bluuebunny/crossref_metadata_2025 huggingface dataset:
Autocrine Motility Factor Enhances Hepatoma Cell Invasion Across the Basement Membrane Through Activation of β1 Integrins
Authors: Torimura Takuji , Ueno Takato , Kin Motoaki , Harada Riko , Nakamura Toru , Kawaguchi Takumi , Harada Masaru , Kumashiro Ryukichi , Watanabe Hideomi , Avraham Raz , Sata Michio
Published: August 2002

Autocrine motility factor/phosphohexose isomerase (AMF/PHI) is a cytokine that is linked to tumor invasion and metastasis. In hepatocellular carcinoma (HCC) tissues, hepatoma cells produce AMF/PHI and its receptor, Mr 78,000 glycoprotein (gp78), is strongly detected in hepatoma cells invading into the stroma and tumor thrombi in the portal vein. Here, we investigated the mechanism of hepatoma cell invasion through Matrigel induced by AMF/PHI using 3 hepatoma cell lines. Production of AMF/PHI, phosphorylation of MEK1/2, and Rho activity were investigated by immunoblotting. Expression of AMF/PHI and gp78 was observed by confocal fluorescence microscopy. The influence of AMF/PHI on activated integrin β1 subunit expression was evaluated by flow cytometry. Changes in invasion, adhesion, and motility induced by AMF/PHI were evaluated using chemoinvasion, adhesion, and phagokinetic track motility assays. The effect of AMF/PHI on matrix metalloproteinase (MMP) secretion was evaluated by gelatin zymography. Hepatoma cells produced AMF/PHI and expressed gp78. Although AMF/PHI was ubiquitously detected, gp78 was strongly expressed in migrating cells. AMF/PHI induced up–regulation of activated integrin β1 subunit expression. AMF/PHI stimulated hepatoma cell invasion through Matrigel, and stimulated the adhesion, motility, and MMP–2 secretion of hepatoma cells. The latter effects were suppressed by the function–blocking antibody for integrin β1 subunit. AMF/PHI also enhanced Rho activity and the phosphorylation of MEK1 and MEK 2. Our results indicate that AMF/PHI enhances hepatoma cell invasion through Matrigel in an autocrine manner by stimulating the adhesion, motility, and MMP–2 secretion of these cells through activation of β1 integrins.
Adenovirus–Mediated Cd40 Ligand Gene Therapy in A Rat Model of Orthotopic Hepatocellular Carcinoma
Authors: Schmitz Volker , Barajas Miguel , Wang Lin , Peng Dacheng , Duarte Marina , Prieto Jesús , Qian Cheng
Published: August 2002

Unresectable hepatocellular carcinoma (HCC) lacks effective therapy and entails very poor prognosis. In this study, we have explored a gene–therapeutic approach to stimulate antitumor immunity by adenoviral–mediated transfer of CD40 ligand to treat HCC in rats. In vitro infection of a rat HCC cell line (McA–RH7777) with adenoviral vector expressing CD40 ligand (AdCMVmCD40L) induced CD40L expression in a dose–dependent manner. Expression of CD40L in McA–RH7777 cells did not alter their growth rate in vitro, but it abrogated their tumorigenicity when CD40L–expressing cells were implanted into the liver of syngenic Buffalo rats. In vivo gene therapy of established orthotopic HCC nodules (6.5 mm in diameter) in Buffalo rats by intratumor injection of AdCMVmCD40L vector led to complete tumor eradication and long–term survival in 69.5% of treated animals. Therapy with AdCMVmCD40L induced strong lymphocytic infiltration of the tumoral tissue and increased apoptosis of malignant cells. The observed antitumoral effect was mediated by CD8+ T cells and was associated with increased interleukin (IL)–12 serum levels and enhanced natural killer (NK) activity. Animals that eliminated the tumor after in vivo gene therapy developed protective antitumor immunity being resistant to rechallenge with neoplastic cells. Toxicity of the therapy with AdCMVmCD40L was slight, with only a transient increase in the level of serum transaminases and minor lymphocyte infiltration of normal liver tissue. These data demonstrate that intratumoral administration of AdCMVmCD40L may provide an efficient and safe treatment for HCC.
Hepatitis C Virus Infection and Needle Exchange Use Among Young Injection Drug Users in San Francisco
Authors: Hahn Judith A. , Page-Shafer Kimberly , Lum Paula J. , Ochoa Kristen , Moss Andrew R.
Published: August 2002

