bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of progressive hepatitis C recurrence after liver transplantation with combination interferon plus ribavirin
Authors: Gopal Deepak V. , Rabkin John M. , Berk Brian S. , Corless Christopher L. , Chou Sunwen , Olyaei Ali , Orloff Susan L. , Rosen Hugo R.
Published: March 2004

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is common, although the majority of cases are mild. A subset of transplant recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety and efficacy of antiviral treatment in this group of patients. The aim of this study is to review our experience in the treatment of moderate to severe HCV recurrence with combination interferon-α2b and ribavirin (IFN/RIB). Between October 1993 and October 1999, a total of 197 patients underwent OLT for HCV-related liver failure. This study describes 12 transplant recipients with moderate to severe recurrence treated with IFN/RIB. All patients met at least 1 of the following inclusion criteria: (1) moderate to severe inflammation (grade III to IV) on allograft biopsy, (2) bridging fibrosis on allograft biopsy, or (3) severe cholestasis attributable solely to HCV recurrence. Two patients had undergone re-OLT for allograft cirrhosis secondary to HCV recurrence and now had evidence of progressive HCV in their second allografts. Appropriate dose reductions of both IFN and RIB, as well as initiation of granulocyte colony-stimulating factor (G-CSF), for marked leukopenia were recorded. IFN/RIB therapy was started 60 to 647 days post-OLT, and duration of therapy ranged from 39 to 515 days. Seven patients were administered G-CSF to successfully treat leukopenia. Six of the 12 patients (50%) became HCV RNA negative by polymerase chain reaction. One of these 6 patients (no. 1) was HCV RNA negative at 6 months but chose to discontinue therapy because of intolerable side effects, experienced a relapse, and was HCV RNA positive at 12 months. Two of the remaining 5 patients were HCV RNA negative at 2 and 9 months off therapy. For the entire group, there was a statistically significant decrease in serum biochemical indices assessed at initiation of therapy and 1, 3, and 6 months into therapy. Most patients required dose reductions of both IFN and RIB. Five patients died; 3 patients died of liver-related complications that included severe intrahepatic biliary cholestasis, severe HCV recurrence, and chronic rejection with profound cholestasis. In the subset of HCV-positive liver transplant recipients with moderate to severe recurrence, combination IFN/RIB therapy resulted in complete virological response (serum RNA negative) in 6 of 12 patients (˜50%). However, only 1 of 12 patients (8.3%) had sustained virological clearance after cessation of IFN/RIB therapy. Dose reductions of both IFN and RIB were required in most patients. The use of G-CSF (sometimes preemptively) allowed correction of leukopenia and full-dose antiviral therapy. Multicenter trials using combination therapy to identify factors predictive of response are needed in the subset of patients with progressive allograft injury.
Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation
Authors: Jonsson Julie R. , Hong Cui , Purdie David M. , Hawley Carmel , Isbel Nicky , Butler Maree , Balderson Glenda A. , Clouston Andrew D. , Pandeya Nirmala , Stuart Katherine , Edwards-Smith Catherine , Crawford Darrell H. , Fawcett Jonathon , Powell Elizabeth E.
Published: March 2004

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-β, interleukin-10, and tumor necrosis factor α (TNF-α) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P = .001), immune-mediated liver disease (P = .018), normal pre-OLT creatinine clearance (P = .037), and fewer HLA class 1 mismatches (P = .038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P = .001), pre-OLT renal dysfunction (P = .0001), and a diagnosis of viral hepatitis (P = .0008). There was a significant difference in the frequency of TNF-α-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-α-308 polymorphism and graft rejection approached significance (P = .06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.
Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function
Authors: Emre Sukru , Gondolesi Gabriel , Polat Kamil , Ben-Haim Menahem , Artis Tarik , Fishbein Thomas M. , Sheiner Patricia A. , Kim-Schluger Leona , Schwartz Myron E. , Miller Charles M.
Published: March 2004

