fulminant liver failure before TIPS insertion, died 4 months later and another patient with cirrhosis at diagnosis had liver transplantation 2 years later. The remaining 11 patients are alive and free of ascites. In 3 of these patients TIPS is patent after 3, 6, and 12 months. The remaining 8 patients developed late TIPS dysfunction. In two of these cases, after angioplasty and restenting, TIPS is patent after a follow-up of 9 and 80 months. In 5 other patients, recurring TIPS occlusion was not further corrected because no signs of portal hypertension were present. In conclusion, in patients with BCS uncontrolled with medical therapy, TIPS is a highly effective technique that is associated with long-term survival.
Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria
Authors: Plösch Torsten , Bloks Vincent W. , Baller Juul F. W. , Havinga Rick , Verkade Henkjan J. , Jansen Peter L. M. , Kuipers Folkert
Published: August 2002

Hepatic complications in erythropoietic protoporphyria (EPP) have been attributed to toxic actions of accumulated protoporphyrin (PP). PP can only be removed via the bile but transport systems involved have not been defined. The aim of this study was to gain insight in the mode of biliary PP excretion, with emphasis on the potential contribution of the Mdr1 P-glycoprotein export pump and biliary lipids as PP carriers. Control mice and mice homozygous for Mdr1a/b (Abcb1) or Mdr2 (Abcb4) gene disruption, the latter unable to secrete phospholipids and cholesterol into bile, were treated with griseofulvin to chemically induce protoporphyria. All groups showed dramatically increased PP levels in erythrocytes and liver after griseofulvin treatment. Histologically, massive PP deposits were found in livers of control and Mdr1a/b
−/− mice but not in those of Mdr2
−/− mice. Serum unesterified cholesterol and phospholipids were increased by griseofulvin because of formation of lipoprotein-X in control and Mdr1a/b
−/− mice only. Yet, bile flow was not impaired in griseofulvin-treated mice, and biliary bile salt, phospholipid, and cholesterol secretion rates were significantly increased. Surprisingly, biliary PP excretion was similar in all 3 groups of griseofulvin-treated mice: the observed linear relationship between hepatic and biliary PP concentrations and identical liver-to-bile concentration ratios in treated and untreated mice suggest a passive mode of excretion. In conclusion, the data show that Mdr P-glycoproteins are not critically involved in biliary removal of excess PP and indicate that the presence of biliary lipids is required for formation of intrahepatic PP deposits.
Intestinal mucosal alterations in experimental cirrhosis in the rat: Role of oxygen free radicals
Authors: Ramachandran Anup , Prabhu Ramamoorthy , Thomas Simmy , Reddy Jayasree Basivi , Pulimood Anna , Balasubramanian Kunissery A.
Published: August 2002

Cirrhosis is associated with altered gastrointestinal function, and bacterial translocation from the gut plays an important role in the etiology of spontaneous bacterial peritonitis (SBP) seen in this condition. Although alterations in gut motility and intestinal permeability are recognized in cirrhosis, the intestinal damage at the cellular and subcellular levels is not well understood. This study looked at the mucosal alterations in experimental cirrhosis and the role of oxygen free radicals in this process. It was shown that cirrhosis results in oxidative stress in the intestine, as seen by increased xanthine oxidase (XO) activity and altered antioxidant status. Cirrhosis also affects enterocyte mitochondrial function, as assessed by respiratory control ratio, swelling, and calcium flux. Increased lipid peroxidation of the brush border membranes (BBMs) was seen along with altered intestinal transport. In conclusion, this study shows that intestinal mucosal alterations are seen in experimental cirrhosis and are possibly mediated by oxidative stress.
Apolipoprotein synthesis in nonalcoholic steatohepatitis
Authors: Charlton Michael , Sreekumar Raghavakaimal , Rasmussen Deborah , Lindor Keith , Nair Sreekumaran K.
Published: August 2002