Young injection drug users (IDUs) in San Francisco may be at high risk for hepatitis C virus (HCV) infection despite access to several needle exchange venues. The authors conducted a cross–sectional study from 1997 to 1999 in San Francisco to estimate the prevalence and incidence of antibody to HCV (anti–HCV) among street–recruited IDUs under age 30, and to examine risk behaviors and sources of sterile needles. Among 308 participants, the prevalence of anti–HCV was 45%. Using statistical modeling, incidence of HCV infection was estimated to be 11 per 100 person years. Independent risk factors for anti–HCV included age (odds ratio [OR], 1.17 per year; 95% confidence interval [CI], 1.05–1.30), years injecting (OR, 1.21 per year; 95% CI, 1.10–1.34), years in San Francisco (OR, 1.06 per year; 95% CI, 1.00–1.14), first injected by a sex partner (OR, 4.06; 95% CI, 1.74–9.52), injected daily (OR, 3.85; 95% CI, 2.07–7.17), ever borrowed a needle (OR, 2.56; 95% CI, 1.18–5.53), bleached last time a needle was borrowed (OR, 0.50; 95% CI, 0.24–1.02), snorted or smoked drugs in the prior year (OR, 0.48; 95% CI, 0.26–0.89), and injected by someone else in the prior month (OR, 0.50; 95% CI, 0.25–0.99). In the prior month, 88% used at least 1 of several needle exchange venues, and 32% borrowed a needle. We conclude that anti–HCV prevalence is lower than in previous studies of older IDUs, but 11% incidence implies high risk of HCV infection in a long injecting career. Despite access to sterile needles, borrowing of needles persisted.
A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver
Authors: Akhurst Barbara , Croager Emma J. , Farley-Roche Caroline A. , Ong Jin Kar , Dumble Melissa L. , Knight Belinda , Yeoh George C.
Published: August 2002

Several reliable and reproducible methods are available to induce oval cells in rat liver. Effective methods often involve inhibiting proliferation in hepatocytes using an alkylating agent, then subjecting the rat to partial hepatectomy (PH). The surgery is difficult to perform reproducibly in mice. Approaches that do not include partial hepatectomy, such as administration of D-galactosamine, are ineffective in mice. We found that a choline-deficient, ethionine-supplemented (CDE) diet, which is very effective in rats, leads to high morbidity and mortality when administered to mice. This article outlines an alternative protocol by which a CDE diet can be administered to mice. This diet is shown to be highly effective for oval cell induction, without causing high mortality. It takes less time and is at least as effective as other commonly used protocols for inducing oval cells in mice. (Hepatology 2001;34:519-522.)
Water movement across rat bile duct units is transcellular and channel-mediated
Authors: Cova Emanuela , Gong Ai-Yu , Marinelli Raul A. , LaRusso Nicholas F.
Published: August 2002

In recent studies using freshly isolated rat cholangiocytes, we established that water crosses the cholangiocyte membrane by a channel-mediated mechanism involving aquaporins, a family of water-channel proteins. Our goal was to address the importance of channel-mediated water transport in ductal bile formation by employing a physiologic experimental model, the enclosed, polarized rat intrahepatic bile duct unit (IBDU). Expansion and reduction of luminal areas as a reflection of water movement into and out of IBDUs prepared from livers of normal rats were measured by quantitative computer-assisted image analysis. When enclosed IBDUs were exposed to inward or outward osmotic gradients, their luminal area rapidly increased (approximately 25%) or decreased (approximately 20%) reflecting net water secretion or absorption, respectively. These effects were specifically inhibited by 2 water channel blockers, DMSO and HgCl2. In both instances, β-mercaptoethanol reversed the inhibitory effects. In the absence of an osmotic gradient, choleretic agents (secretin and forskolin) and a cholestatic hormone (somatostatin) induced a significant increase or decrease of IBDU luminal area by 21% and 22%, respectively. These effects were also inhibited by DMSO and reversed by β-mercaptoethanol. Under our experimental conditions, DMSO did not interfere with either forskolin-induced cAMP synthesis or the generation of osmotic driving forces via the apical chloride-bicarbonate exchanger. Protamine, an inhibitor of the paracellular pathway, had no effect on hypotonic or forskolin-induced water secretion in IBDUs. These results in a physiologically relevant model of ductal bile formation provide additional support for the concept that osmotically driven and agonist-stimulated water movement into (secretion) and out of (absorption) the biliary ductal lumen is transcellular and water channel-mediated. (Hepatology 2001;34:456-463.)
Cis -preferential recruitment of duck hepatitis B virus core protein to the RNA/polymerase preassembly complex
Authors: von Weizsäcker Fritz , Köck Josef , Wieland Stefan , Beck Jürgen , Nassal Michael , Blum Hubert E.
Published: August 2002