The addition of daclizumab (a human immunoglobulin G1 monoclonal antibody that blocks interleukin-2 receptors on T lymphocytes) to mycophenolate mofetil (MMF) and steroids is a new option for initial immunosuppression in patients undergoing liver transplantation (LT) with impaired renal function. We evaluated the efficacy and safety of daclizumab in preventing rejection in 25 patients with impaired kidney function undergoing LT. Patients with serum creatinine (Cr) levels greater than 2 mg/dL immediately before LT were administered initial immunosuppression with daclizumab, 1 mg/kg, in addition to MMF, 2 g/d, and methylprednisolone. Tacrolimus was added after kidney function improved (when Cr levels improved by >25% of initial value). Daclizumab-treated patients were compared retrospectively with 2 other groups of patients who underwent LT with kidney impairment (Cr > 2 mg/dL): 56 patients were administered OKT3 induction, and 48 patients were administered low-dose tacrolimus. The incidence of rejection and infection (bacterial, fungal, and viral), need for preoperative and postoperative dialysis, Cr level immediately post-LT and at 3 months, and graft and patient survival were analyzed. There was no difference among the groups in 3-month Cr levels or the incidence of rejection or fungal or viral infection. The daclizumab group had fewer bacterial infections (n = 13) than the tacrolimus group (n = 28) and significantly fewer than the OKT3 group (n = 58; P = .006). Only 1 patient (4%) in the daclizumab group required dialysis post-LT versus 13 patients in each of the other groups (OKT3, 23.21%; P < .05; tacrolimus, 27%). In the daclizumab group, 2-year patient and graft survival rates were statistically significant compared with the low-dose tacrolimus group (89% and 81% v 73% and 69%, respectively; P = .06). There were no side effects related to daclizumab use, and all patients tolerated the drug well. In patients with impaired renal function before LT, daclizumab-based initial immunosuppression can be used safely to reduce the risk for infection and need for dialysis post-LT, with improved long-term graft and patient survival.
Prognostic model for early acute rejection after liver transplantation
Authors: Gómez-Manero Noemí , Herrero Ignacio J. , Quiroga Jorge , Sangro Bruno , Pardo Fernando , Cienfuegos Javier A. , Prieto Jesús
Published: March 2004

Hepatic graft rejection is a common complication after liver transplantation (LT), with a maximum incidence within the first weeks. The identification of high-risk patients for early acute rejection (EAR) might be useful for clinicians. A series of 133 liver graft recipients treated with calcineurin inhibitors was retrospectively assessed to identify predisposing factors for EAR and develop a mathematical model to predict the individual risk of each patient. The incidence of EAR (≤45 days after LT) was 35.3%. Multivariate analysis showed that recipient age, underlying liver disease, and Child’s class before LT were independently associated with the development of EAR. Combining these 3 variables, the following risk score for the development of EAR was obtained: EAR score [F(x)] = 2.44 + (1.14 × hepatitis C virus cirrhosis) + (2.78 × immunologic cirrhosis) + (2.51 × metabolic cirrhosis) − (0.08 × recipient age in years) + (1.65 × Child’s class). Risk for rejection = eF(x)/1 + eF(x). The combination of age, cause of liver disease, and Child’s class may allow us to predict the risk for EAR.
Morbidity and mortality associated with large-bore percutaneous venovenous bypass cannulation for 312 orthotopic liver transplantations
Authors: Budd Joanna M. , Isaac John L. , Bennett James , Freeman Jonathan W.
Published: March 2004

The aim of this study is to establish the incidence of serious morbidity and mortality associated with the placement of large-bore (18 to 20 F) percutaneous bypass cannulae for venovenous bypass (VVBP) during orthotopic liver transplantation (OLT). This technique has been reported to be rapid, simple, and safe. We reviewed the case notes of 312 patients who underwent OLT in our center using this technique. We describe 4 cases of serious morbidity (incidence, 1.28%) and 1 death (incidence, 0.32%) related directly to percutaneous placement of the bypass cannula. We conclude that percutaneous cannula placement for VVBP during OLT has the potential for life-threatening complications, and this must be considered when electing to use this technique. When percutaneous cannulae are to be used, we recommend the use of the right internal jugular vein for return cannulation and the use of ultrasound guidance, particularly in those patients in whom cannulation is predictably difficult.
Adult living donor liver transplantation: Preferences about donation outside the medical community
Authors: Cotler Scott J. , McNutt Robert , Patil Raj , Banaad-Omiotek Geraldine , Morrissey Mary , Abrams Richard , Cotler Sheldon , Jensen Donald M.
Published: March 2004

An increasing number of transplant centers are performing adult living donor liver transplantation (LDLT). We evaluated peoples’ perspectives on possible outcomes of living donation, thresholds for donating, and views regarding the donation process. One hundred fifty people were surveyed; half were from a medical care group serving an indigent population and half were from a private clinic. Preferences about outcomes of adult living donation were ranked and quantified on a visual analogue scale. Thresholds for donation to a loved one were quantified. Sixty percent of the respondents suggested they would prefer to donate and die and have the transplant recipient live rather than forgo donation and have the potential transplant recipient die of liver failure. Participants’ stated threshold for living donation was a median survival for themselves of only 79%. They would require that their loved one have a median survival of 55% with transplantation before they would agree to donate. Respondents from the medical care group reported higher survival thresholds for themselves and the transplant recipient, and race was the most statistically significant predictor of those thresholds. Sex was more predictive of threshold probabilities from the private clinic. Eighty-one percent of the respondents believed that the potential donor, not a physician, should have the final say regarding candidacy for living donation. In conclusion, the findings of this survey support the use of adult LDLT. Most respondents were willing to accept mortality rates that far exceed the estimated risk of donation and favored outcomes in which a loved one was saved.
Living related liver transplantation in biliary atresia with absent inferior vena cava
Authors: Srinivasan Parthi , Bowles Matthew J. , Muiesan Paolo , Heaton Nigel D. , Rela Mohamed
Published: March 2004