The pathophysiology of hepatic steatosis, a prerequisite of nonalcoholic fatty liver disease, is poorly understood. Because very-low-density lipoprotein (VLDL) formation is the chief route of hepatic lipid export, we hypothesized that the synthesis of apoB-100, a rate-determining step in hepatic VLDL formation, may be altered in patients with nonalcoholic steatohepatitis (NASH). This study evaluated the relative synthesis rates of apolipoprotein B-100 (apoB-100) in patients with NASH and in lean and body mass index (BMI)-matched (obese) controls without NASH. A primed continuous infusion of L-[1-13C] leucine was used to measure the absolute synthesis rates (ASR) of apoB-100 and fibrinogen in 7 patients with NASH and compared them with 7 lean and 7 obese (BMI-matched) controls without NASH. The ASRs of fibrinogen and albumin also were measured. The mean ASR of apoB-100 in patients with NASH was lower (31.5 ± 3.4 mg/kg/d) than that of obese (115.2 ± 7.2 mg/kg/d, P < .001) and lean controls (82.4 ± 4.1 mg/kg/d, P = .002). In contrast, the mean ASR of fibrinogen was greater in subjects with NASH than in both control groups. These data indicate that NASH is associated with markedly altered hepatic synthesis of apoB-100. The finding that albumin synthesis was not similarly decreased in patients with NASH shows that the attenuation of apoB-100 synthesis is not on the basis of globally impaired hepatic protein synthesis. In conclusion, because apoB-100 synthesis is a rate-determining step in hepatocyte lipid export, decreased synthesis of this protein may be an important factor in the development of hepatic steatosis, a prerequisite for NASH.
Statins as immunosuppressive agents
Authors: Kobashigawa Jon A.
Published: August 2002

Abstract Unavailable. Please See Print Journal.
Use of intraoperative Doppler ultrasound to diagnose hepatic venous obstruction in a right lobe living donor liver transplant
Authors: Shapiro Robert S. , Fishbein Thomas , Schwartz Myron , Miller Charles M.
Published: August 2002

Right lobe liver transplantation is a relatively new and technically challenging method of living donor transplantation. Integrity of the hepatic venous anastomosis is crucial for successful transplantation. We describe the use of intraoperative Doppler sonography to diagnose stenosis of the hepatic vein anastomosis, with associated compromise of venous drainage and graft perfusion.
Successful recanalization of portal vein thrombosis before liver transplantation using transjugular intrahepatic portosystemic shunt
Authors: Liatsos Christos , Vlachogiannakos John , Patch David , Tibballs John , Watkinson Anthony , Davidson Brian , Rolles Keith , Burroughs Andrew K.
Published: August 2002

A frequent complication in patients with end-stage liver disease is portal vein thrombosis (PVT). Although PVT is not considered an absolute contraindication to orthotopic liver transplantation (OLT), more complex surgery is required and patients have more postoperative complications and greater mortality rates. We describe 2 patients who experienced complete PVT either while waiting for liver transplantation or during the workup, resulting in acute deterioration of liver function. Recanalization of the portal vein was successfully performed in both patients using transjugular intrahepatic portosystemic stent shunt (TIPS), and patency was maintained by the addition of anticoagulation therapy. They subsequently underwent successful OLTs and remain well. In conclusion, we believe that TIPS placement can be performed safely in patients with recent PVT, ensuring the patency of the portal vein until OLT.
A cross-sectional study of SEN virus in liver transplant recipients
Authors: Yoshida Eric M. , Buczkowski Andrzej K. , Giulivi Antonio , Zou Shimian , Forrester Leslie A.
Published: August 2002