Hepadnaviral replication requires the concerted action of the polymerase and core proteins to ensure selective packaging of the RNA pregenome into nucleocapsids. Virus assembly is initiated by cis-preferential binding of polymerase to the encapsidation signal η, present on pregenomic RNA. Using the duck hepatitis B virus (DHBV) model, we analyzed how core protein is recruited to the RNA/polymerase preassembly complex. Two sets of trans-complementation assays were performed in cotransfected hepatoma cells. First, a replication-competent DHBV construct was tested for its ability to rescue replication of genomes bearing mutations within the core region. Self-packaging of wild-type pregenomes was more efficient than cross-packaging of core-deficient pregenomes, and this bias was strongly enhanced if mutant pregenomes coded for self-assembly-competent, but packaging-deficient, core proteins. Second, the site of wild-type core protein translation, i.e., pregenomic RNA (cis) or separate messenger RNA (trans), was analyzed for its effect on the phenotype of a previously described dominant-negative (DN) DHBV core protein mutant. This mutant forms chimeric nucleocapsids with wild-type core proteins and blocks reverse transcription within most, but not all, mixed particles. Strikingly, suppression of viral DNA synthesis by the mutant increased 100-fold when wild-type core protein was provided in trans. Our results suggest that recruitment of core protein to the DHBV preassembly complex occurs in a cis-preferential manner. This mechanism may account for the leakiness of DN DHBV core protein mutants targeting reverse transcription.
Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: Correlation with clinical disease stages
Authors: Rosen Hugo R. , Miner Camette , Sasaki Anna W. , Lewinsohn David M. , Conrad Andrew J. , Bakke Antony , Bouwer Archie H.G. , Hinrichs David J.
Published: August 2002

Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, affecting approximately 2% of the world' population. The immune mechanisms responsible for the highly variable natural history in a given individual are unknown. We used a multiparameter flow cytometric technique to functionally and phenotypically characterize HCV-specific effector T cells in the peripheral blood of 32 individuals with different stages of hepatitis C disease (resolved, mild chronic, advanced chronic) and normal controls. We found the highest frequencies of virus-specific effector cells with an activated memory phenotype (CD45RO+CD69+) in subjects who had resolved HCV infection, either spontaneously or with antiviral therapy. Effector cells from patients with resolved infection produced Th1 type cytokines following stimulation with nonstructural antigens (NS3 and NS4), whereas effector cells from chronically infected patients produced Th1 type cytokines predominantly following stimulation with the HCV core antigen. Stimulation with superantigen staphylococcal enterotoxin (SEB) induced the same levels of cytokine production in the different patient groups. Among the HCV-seropositive patients, viral load inversely correlated with the Th1 effector cell response to NS3. Interleukin (IL)-4 was produced only in response to the control antigens, but not in response to the HCV recombinant proteins. Taken together, these findings suggest that a vigorous HCV-specific CD4+ Th1 response, particularly against the nonstructural proteins of the virus, may be associated with viral clearance and protection from disease progression. Prospective studies using this new flow cytometric assay will be required to determine whether antiviral therapy modifies the frequency, specificity, and function of these virus-specific effector cells.
Adenovirus-mediated increase in HNF-3β or HNF-3α shows differences in levels of liver glycogen and gene expression
Authors: Tan Yongjun , Hughes Douglas , Wang Xinhe , Costa Robert H.
Published: August 2002