The success of the triangulation technique for hepatic venous anastomosis in left lateral segment liver transplantation has led to standardization of this procedure. We report a case of syndromic biliary atresia with absent inferior vena cava in which we constructed a neo cava to implant a living related left lateral segment graft by using the triangulation technique.
Immune response to influenza vaccine in adult liver transplant recipients
Authors: Duchini Andrea , Hendry Michael R. , Nyberg Lisa M. , Viernes Eric M. , Pockros Paul J.
Published: March 2004

Influenza virus infection may cause significant complications in liver transplant recipients, and whether vaccination is effective in these patients is controversial. We performed a study to assess the immune response to influenza vaccine in liver transplant recipients and patients with cirrhosis compared with healthy controls. Liver transplant recipients (n = 20), patients with compensated cirrhosis awaiting transplantation (n = 14), and healthy volunteers (n = 9) were administered the standard dose of the 1999 to 2000 inactivated trivalent vaccine (A/Bejing/262/95[H1N1]; A/Sidney/5/97[H3N2]; B/Yamanashi/166/98). Antibody responses to each component of the vaccine were measured at baseline and after 6 weeks by hemagglutination inhibition. Vaccination was well tolerated, and no major side effects were observed. A significant postvaccination increase in antibody titer to all 3 vaccine components was obtained in all groups. However, liver transplant recipients had significantly lower postvaccination geometric mean titers and geometric mean increases to the H3N2 component compared with patients with cirrhosis and controls. The rate of seroconversion to H3N2 after vaccination was also significantly lower in liver transplant recipients (15% v 89%). We conclude that liver transplant recipients have a significantly impaired immune response to the influenza vaccine, and some patients may remain unprotected from influenza infection after vaccination. Further studies of modified protocols of influenza vaccination for these patients are recommended.
Modulation of steady-state messenger RNA levels in the regenerating rat liver with bile acid feeding
Authors: Kren Betsy T. , Rodrigues Cecilia M.P. , Setchell Kenneth D.R. , Steer Clifford J.
Published: March 2004

Liver regeneration after two thirds partial hepatectomy (PH) is an orchestrated hyperplastic growth process requiring coordinated expression of many genes. The synchronous progression of 95% of the remnant hepatocytes through the cell cycle provides an in vivo model for examining the influence of bile acids on the molecular regulation of hepatocyte replication and growth. In this study, we examined the effects of endogenous deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on messenger RNA (mRNA) expression and growth rate during liver regeneration. Rats were fed diets containing no addition, 0.4% DCA, UDCA, or both for 14 days; they then underwent 70% PH and were maintained on the diets for an additional 14 days. mRNA transcript levels for a variety of cell cycle-regulated genes were examined post-PH by Northern blot analysis. Bile acid concentrations were determined in liver, isolated nuclei, and plasma by gas chromatography and mass spectrometry. The results indicated that the addition of DCA and UDCA to the diet markedly shifted the bile-acid compositions of liver and plasma. In addition, DCA dramatically altered the abundance of many transcripts post-PH, whereas coadministration of UDCA suppressed the effect. DCA feeding significantly inhibited liver growth through day 3; however, by day 8, it induced an approximately 20% increase in mass compared with controls, UDCA-fed, or combination-fed animals. UDCA was concentrated greater than 20-fold in nuclei compared with whole liver in controls and DCA-fed animals and greater than 2-fold with UDCA feeding. These data suggest that bile acids may have a key role in liver regeneration, which is significantly altered by modulation of the bile-acid pool.
Double-dose accelerated hepatitis B vaccine in patients with end-stage liver disease
Authors: Arslan Mehmet , Wiesner Russell H. , Sievers Corey , Egan Kathleen , Zein Nizar N.
Published: March 2004