A new DNA virus, referred to as SEN virus (SEN V), has been isolated and is associated with blood-product transfusion and possibly Non A to Non E hepatitis. We performed a cross-sectional analysis of SEN V in liver transplant recipients at our center. Polymerase chain reaction was used to test for 2 genotypes of SEN V (SEN V:C/H and SEN V:D) in 58 unselected patients. Comparisons were made between SEN V-positive and SEN V-negative groups in terms of age, time posttransplantation, indications for transplantation, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and cytomegalovirus and Epstein-Barr virus status. Thirty of 58 transplant recipients (51.7%) were SEN V positive; 15.5% were positive for SEN V:C/H, 24.1% for SEN:D, and 12.1% for both strains. No significant differences were found based on primary indication for transplantation, including hepatitis C virus (HCV). Of the 14 of 21 patients with HCV seropositivity and HCV reinfection, 79% were positive for SEN V (P = .02). There was no difference in the proportion of patients with abnormal serum ALT and/or AST levels. A trend for the SEN V-positive group to have a greater mean ALT level (82 v 41 U/L; P = .067) was attributable to the subgroup with HCV recurrence because there was no difference in mean ALT levels (34.9 v 34.5 U/L; P = .968) in non-HCV-infected transplant recipients. Even in the subgroup (n = 14) with recurrent HCV, there was no statistically significant difference in mean ALT levels (140 v 105 U/L; P = .665). Age and cytomegalovirus or Epstein-Barr virus status were not significantly different between the 2 groups, but a significant difference in posttransplantation time was noted (16.8 v 32 months; P = .021). We conclude that SEN V is common among liver transplant recipients but does not appear to cause graft dysfunction as an isolated agent. There is a suggestion that SEN V may be associated with HCV recurrence, but we did not detect biochemical differences attributable to SEN V.
mTOR inhibitors: An overview
Authors: Neuhaus Peter , Klupp Jochen , Langrehr Jan Michael
Published: August 2002

Inhibitors of the mammalian target of rapamycin are a new class of immunosuppressants. In contrast to other macrolides, such as tacrolimus and cyclosporine A, they do not inhibit calcineurin and thus signal I of T-cell activation. By inhibiting signal III, the mechanism of action and side effects of sirolimus (rapamycin) and its derivative RAD are distinct from other immunosuppressants. Reports of synergism with cyclosporine A and tacrolimus in preclinical and clinical studies, avoidance of nephrotoxicity, and possible treatment or prevention of chronic allograft rejection are leading to high expectations for this new class of immunosuppressants. Furthermore, studies evaluating tolerance induction are being conducted. This review summarizes preclinical and clinical results published to date and exploits the future value of sirolimus and RAD for clinical transplantation.
Disease recurrence after living liver transplantation for primary biliary cirrhosis: A clinical and histological follow-up study
Authors: Hashimoto Etsuko , Shimada Masahiko , Noguchi Sanshirou , Taniai Makiko , Tokushige Katsutoshi , Hayashi Naoaki , Takasaki Ken , Fuchinoue Syouhei , Ludwig Jurgen
Published: August 2002

We describe the recurrence of primary biliary cirrhosis (PBC) in recipients of living liver transplants. We are not aware of similar previous reports. Because most donors for living liver transplantation (LLT) are blood relatives with close HLA matches, the recurrence of PBC in transplant recipients might offer additional insights in the pathogenesis of the condition. We studied 6 women (age, 29 to 61 years) with PBC who survived LLT for at least 1 year. Tests for antimitochondrial autoantibody (AMA), antipyruvate dehydrogenase complex-E2, immunoglobulin G (IgG) anti-M2, and IgM anti-M2 had confirmed the diagnosis. Donors were blood relatives in 5 instances, and one donor who was not a blood relative still had multiple HLA matches with the recipient. After LLT, we observed a decrease in AMA titers, but within 1 year, these titers increased again in 5 of the 6 patients to pre-LLT levels or greater. Immunoblotting analysis of the anti-M2 protein profile failed to show loss of bands and showed new bands in 3 of 6 patients. Histologically, strong evidence of recurrent PBC was found in 2 patients, and findings compatible with PBC were present in 1 additional patient. All 6 patients are doing well, without symptoms of recurrent PBC (median time post-LLT, 35.5 months; range, 12 to 50 months).
Liver transplantation for hereditary hemochromatosis
Authors: Brandhagen David J.
Published: August 2002