We previously generated a transgenic mouse line (T-77) in which increased hepatic expression of the hepatocyte nuclear factor-3β (HNF-3β) protein was used to assess its role in hepatocyte-specific gene transcription. The T-77 transgenic mice displayed elevated serum bile acid and bilirubin levels and a complete absence of hepatic glycogen storage. These postnatal liver defects were associated with diminished expression of hepatocyte genes involved in gluconeogenesis and bile acid transport as well as reduced levels of hepatocyte transcription factors. In this study, we show that mouse tail vein injections of adenovirus expressing the rat HNF-3β (AdHNF3β) cDNA efficiently increased its levels throughout the liver lobule and recapitulated the T-77 transgenic liver phenotype within several days postinfection. Likewise, the AdHNF3β-infected liver phenotype was associated with reduced hepatic expression of genes involved in glucose homeostasis, bile acid transport, and bilirubin conjugation, which were not found with control adenovirus infections. These studies show that adenovirus-mediated gene transfer is an effective method for rapid hepatic increases in transcription factor levels to determine in vivo target genes. In contrast, AdHNF3α-infected liver displayed only a transient reduction in hepatic glycogen levels and was associated with less severe decreases in hepatic expression of gluconeogenic and bilirubin metabolism genes. Consistent with these findings, only T-77 transgenic and AdHNF3β-infected liver exhibited diminished hepatic expression of the HNF-6 transcription factor, suggesting that reduced HNF-6 levels contribute to diminished HNF-3β-specific transcriptional activity.
Oligoclonal expansion of T cell receptor V beta 2 and 3 cells in the livers of mice with graft-versus-host disease
Authors: Chen Weiran , Howell Charles D.
Published: August 2002

The nonsuppurrative destructive cholangitis lesions in the B10.D2 (donor) into BALB/c (host) mouse graft-versus-host disease (GVHD) model are dependent on CD4 T cells that use a T cell receptor-β chain variable region (Vβ) repertoire, which is heavily biased toward Vβ2 and Vβ3 usage. We hypothesized that liver Vβ2+ and Vβ3+ CD4 T cells originate from donor mice and recognize BALB/c minor histocompatibility alloantigens and BALB/c endogenous retroviral superantigen-6, respectively. To test this hypothesis, we determined the donor:host chimera status of infiltrating liver lymphocytes and the clonal states of liver Vβ2+ and liver Vβ3+ CD4 cells isolated from GVHD mice. A limited donor TCR Vβ repertoire composed of Vβ1+, 2+, 3+, 4+, 6+, and 8+ cells infiltrated the livers of GVHD mice on day 3. Consistent with a response to immunodominant host minor histocompatibility antigens, we detected oligoclonal liver Vβ2+ T cells in 40% of GVHD mice studied on day 3 and in 100% of GVHD mice studied on day 14. Typical of superantigen stimulation, extremely polyclonal liver Vβ3+ T cells were detected in 100% of GVHD mice studied on day 3 and 40% of GVHD mice studied on day 14. Yet, the liver Vβ3+ T cells in 60% of the day 14 GVHD mice were oligoclonal, pointing to a response to minor histocompatibility antigens.
Time-dependent Cox regression model is superior in prediction of prognosis in primary sclerosing cholangitis
Authors: Boberg Kirsten Muri , Rocca Giuseppe , Egeland Thore , Bergquist Annika , Broomé Ulrika , Caballeria Llorenc , Chapman Roger , Hultcrantz Rolf , Mitchell Stephen , Pares Albert , Rosina Floriano , Schrumpf Erik
Published: August 2002