The aims of this study are to assess the efficacy of hepatitis B virus (HBV) vaccination using an accelerated schedule and double dose of recombinant vaccine in liver transplant recipients and identify factors associated with seroconversion and persistence of antibody to hepatitis B surface antigen (anti-HBs). Three hundred fifty-six patients were enrolled. Exclusion criteria were previous HBV infection, fulminant liver failure, or less than 2 years of follow-up after orthotopic liver transplantation (OLT). The vaccination schedule was 0, 2 weeks, 4 weeks, and 6 months using double-dose recombinant vaccine. Seroconversion was evaluated prospectively by measuring anti-HBs on the day of OLT and 1 and 2 years after OLT. Quantitative analyses of anti-HBs were performed retrospectively on stored sera. Geometric mean concentrations (GMCs) were calculated using a standard formula. All patients completed the full vaccination schedule, and 129 patients (36%) completed the schedule before OLT. The overall prevalence of anti-HBs was 128 of 356 pre-OLT samples (36%) compared with 41 of 353 (11.6%) and 26 of 325 post-OLT samples (8%) 1 and 2 years after OLT, respectively (both P = .001). The pre-OLT GMC was 86.7 compared with 0.32 and 0.33 at 1 and 2 years after OLT, respectively (P = .001). Patients with high titers of anti-HBs before OLT were more likely to have persistence of antibodies 1 or 2 years after OLT. Younger age (P = .02), low Child-Pugh score (P = .02), underlying chronic hepatitis C (P= .03), and specific host HLA subtypes were most strongly associated with seroconversion and/or persistence of anti-HBs. Thus, (1) seroconversion before or after OLT using double-dose accelerated-schedule vaccination against HBV is low, (2) there is a rapid, significant decrease in antibody titer after OLT, (3) pre-OLT anti-HBs titer potentially may be useful in predicting persistence of protective antibodies after OLT, and (4) several factors (age, genetic predisposition, severity of liver disease, and underlying liver disease) may have a role in poor vaccine responsiveness.
Transcranial doppler sonography and internal jugular bulb saturation during hyperventilation in patients with fulminant hepatic failure
Authors: Strauss Gitte Irene , Møller Kirsten , Holm Søren , Sperling Bjørn , Knudsen Gitte Moos , Larsen Fin Stolze
Published: March 2004

Mechanical hyperventilation is often used to postpone or ameliorate intracranial hypertension in patients with fulminant hepatic failure (FHF). Because such treatment may critically reduce cerebral blood flow (CBF), bedside techniques to monitor CBF are warranted. In this study, we evaluated the efficacy of transcranial Doppler (TCD) sonography of the middle cerebral artery (MCA) and internal jugular bulb saturation (svJo2) to determine relative changes in CBF during mechanical hyperventilation in 8 patients with FHF (median age, 40 years; range, 20 to 54 years). We found that TCD and svJo2 decreased during hyperventilation in parallel with CBF, determined by the xenon 133 (133Xe) washout technique. Quantitatively, the TCD method was less accurate to determine carbon dioxide (co2) reactivity compared with svJo2 and the 133Xe technique. This indicates a slight change in MCA diameter during hyperventilation. We conclude that TCD and svJo2 monitoring may give valuable information on relative changes in CBF during hyperventilation. However, the TCD method appears less accurate for quantitative estimation of co2 reactivity in patients with FHF. (Liver Transpal 2001;7:352-358.)
Ischemic preconditioning of rat livers against cold storage-reperfusion injury: Role of nonparenchymal cells and the phenomenon of heterologous preconditioning
Authors: Arai Masahiro , Thurman Ronald G. , Lemasters John J.
Published: March 2004

Brief periods of ischemia followed by reperfusion render tissues resistant against subsequent prolonged ischemia, a phenomenon called ischemic preconditioning. The effect of ischemic preconditioning on liver transplantation was investigated in relation to sinusoidal endothelial cell injury and Kupffer-cell activation, which are prominent features of storage and reperfusion injury leading to liver graft failure. Rat livers were preconditioned by 5 or 10 minutes of ischemia and 5 minutes of reperfusion and stored in University of Wisconsin (UW) solution for 30 hours. Livers were then reperfused for 15 minutes with physiological buffer containing trypan blue. Under these conditions, injury occurs predominantly to sinusoidal endothelial cells, reflected by trypan blue staining of nonparenchymal cells in histological sections. Ischemic preconditioning decreased nonparenchymal cell killing by more than 50%. When half the liver was preconditioned, sinusoidal endothelial cells were also protected in the contralateral half. Other stored livers were reperfused with nitroblue tetrazolium, which is converted to insoluble formazan by superoxide radicals. Ischemic preconditioning decreased the intensity of formazan deposition over Kupffer cells. Finally, stored livers were transplanted into nontreated rats. Ischemic preconditioning improved recipient long-term survival after 30 hours of cold ischemic storage in UW solution from 30% to 80% and decreased serum tumor necrosis factor-α levels in posthepatic blood 4 hours postoperatively from 98 to 54 pg/mL. In conclusion, ischemic preconditioning protects sinusoidal endothelial cells and suppresses Kupffer-cell activation after storage and reperfusion. As a result, graft survival improves after liver transplantation. Moreover, ischemia to half the liver confers protection to the other half. Such heterologous preconditioning provides a new means to protect liver tissue against ischemia-reperfusion injury without imposing ischemia on the target tissue.
Recurrent autoimmune hepatitis after liver transplantation: Diagnostic criteria, risk factors, and outcome
Authors: Hübscher Stefan G.
Published: March 2004