Although hereditary hemochromatosis (HHC) is relatively common, it is an uncommon indication for orthotopic liver transplantation (OLT). The diagnosis of HHC in patients with end-stage liver disease is difficult because many of these patients have elevated serum and tissue iron levels. Of patients undergoing OLT with iron stores in the range typical for HHC, approximately 10% are homozygous for the C282Y mutation. Most studies published to date noted decreased survival in patients who underwent OLT for HHC compared with those who underwent OLT for other indications. Death in patients with HHC was caused by increased infectious and cardiac complications. Decreased post-OLT survival in patients with iron overload appears to be independent of HFE gene status. This suggests that regardless of the cause, iron overload may be detrimental in patients undergoing OLT. Follow-up of patients undergoing OLT for HHC and case reports of the inadvertent transplantation of a liver from a donor with HHC has furthered our understanding of the pathophysiological state of iron overload in HHC.
Influence of extracorporeal porcine liver perfusion on nonhuman primates: Minimizing hemolysis improves subsequent survival
Authors: Nishitai Ryuta , Ikai Iwao , Terajima Hiroaki , Kanazawa Akiyoshi , Takeyama Osamu , Uesugi Takehiko , Okabe Hiroshi , Katsura Nagato , Matsushita Takakazu , Yamanokuchi Satoshi , Matsuo Koichi , Sugimoto Shinichi , Shiotani Tomohiro , Yamaoka Yoshio
Published: August 2002

The aim of this study is to detect and analyze risk factors of direct cross-circulation between porcine liver and nonhuman primates before a clinical application of extracorporeal liver perfusion (ECLP) as a liver-assist method. Porcine livers were perfused with baboon blood in an ECLP system. Six healthy baboons were directly connected to the ECLP system with continuous prostaglandin E1 administration. Cross-circulation was terminated in the following circumstances: (1) hepatic arterial or portal perfusion pressures elevated to 200 or 60 mm Hg, respectively; (2) massive exudative bleeding from the graft surface; or (3) bile output decreased to less than 5 μL/h/g of liver weight. In case 1, cross-circulation was continued for 10 hours. Severe macroscopic hemolysis occurred, and serum hemoglobin (s-Hb) concentration reached a peak of 47 mg/dL. The baboon died of acute renal failure 2 days later. Histological study of the perfused porcine liver showed marked microthrombi formation. In 3 of the later 5 cases, cross-circulation was discontinued when mild macroscopic hemolysis was observed. The duration of the 5 cross-circulations was maximally 6 hours (mean, 4.4 ± 1.2 [SD] hours). Mean s-Hb concentration in the 5 cases was elevated to 14.8 ± 5.8 mg/dL at the end of cross-circulation and decreased to the baseline level within 24 hours. These 5 baboons survived without organ dysfunction or immunologic disturbance. When severe hemolysis is avoided, direct cross-circulation using the ECLP system can be achieved without serious complications in nonhuman primates.
Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease
Authors: Charlton Michael , Kasparova Pavla , Weston Shiobhan , Lindor Keith , Maor-Kendler Yaakov , Wiesner Russell H. , Rosen Charles B. , Batts Kenneth P.
Published: August 2002

Although nonalcoholic steatohepatitis (NASH) has generally been considered a benign condition, the increasing prevalence and severity of obesity has heightened concerns about the frequency with which NASH progresses to end-stage liver disease. The aim of this study is to determine the frequency, clinical features, and posttransplantation history of decompensated liver disease secondary to NASH. The frequency of NASH as a cause of end-stage liver disease was prospectively determined in patients evaluated for liver transplantation. NASH was considered to be the primary cause of liver disease in patients who had histological evidence of steatohepatitis and in whom chronic liver diseases other than NASH were excluded. Posttransplantation histological characteristics were also determined in patients with NASH and compared with those of patients with pretransplantation diagnoses of cholestatic liver diseases, alcoholic disease, and hepatitis C. Of 1,207 patients evaluated for liver transplantation during the study period, 31 patients (2.6%) had NASH as the primary cause of liver disease. In the same period, 546 liver transplantations were performed, 16 of which (2.9%) were for end-stage disease secondary to NASH. Posttransplantation steatosis was seen in 60% of transplant recipients with NASH versus 5% of those with cholestatic disease, 15% of those with alcoholic disease, and 15% of those with hepatitis C. Steatohepatitis recurred in 33% of transplant recipients with NASH, with progression to cirrhosis in 12.5%. NASH can progress to end-stage liver disease in a minority of affected patients and was the primary cause of liver disease in 2.9% of patients evaluated for liver transplantation at our center. Recurrence of steatosis and NASH is frequent and can be severe after liver transplantation.
Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol
Authors: Tan Henkie P. , Markowitz Jay S. , Montgomery Robert A. , Merritt William T. , Klein Andrew S. , Thuluvath Paul J. , Poordad Fred F. , Maley Warren R. , Winters Bradford , Akinci Seda B. , Gaine Sean P.
Published: August 2002