More precise prognostic models are needed for prediction of survival in patients with primary sclerosing cholangitis (PSC), particularly for the selection of candidates for liver transplantation. The aim of this study was to develop a time-dependent prognostic model for the calculation of updated short-term survival probability in PSC. Consecutive clinical and laboratory follow-up data from the time of diagnosis were collected from the files of 330 PSC patients from 5 European centers, followed for a median of 8.4 years since diagnosis. Time-fixed and time-dependent Cox regression analyses, as well as the additive regression model, were applied. The reliability of the models was tested by a cross-validation procedure. Bilirubin (on a logarithmic scale), albumin, and age at diagnosis of PSC were identified as independent prognostic factors in multivariate analysis of both the time-fixed and the time-dependent Cox regression models. The importance of bilirubin was more pronounced in the time-dependent model (hazard ratio [HR], 2.84) than in the time-fixed analysis (hazard ratio, 1.51). The additive regression model indicated that once the patients survive beyond the first 5 years, the impact on prognosis of albumin at diagnosis ceases. The time-dependent prognostic model was superior to the time-fixed variant in assigning low 1-year survival probabilities to patients that actually survived less than 1 year. In conclusion, a time-dependent Cox regression model has the potential to estimate a more precise short-term prognosis in PSC compared with the traditional time-fixed models.
Polymorphism of the N -acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis
Authors: Huang Yi-Shin , Chern Herng-Der , Su Wei-Juin , Wu Jaw-Ching , Lai Shinn-Liang , Yang Shi-Yi , Chang Full-Young , Lee Shou-Dong
Published: August 2002

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis drug-induced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P = .013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P = .003) and age (OR, 1.09; 95% CI, 1.04-1.14; P < .001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators.
Biliary atresia and the Kasai portoenterostomy: Never say never?
Authors: Ishitani Michael B.
Published: August 2002

Abstract

Background/Purpose:

Kasai portoenterostomy is recommended as the primary initial therapy for extrahepatic biliary atresia if the procedure can be performed within 10 to 12 weeks of life. The optimal management for infants with delayed presentation of biliary atresia remains controversial. The purpose of this study was to determine the success rate and outcome for patients who underwent a “late” Kasai portoenterostomy.

Methods:

The authors conducted a retrospective review of the medical records of all patients with biliary atresia who underwent a Kasai portoenterostomy at their institution from 1986 to 1999 (n = 31). The authors analyzed success rates compared with age at the time of the Kasai procedure and the association with patient demographics. Surgical success was defined as achievement of a total serum bilirubin less than or equal to 2 mg/dL. Long-term follow-up assessments included the need for liver transplantation and patient survival rate.

Results:

The demographics of this study cohort showed a predominance of African-Americans. 19 of 31 (61%), and girls, 23 of 31 (74%). Assessment of success compared with subject age at the time of the initial portoenterostomy showed that 52% had successful Kasai procedure at 0 to 75 days, compared with 83% success rate at age 76 days or older (P = .359), Liver transplantation was performed in 16 of 31 patients (45%). Overall survival rate for the entire cohort is 23 of 31 (74%), whereas 12 of 31 (39%) are currently alive without a liver transplant.

Conclusion:

These data suggest that there is no contraindication to performing a Kasai portoenterostomy for biliary atresia in children over 75 days of age.
Clinical validation of an artificial neural network trained to identify acute allograft rejection in liver transplant recipients
Authors: Hughes Victoria F. , Melvin David G. , Niranjan Mahesan , Alexander Graeme A.M. , Trull Andrew K.
Published: August 2002

Artificial neural networks (ANNs) are techniques of nonlinear data modeling that have been studied in a wide variety of medical applications. An ANN was developed to assist in the diagnosis of acute rejection in liver transplant recipients. We investigated the diagnostic accuracy of this ANN on a new data set of patients from the same hospital. In addition, we compared the diagnostic accuracy of the ANN with that of the individual input variables (alanine aminotransferase [ALT] and bilirubin levels and day posttransplantation). Clinical and biochemical data were collected retrospectively for 124 consecutive liver transplantations (117 patients) over the first 3 months after transplantation. Diagnostic accuracy was calculated using receiver operating characteristic (ROC) curve analysis. The ANN differentiated rejection from rejection-free episodes in the new data set over the first 3 months posttransplantation with an area under the ROC curve of 0.902 and sensitivity and specificity of 80.0% and 90.1% at the optimum decision threshold, respectively. The ANN was significantly more specific than ALT or bilirubin level or day posttransplantation at their corresponding optimum decision thresholds (P < .0001). Peak ANN output occurred 1 day earlier than peak values for either ALT or bilirubin (P < .005). The diagnostic accuracy of the ANN was greater than that of any of the individual variables that had been used as inputs. It would be a useful adjunct to conventional liver function tests for monitoring liver transplant recipients in the early postoperative period.
Late hepatic allograft dysfunction
Authors: Wiesner Russell H. , Narayanan Menon K. V.
Published: August 2002