Approximately 20% to 30% of patients undergoing liver transplantation for autoimmune hepatitis (AIH) develop features of recurrent disease. Diagnostic criteria for recurrent AIH are similar to those used in the nontransplanted liver and include, in varying combinations, biochemical, serological, and histological abnormalities and steroid dependency. However, these criteria are more difficult to apply in the liver allograft because of potential interactions between recurrent AIH and other complications of liver transplantation, particularly rejection, and the uncertain effects of long-term immunosuppression. In the absence of other reliable diagnostic markers, a number of studies have used the histological finding of chronic hepatitis as the main or sole criterion for diagnosing recurrent AIH. However, this also lacks diagnostic specificity because there are many other possible causes of chronic hepatitis in the liver allograft. In addition, approximately 20% to 40% of biopsies performed on patients as part of routine annual review have histological features of chronic hepatitis, for which no definite cause can be identified. Risk factors that have been associated with the development of recurrent AIH include suboptimal immunosuppression, HLA phenotype, disease type and severity in the native liver, and duration of follow up. In many cases in which recurrent AIH seems to be related to underimmunosuppression, biochemical and histological features rapidly resolve once adequate immunosuppression is restored. However, in other cases, recurrent AIH behaves more aggressively, with progression to cirrhosis and graft failure. Areas that require further study include developing uniform criteria for the diagnosis of recurrent AIH, identifying risk factors for severe recurrent disease, and determining optimal levels of immunosuppression that minimize the impact of disease recurrence without exposing patients to the risks of overimmunosuppression.
Improved survival with screening for hepatocellular carcinoma
Authors: Wong Linda L. , Limm Whitney M. , Severino Richard , Wong Livingston M.
Published: March 2004

Hepatocellular cancer (HCC) is a frequent cause of cancer death worldwide. Although successful screening programs exist in Asian countries, the role for screening in the United States is not clear. The purpose of this study is to determine if screening has an effect on survival in a predominantly Asian population in Hawaii. We retrospectively reviewed cases of HCC from 1993 to 1998 for demographic data, risk factors, symptoms, stage, treatment, and survival. Patients were divided into 3 groups according to presentation: symptomatic (S), asymptomatic (A), and asymptomatic but screened for disease (A/Sc). Kaplan-Meier analysis was performed on overall survival by group. Ninety-one patients were referred for HCC. There were 56 patients in group S, 19 patients in group A, and 16 patients in group A/Sc. Patients in group A/Sc survived significantly longer than those in group S (P= .009), with the former group having a median survival of 1,399 versus 234 days for group S. Median survival for group A was 545 days and did not differ significantly from the other groups. Patients who are asymptomatic and screened for HCC have an increased survival compared with those patients who present with symptoms. This may justify the use of a formal screening program for HCC in Hawaii, but we would need to investigate this prospectively.
Biliary stenting versus bypass surgery for the palliation of malignant distal bile duct obstruction: A meta-analysis
Authors: Taylor Mark C. , McLeod Robin S. , Langer Bernard
Published: March 2004

The objective of this analysis is to compare endoscopic stenting with surgical bypass in patients with unresectable, malignant, distal common bile duct obstruction using the technique of meta-analysis. The inclusion criteria for the studies were randomized patient assignment, publication in the English language, 20 or more patients per group, all patients followed up until death, and follow-up and complications reported in an equivalent way for both treatment arms. Data extraction was performed independently by 2 of the authors. The number of treatment failures, serious complications, requirement for additional treatment sessions, and 30-day mortality were extracted. Three existing trials met the inclusion criteria, all of which compared surgery with the use of plastic stents. There were no studies identified that used metallic expandable stents. For the rate of treatment failure and serious complications, the odds ratios (ORs) of the 3 trials were heterogeneous, and no summary ORs were calculated. More treatment sessions were required after stent placement than after surgery, and a common OR was estimated to be 7.23 (95% confidence interval [CI], 3.73 to 13.98). Thirty-day mortality was not significantly different (OR = 0.522; 95% CI, 0.263 to 1.036). Although surgical bypass required fewer additional treatment sessions, existing data do not allow a definitive conclusion on which treatment is preferable. A larger randomized controlled trial using newer metallic stents and proper quality-of-life instruments is required.
Health-related quality of life in long-term survivors of pediatric liver transplantation
Authors: Midgley Deborah E. , Bradlee Tatum A. , Donohoe Christopher , Kent Kevin P. , Alonso Estella M.
Published: March 2004