Portopulmonary hypertension (PPHTN) is no longer an absolute contraindication to orthotopic liver transplantation (OLT). The pre-OLT management of patients with PPHTN requires early diagnosis and chronic therapy with intravenous epoprostenol to decrease pulmonary vascular resistance (PVR). Close follow-up is necessary to reassess pulmonary artery pressures (PAPs) and evaluate right ventricular (RV) function. This assists in the optimal timing of OLT. Successful management also necessitates reassessment of pulmonary artery hemodynamics just before OLT, with clearly defined parameters used to determine whether to proceed. Even with the intraoperative and postoperative availability of potent pulmonary vasodilators, clinical management may be suboptimal in reducing PAP. Adequate reduction in PVR and improvement in RV function in response to chronic epoprostenol therapy may facilitate successful OLT. We present a case report and review the limited experience with this treatment.
Outcome of liver transplantation for hepatitis B: Report of a single center’s experience
Authors: Chu Chi-Jen , Fontana Robert J. , Moore Charles , Armstrong Douglas R. , Punch Jeffrey D. , Su Grace L. , Magee John C. , Merion Robert M. , Lok Anna S.F.
Published: August 2002

Results of liver transplantation (LT) for hepatitis B have improved significantly with the use of hepatitis B immune globulin (HBIG) and/or lamivudine. The aim of this study is to review the long-term outcome of patients who underwent LT for hepatitis B. Records of 41 patients who underwent LT for hepatitis B and survived 3 months or longer post-LT were reviewed. Twenty patients were administered no immunoprophylaxis or short-term intramuscular HBIG, whereas 21 patients were administered high-dose intravenous (IV) HBIG. Median post-LT follow-up in these 2 groups was 76 months (range, 4 to 155 months) and 25 months (range, 4 to 68 months), respectively. Hepatitis B recurred in 15 (75%) and 4 patients (19%) who underwent LT in the pre-HBIG and post-HBIG eras, respectively. Cumulative rates of recurrent hepatitis B at 1 and 3 years post-LT in these 2 groups were 66% and 77% and 20% and 20%, respectively (P < .001). Recurrent hepatitis B in the post-HBIG era correlated with antibody to hepatitis B surface antigen titer less than 100 IU/L. Nine patients with recurrent hepatitis B were administered lamivudine for 13 to 49 months (median, 28 months); 6 patients continued to have stable or improved liver disease, whereas 3 patients developed virological breakthrough with slow deterioration of liver disease. Long-term IV HBIG is effective in preventing recurrent hepatitis B. The risk for recurrent hepatitis B is negligible after the first year post-LT. Among patients with no virological breakthrough, lamivudine can stabilize or improve liver disease for up to 4 years in patients with recurrent hepatitis B post-LT.
The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients
Authors: Schmidt Lars E. , Rasmussen Allan , Nørrelykke Mette Rindom , Poulsen Henrik Enghusen , Hansen Bent Adel
Published: August 2002