Key Points
Hemodynamic changes during a single treatment with the molecular adsorbents recirculating system in patients with acute-on-chronic liver failure
Authors: Schmidt Lars E. , Sørensen Vibeke Rømming , Svendsen Lars Bo , Hansen Bent A. , Larsen Fin Stolze
Published: August 2002

The aim of this pilot study is to evaluate the circulatory safety of treatment with the molecular adsorbents recirculating system (MARS) by determining the effect on systemic hemodynamics of a single MARS treatment in patients with acute-on-chronic liver failure (AOCLF). In eight patients admitted with AOCLF, a single 10-hour MARS treatment was performed. Systemic hemodynamic variables were determined before and during treatment. Bilirubin and urea were monitored as measures of protein-bound and water-soluble toxins. During MARS treatment, mean arterial pressure increased from 67 ± 9 to 76 ± 6 mm Hg (P < .05). Systemic vascular resistance index increased from 757 ± 134 to 884 ± 183 dyne · s/cm5/m2 (P < .05), whereas cardiac index remained constant (5.9 ± 0.7 v 6.0 ± 1.1 L/min/m2). No episode of dialysis-induced hypotension was observed. Systemic oxygen consumption remained constant (92 ± 30 v 93 ± 11 mL/min/m2). Bilirubin levels decreased from 537 ± 192 to 351 ± 106 μmol/L (P < .05), and urea levels, from 19.1 ± 13.9 to 6.7 ± 5.1 mmol/L (P < .05). In conclusion, MARS treatment proved safe in critically ill patients with no attributing side effects.
Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?
Authors: McCaughan Geoffrey W.
Published: August 2002

Abstract Unavailable. Please See Print Journal.
Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model
Authors: Tector Joseph A. , Fridell Jonathan A. , Elias Nahel , Watanabe Taichi , Salazar Julie , Greinke Doris , Metrakos Peter , Tchervenkov Jean I.
Published: August 2002

Discordant liver xenotransplantation is a poorly explored entity. Data from the few large animal studies of hepatic xenotransplantation suggest that severe hemorrhage is encountered. The purpose of the studies described here is to characterize the nature of the hemorrhage that accompanies liver xenotransplantation. Canine livers were transplanted into porcine recipients, and lethal hemorrhage was encountered. Analysis of recipient blood showed that factors V, IX, and X were present in adequate levels until after the hemorrhage appeared, suggesting that coagulation factor loss was the result and not the cause of hemorrhage. Platelet counts decreased dramatically in recipients within minutes of graft reperfusion. There also was no evidence of clotting activity in the blood of recipients of liver xenografts within minutes of graft reperfusion. This loss of clotting activity was specific to liver xenografts, was not seen in renal xenografts with or without venovenous bypass, and also was absent in pig-to-pig liver allografts. In brief, the hemorrhage that accompanies liver xenotransplantation occurs because of a decrease in the number and function of circulating platelets in the recipient.
Influence of albumin supplementation on tacrolimus and cyclosporine therapy early after liver transplantation
Authors: Trull Andrew , Hughes Victoria , Cooper Dawn , Wilkins Matthew , Gimson Alexander , Friend Peter , Johnston Atholl , Sharples Linda , Park Gilbert
Published: August 2002

Liver transplant recipients administered gelatin (GEL) rather than human albumin solution (HAS) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time. The combined effect of these two abnormalities could be an increase in the unbound (active) concentration of low-extraction highly albumin-bound drugs, such as tacrolimus (TAC). This may increase the efficacy and/or toxicity of such drugs. We prospectively compared the clinical outcome of 69 de novo liver transplant recipients randomized primarily to TAC or cyclosporine (CYA) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation. Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function. Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days (P < .001). Although antipyrine clearance was similar in all four trial arms, it was intermediate between that found in historic healthy controls and patients with cirrhosis (P < .0001). Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms (P < .001). The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms (relative risk, 2.02; 95% confidence interval, 1.07 to 3.78; P = .03). These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL. In addition, supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest.
The impact of human herpesvirus-6 and -7 infection on the outcome of liver transplantation
Authors: Razonable Raymund R. , Paya Carlos V.
Published: August 2002