The purpose of this study is to measure the health-related quality of life (HRQOL) in children who are long-term survivors of liver transplantation and to pilot the Liver Transplant Disability Scale (LTDS), a newly developed 12-point scale that quantifies chronic medical disability related to liver transplantation. This study is a cross-sectional survey of 51 children surviving liver transplantation by at least 2 years, with a median age of 4.94 years. Functional capacity and utility scores were measured by the Health Utilities Index Mark II (HUI2), and chronic disease-specific medical disability was measured by the LTDS. HUI2 results were compared with a reference population. LTDS scores were compared with utility scores and patient survival 3 years later. Ninety percent of the study patients had functional deficits compared with 50% of controls. Functional impairment was typically mild. The resulting mean utility score, 0.86 ± 0.13 (0 = dead, 1 = perfect health), was significantly less than that of the reference population, 0.95 ± 0.07 (P < .001). LTDS scores ranged from 0 (no disability) to 6 (moderate disability). Seventy-one percent of the children had mild disability (scores 0 to 3), and 29% had moderate disability (scores 4 to 6). LTDS scores did not correlate with utility scores but were predictive of survival. The majority of pediatric liver transplant recipients have mild functional deficits. Their utility scores reflected a high level of HRQOL but were significantly less than those of a reference population. The majority also had mild medical disability, predominantly delayed growth. Medical disability did not correlate with HRQOL but predicted survival 3 years later.
Erythropoietin response to post-liver transplantation anemia
Authors: Vasilopoulos Sotirios , Hally Robert , Caro Jaime , Martin Paul , Westerberg Sharon , Moritz Michael , Jarrell Bruce , Muñoz Santiago
Published: March 2004

Anemia frequently accompanies end-stage liver disease. Erythropoietin has recently been shown to be of benefit in a number of diseases complicated by anemia. We studied erythropoietin levels before and after orthotopic liver transplantation (OLT) and correlated these with the degree of anemia. Twenty-seven patients with end-stage cirrhosis who underwent OLT had preoperative and weekly postoperative serum erythropoietin levels determined by a highly sensitive radioimmunoassay. The relation of erythropoietin level to the values for hematocrit, serum creatinine, and cyclosporine and other biochemical test results was evaluated. Before transplantation, 23 patients were anemic; erythropoietin levels were appropriately elevated (72.7 ± 37 mU/mL; normal, 10 to 15 mU/mL) for the degree of anemia (hematocrit, 33.1% ± 1%) in 16 patients (70%). A blunted erythropoietin response to anemia was found in 7 of the anemic patients with cirrhosis (30%). After OLT, the hematocrit decreased to 29.5% ± 0.6% at 4 weeks, with a reciprocal increase in serum erythropoietin levels to 36 ± 5 mU/mL. Erythropoietin response appeared appropriate to the degree of anemia in 82% of the liver transplant recipients and blunted in 18%. We conclude that the ability to secrete erythropoietin in response to anemia is defective in many patients with end-stage liver disease, and a normal response may be restored after OLT. The results suggest that exogenous erythropoietin administration may be beneficial in anemic patients with cirrhosis and liver transplant recipients who have inappropriately low serum erythropoietin levels.
Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma
Authors: De Vreede Ilja , Steers Jeff L. , Burch Patrick A. , Rosen Charles B. , Gunderson Leonard L. , Haddock Michael G. , Burgart Lawrence , Gores Gregory J.
Published: March 2004

Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.
Liver transplantation for hereditary transthyretin amyloidosis
Authors: Suhr Ole B. , Herlenius Gustav , Friman Styrbjörn , Ericzon Bo-Göran
Published: March 2004

Transthyretin (TTR) amyloidosis is the most common form of hereditary amyloidosis. It is a systemic amyloidosis caused by an amyloidogenic variant TTR (ATTR), of which the methionine for valine at position 30 (ATTR Val30Met) gives rise to a fatal neuropathic amyloidosis. Because more than 95% of TTR is produced by the liver, a liver transplantation should abolish the liver’s production of amyloidogenic mutant TTR and thereby halt amyloid formation. The first liver transplantation for hereditary TTR amyloidosis was performed in Sweden in 1990 on a patient with ATTR Val30Met amyloidosis, and the result was encouraging. Today, liver transplantation for TTR amyloidosis is an established treatment. However, the disease is rarely seen except in a few endemic areas; therefore, most transplantation centers only receive a few cases. Because the disease phenotype varies with different TTR mutations and variability is even encountered for the same mutation, an evaluation of patients for transplantation must include an investigation of all organs that may be affected by the disease and may impact on the morbidity and mortality of the procedure. The aim of this review is to present the results of liver transplantation for TTR amyloidosis and give recommendations for patient evaluation and selection based on the literature and our experience with the disease.
Skin cancer in liver transplant recipients
Authors: Otley Clark C. , Pittelkow Mark R.
Published: March 2004