Mycophenolate mofetil (MMF) is a prodrug immunosuppressant with a high oral bioavailability. Enterohepatic cycling of a glucuronide derivative of MMF contributes substantially to the bioavailability, but is dependent on bacterial deglucuronidation by intestinal flora. This study aims to determine whether an antibiotic regimen with activity against such organisms reduces the bioavailability of MMF by impairing enterohepatic cycling. In a prospective trial, 6 liver transplant recipients were administered MMF and a 21-day antibiotic regimen for selective bowel decontamination (SBD). Time-concentration profiles of the pharmacologically active metabolite, mycophenolic acid (MPA), were obtained during and after the SBD regimen. The bioavailability of MPA was reduced during compared with after the regimen (14.5 ± 3.5 v 21.1 ± 9.8 mg · h/mL; P = .07). The most pronounced contribution to this reduction was observed from 6 hours onward (2.4 ± 1.4 v 5.6 ± 4.4 mg · h/mL; P < .05). The presence of secondary maxima in the time-concentration profiles of MPA after, but not during, SBD indicates that enterohepatic cycling may be inhibited during SBD and restored afterward. Enterohepatic cycling may contribute 7% to 54% (mean, 29%) of the bioavailability of MPA. We conclude that the bioavailability of MMF may be reduced when SBD is used, and the reduction is likely to result from the interruption of enterohepatic cycling. This mechanism should be taken into consideration not only during SBD, but in any clinical setting combining MMF and broad-spectrum antibiotics.
Orthotopic liver transplantation using low-dose tacrolimus and sirolimus
Authors: McAlister Vivian C. , Peltekian Kevork M. , Malatjalian Dickran A. , Colohan Shannon , MacDonald Sara , Bitter-Suermann Hinrich , MacDonald Allan S.
Published: August 2002

Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r2
= 0.82 and r2
= 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.
Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation
Authors: Faust Thomas W.
Published: August 2002

Key Points
Quality of life and employment after liver transplantation
Authors: Bravata Dena M. , Keeffe Emmet B.
Published: August 2002

Key Points
Higher intracerebral concentration of tacrolimus after intermittent than continuous administration to rats
Authors: Sakamoto Yoshihiro , Makuuchi Masatoshi , Harihara Yasushi , Imamura Hiroshi , Sato Hitoshi
Published: August 2002

Neurotoxicity associated with tacrolimus after liver transplantation is a serious problem. The optimal way to administer tacrolimus to reduce neurotoxicity remains to be clarified. Three groups of rats were administered tacrolimus for 2 weeks: group C, continuous intravenous infusion (0.25, 0.5, and 1.0 mg/kg/d); group I, intermittent intravenous bolus injection twice daily (0.25, 0.5, and 1.0 mg/kg/d); and group O, oral administration twice daily (5 mg/kg/d; n = 12 each). Rats were killed either day 7 or 14 to measure whole-blood and intracerebral trough concentrations of tacrolimus. The area under the whole-blood concentration-time curve (AUC) was determined day 7. The relative risk ratio of neurotoxicity was evaluated on the basis of the brain to blood concentration ratio (Kp) and intracerebral concentration to AUC ratio (RAUC). The whole-blood concentration of tacrolimus and AUC value were greater in group C than group I. Conversely, the intracerebral concentration and Kp and RAUC values were significantly greater in group I than group C. The difference in Kp values between groups C and I significantly increased with the dose and duration of administration. Whole-blood and intracerebral concentrations in group O were similar to those at the 0.25-mg/kg/d dose in group I. In conclusion, the intracerebral concentration of tacrolimus was greater after intermittent than continuous administration of the drug. Continuous administration of tacrolimus might be more advantageous than the intermittent method to reduce the intracerebral concentration and neurotoxicity.
New venoplasty technique for the left liver plus caudate lobe in living donor liver transplantation
Authors: Sugawara Yasuhiko , Makuuchi Masatoshi , Kaneko Junichi , Ohkubo Takao , Matsui Yuichi , Imamura Hiroshi
Published: August 2002

A new technique is reported for complete venous drainage for a left liver with caudate lobe graft when a short hepatic vein and left and middle hepatic veins are located close to each other.