Human herpesvirus (HHV)-6 and -7 are novel members of the β-herpesvirus family that maintain latency in the human host after primary infection. Reactivation from latency and/or increased degree of viral replication occurs during periods of immune dysfunction. The clinical effect of HHV-6 and HHV-7 reactivation in recipients of liver transplants is now being recognized. Clinical illnesses such as fever, rash, pneumonitis, encephalitis, hepatitis, and myelosuppression have been described in a number of anecdotal reports. Moreover, a growing body of evidence suggests that the more important effect of HHV-6 and HHV-7 reactivation on the outcomes of liver transplantation may be mediated indirectly by their interactions with the other β-herpesvirus—cytomegalovirus (CMV). Coinfection among these three β-herpesviruses in clinical syndromes that were classically ascribed to be solely caused by CMV has been shown and has raised substantial interest in the potential role of HHV-6 and HHV-7 as copathogens in the direct and indirect illnesses caused by CMV. This article reviews the current scientific data on the role and the magnitude of impact of HHV-6 and HHV-7 infection on the outcomes of liver transplantation.
Screw Fixation in Lag Fashion of Equine Cadaveric Metacarpal and Metatarsal Condylar Bone Specimens: A Biomechanical Comparison of Shaft and Cortex Screws
Authors: Rahm Claudia , Ito Keita , Auer Jörg
Published: August 2002

Objective—To compare acute fixation stability and insertion effort of cortex bone screws with and without a shaft inserted in lag fashion in equine metacarpal (metatarsal, MC(T)III) bone.

Methods—Screw types with independent variables of screw diameter (4.5 or 5.5 mm) and shaft type (without shaft, with 20‐mm shaft, or with 25‐mm shaft) were studied. Bone specimens cut from distal equine MC(T)III condyles were used. After screw insertion in lag fashion into 2 bone blocks with an instrumented device, shear tests were conducted in a mechanical testing machine. Outcome variables of peak insertion torque, insertion energy, stiffness, yield strength, and displacement at 3 kN of load were compared.

Results—The effects of screw design were substantial. Screws with shaft were 30% to 40% stiffer and 60% to 70% stronger than screws without shaft. Screws with shaft could tolerate 80 to 95 kg more force than screws without shaft before yielding. At 3 kN load, the displacement with screws with shaft was 55% to 60% of that with screws without shaft. Screws with a long shaft tended to perform better than those with a short shaft. There was no difference in the shear stiffness, shear yield strength, or shear displacement between the 2 screw diameters. Although larger diameter screws required more insertion effort, and screws with a short shaft required the most insertion energy, these differences were small.

Conclusions—Cortex screws with a long shaft of 4.5‐ or 5.5‐mm diameter provide better stability in equine MC(T)III condyle bone with less insertion effort compared with those with a short shaft or no shaft.

Clinical Significance—Cortex bone screws with a shaft inserted in lag fashion should be considered for the fixation of equine MC(T)III condylar fractures.
Definition and Determination of Acetabular Component Orientation in Cemented Total Hip Arthroplasty
Authors: Cross Alan R. , Newell Susan M.
Published: August 2002

Objective—To describe the spatial orientation of the cemented acetabular component in cemented total hip arthroplasty, based on a ventrodorsal and lateral radiographic projection of the pelvis.