Skin cancer is the most common malignancy arising in the posttransplantation setting. Multiple factors contribute to the high risk for cutaneous carcinoma in immunosuppressed organ-transplant recipients. We review the phenomenon of skin cancer in solid-organ transplant recipients and further delineate the problem in the context of liver transplantation. Skin cancer is a significant medical and surgical problem for organ-transplant recipients. With prolonged allograft function and patient survival, the majority of solid-organ transplant recipients will eventually develop skin cancer. Although squamous cell carcinoma is the most common cutaneous malignancy in this population, basal cell carcinoma, melanoma, and Kaposi’s sarcoma, as well as uncommon skin malignancies, may occur. Highly susceptible patients may develop hundreds of squamous cell carcinomas, which may be life threatening. Management strategies focus on regular full-skin and nodal examination, aggressive treatment of established malignancies, and prophylactic measures to reduce the risk for additional photodamage and malignant transformation. Skin cancer is a substantial cause of morbidity and even mortality among solid-organ transplant recipients. As a byproduct of immunosuppression, liver transplant recipients experience a high incidence of skin cancer and should be educated and managed accordingly.
Convergence of the natural approximations of piecewise monotone interval maps
Authors: Haydn Nicolai
Published: March 2004

We consider piecewise monotone interval mappings which are topologically mixing and satisfy the Markov property. It has previously been shown that the invariant densities of the natural approximations converge exponentially fast in uniform pointwise topology to the invariant density of the given map provided its derivative is piecewise Lipshitz continuous. We provide an example of a map which is Lipshitz continuous and for which the densities converge in the bounded variation norm at a logarithmic rate. This shows that in general one cannot expect exponential convergence in the bounded variation norm. Here we prove that if the derivative of the interval map is Hölder continuous and its variation is well approximable (γ-uniform variation for γ>0), then the densities converge exponentially fast in the norm.
Boolean networks with variable number of inputs (K)
Authors: Skarja Metod , Remic Barbara , Jerman Igor
Published: March 2004

We studied a random Boolean network model with a variable number of inputs K per element. An interesting feature of this model, compared to the well-known fixed-K networks, is its higher orderliness. It seems that the distribution of connectivity alone contributes to a certain amount of order. In the present research, we tried to disentangle some of the reasons for this unexpected order. We also studied the influence of different numbers of source elements (elements with no inputs) on the network’s dynamics. An analysis carried out on the networks with an average value of K=2 revealed a correlation between the number of source elements and the dynamic diversity of the network. As a diversity measure we used the number of attractors, their lengths and similarity. As a quantitative measure of the attractors’ similarity, we developed two methods, one taking into account the size and the overlapping of the frozen areas, and the other in which active elements are also taken into account. As the number of source elements increases, the dynamic diversity of the networks does likewise: the number of attractors increases exponentially, while their similarity diminishes linearly. The length of attractors remains approximately the same, which indicates that the orderliness of the networks remains the same. We also determined the level of order that originates from the canalizing properties of Boolean functions and the propagation of this influence through the network. This source of order can account only for one-half of the frozen elements; the other half presumably freezes due to the complex dynamics of the network. Our work also demonstrates that different ways of assigning and redirecting connections between elements may influence the results significantly. Studying such systems can also help with modeling and understanding a complex organization and self-ordering in biological systems, especially the genetic ones.
Effects of Stress on Alcohol Consumption in Rats Selectively Bred for High or Low Alcohol Drinking
Authors: Chester Julia A. , Blose Annette M. , Zweifel Mark , Froehlich Janice C.
Published: March 2004

Abstract: Background: Stress has long been thought to influence the initiation and maintenance of alcohol drinking in humans. However, results of studies in animals suggest that the relationship between stress and alcohol drinking is not well understood. The purpose of this study was to examine the effect of unpredictable and uncontrollable restraint stress on alcohol consumption in two sets of rat lines selectively bred for alcohol preference (P) and high alcohol drinking (HAD1) and for alcohol nonpreference (NP) and low alcohol drinking (LAD1).

Methods: Male P (n= 26) and NP (n= 26) and HAD1 (n= 17) and LAD1 (n= 20) rats were counterbalanced on the basis of alcohol intake and assigned, in matched pairs, to either a stress (Stress) or a no‐stress (Control) group. All rats were given a free choice between a 10% v/v alcohol solution and water, with food freely available. Unpredictable, uncontrollable stress, which consisted of immobilization in a nylon restraint sleeve for 30 to 120 min/day, was applied for 10 consecutive days.

Results: Stress moderately reduced alcohol intake in both P and HAD1 rats versus controls and had no effect on alcohol intake in either the NP or the LAD1 rats during the 10 days of stress application. Alcohol intake was increased for the first 5 days after stress termination in P rats but not in HAD1 rats. Alcohol intake remained stable for several weeks in both the NP and LAD1 lines after stress termination and then increased during the last 15 days of the 35‐day poststress period in NP rats, but not in LAD1 rats.

Conclusions: A reduction in alcohol intake during stress in rats with a genetic predisposition toward high alcohol intake seems to be a moderate but consistent finding, whereas an increase in alcohol intake after stress termination is less consistent and may be influenced by genetic background.
Possible Interaction of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Genes With the Dopamine D2 Receptor Gene in Anxiety‐Depressive Alcohol Dependence
Authors: Huang San‐Yuan , Lin Wei‐Wen , Ko Huei‐Chen , Lee Jia‐Fu , Wang Tso‐Jen , Chou Yuan‐Hwa , Yin Shih‐Jiun , Lu Ru‐Band
Published: March 2004

Abstract:Background:The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, theADH1BandALDH2genes might be involved in dopamine metabolism. We hypothesized that theADH1BandALDH2genes might interact with theDRD2gene and that the association between theDRD2gene and alcohol dependence might be affected by differentADH1BandALDH2genotypes. This study examined whether theDRD2gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between theDRD2gene and alcohol‐metabolizing genes in a specific subtype of alcohol dependence.

Methods:Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety‐depression (ANX/DEP ALC), and 129 with anxiety‐depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and Schizophrenia‐Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM‐IV criteria.

Results:TheDRD2gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between theDRD2gene and ANX/DEP ALC was shown to be under the control of theALDH2*1/*1andADH1B*1/*2genotypes.

Conclusions:ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with theDRD2gene only under the stratification ofADH1B*1/*2orALDH2*1/*1, theDRD2gene might interact with theADH1Bgene and theALDH2gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population.
Alcohol Affects Eye Movements Essential for Visually Guided Stepping
Authors: Crowdy K. A. , Marple‐Horvat D. E.
Published: March 2004

Abstract: Background: To understand how and why alcohol intoxication affects visually guided stepping, the eye movements and performance of 6 subjects (aged 22–35 years) were monitored as they progressed along a pathway of 18 irregularly placed stepping stones before and after consumption of an acute oral dose of alcohol.

Methods: Horizontal eye movements were measured with infrared reflectometry; footfall on or off target was monitored via copper fabric soles stuck to subjects’ footwear. Breath alcohol concentration was monitored with an Alco‐Sensor III breathalyzer.

Results: After alcohol loading, both locomotor and oculomotor deficits were evident. All subjects increased their step cycle duration—with prolonged stance, swing, and double support phases—and occasionally missed footfall targets. A large proportion of saccades made to fixate successive stepping stones were inaccurate and were accompanied by one or more corrective saccades. These problems with looking and stepping to footfall targets tended to occur together and were comparable to those seen previously in cerebellar patients undertaking the same task.

Conclusions: The fact that healthy subjects acutely intoxicated by alcohol show symptoms of cerebellar dysfunction suggests that alcohol acutely and adversely affects the cerebellar contribution to performance of visually guided movements.
Using Alcohol Screening Results and Treatment History to Assess the Severity of At‐Risk Drinking in Veterans Affairs Primary Care Patients
Authors: Bradley Katharine A. , Kivlahan Daniel R. , Zhou Xiao‐Hua , Sporleder Jennifer L. , Epler Amee J. , McCormick Kinsey A. , Merrill Joseph O. , McDonell Mary B. , Fihn Stephan D.
Published: March 2004

Abstract: Background: Primary care providers need practical methods for managing patients who screen positive for at‐risk drinking. We evaluated whether scores on brief alcohol screening questionnaires and patient reports of prior alcohol treatment reflect the severity of recent problems due to drinking.

Methods: Veterans Affairs general medicine outpatients who screened positive for at‐risk drinking were mailed questionnaires that included the Alcohol Use Disorders Identification Test (AUDIT) and a question about prior alcohol treatment or participation in Alcoholics Anonymous (“previously treated”). AUDIT questions 4 through 10 were used to measure past‐year problems due to drinking (PYPD). Cross‐sectional analyses compared the prevalence of PYPD and mean Past‐Year AUDIT Symptom Scores (0–28 points) among at‐risk drinkers with varying scores on the CAGE (0–4) and AUDIT‐C (0–12) and varying treatment histories.

Results: Of 7861 male at‐risk drinkers who completed questionnaires, 33.9% reported PYPD. AUDIT‐C scores were more strongly associated with Past‐Year AUDIT Symptom Scores than the CAGE (p < 0.0005). The prevalence of PYPD increased from 33% to 46% over the range of positive CAGE scores but from 29% to 77% over the range of positive AUDIT‐C scores. Among subgroups of at‐risk drinkers with the same screening scores, patients who reported prior treatment were more likely than never‐treated at‐risk drinkers to report PYPD and had higher mean Past‐Year AUDIT Symptom Scores (p < 0.0005). We propose a simple method of risk‐stratifying patients using AUDIT‐C scores and alcohol treatment histories.

Conclusions: AUDIT‐C scores combined with one question about prior alcohol treatment can help estimate the severity of PYPD among male Veterans Affairs outpatients.