Methods—Equations were derived by using trigonometric relationships that describe the radiographic rotation about the longitudinal pelvic axis (α), transverse pelvic axis (β), acetabular inclination (φ), acetabular inclination corrected for longitudinal pelvic rotation, version (φC), acetabular version (θ), acetabular version corrected for longitudinal pelvic rotation (θC), acetabular inclination corrected for transverse pelvic rotation (φβ), and acetabular version corrected for transverse pelvic rotation (θβ)

Results—α was calculated by using the equation α= sin−1(x/y) wherexis the transverse distance between the dorsal spinous processes and the center of the pubis on a ventrodorsal radiograph andyis the distance from the pubis to the dorsal aspect of the first coccygeal vertebra perpendicular to the long axis of the pelvis on a lateral radiograph. φ was calculated from the long axis (LA) and short axis (SA) of the ellipse formed by the radiopaque acetabular marker ring by using the equation φ= sin−1(SA/LA). φCwas calculated by using the equation φC=φ± (α ‐ tan−1(tan α cos θC)). θ was determined as previously described. θCwas calculated by using the equation θC= tan−1(tan θ cos α). φβand θβwere calculated with the equations φβ= tan−1(tan φ cos β) and θβ=θ− tan−1(sin β), respectively. β could not be accurately determined from ventrodorsal and lateral pelvic radiographs.

Conclusions and Clinical Relevance—These techniques allow for more accurate postoperative radiographic assessment of acetabular component positioning. This information can then be used in retrospective or prospective analyses examining that effects of implant positioning on clinical outcome.
Application of Arthroplasty Principles to Canine Cemented Total Hip Replacement
Authors: Schulz Kurt S.
Published: August 2002

“Taking a long view, one may wonder whether joint replacement, though a brilliant tactical success, represents the true path of progress in orthopedics or whether it represents a very specialized but temporary makeshift.… A more fundamental knowledge of the biology of the cartilage cell … may lead to presently unconceived methods of preventing and treating chronic arthritis that will leave joint replacement as dead as a dinosaur.”

–Davis LeVay, The History of Orthopedics
Fracture Healing After Stabilization With Intramedullary Xenograft Cortical Bone Pins: A Study in Pigeons
Authors: Wander Kathy W. , Schwarz Peter D. , James Susan P. , Powers Barbara E. , Taylor Bobbi , Wimsatt Jeffrey H.
Published: August 2002

Objective—To investigate the effectiveness of intramedullary xenograft cortical bone pins compared with stainless steel Kirschner wire for the repair of a standardized avian humeral fracture.

Study Design—Prospective randomized study.

Sample Population—Thirty mature pigeons (Columba livia).

Methods—Birds were randomly assigned to 3 groups. Transverse mid‐diaphyseal humeral fractures were created in 1 humerus in each bird. Fractures were stabilized with intramedullary ostrich or canine xenograft cortical bone pins or Kirschner wire. Radiographic, histological, and biomechanical assessments were used to compare fracture healing 6 weeks after fracture stabilization. The contralateral humerus of each bird was used as a control.

Results—All fractures healed regardless of intramedullary pin type. There were no statistically significant biomechanical differences among groups or within groups. Xenograft cortical bone pins induced a mononuclear inflammatory reaction that did not impair bone healing. Bones stabilized with intramedullary cortical bone pins had more periosteal callus and inflammation at the fracture site than bones stabilized with stainless steel Kirschner wires.

Conclusions—Intramedullary xenograft cortical bone pins, derived from mammalian or avian sources, appear to represent an alternative for the repair of avian humeral fractures.

Clinical Relevance—Intramedullary xenograft cortical bone pins are biodegradable and may reduce the need for additional surgery to remove implants after fracture healing.
Evaluation of a Portocaval Venograft and Ameroid Ring for the Occlusion of Intrahepatic Portocaval Shunts in Dogs
Authors: Kyles Andrew E. , Gregory Clare R. , Jackson Joshua , Ilkiw Janet E. , Pascoe Peter J. , Adin Christopher , Samii Valerie F. , Herrgesell Eric
Published: August 2002

Objective—To evaluate the use of a portocaval venograft and ameroid constrictor in the surgical management of intrahepatic portosystemic shunts (PSS).

Study Design—Prospective, clinical study.

Animal Population—Ten client‐owned dogs with intrahepatic PSS.

Methods—Portal pressure was measured after temporary suture occlusion of the intrahepatic PSS. In dogs with an increase in portal pressure greater than 8 mm Hg, a single extrahepatic portocaval shunt was created using a jugular vein. An ameroid ring was placed around the venograft and the intrahepatic PSS was attenuated. Transcolonic pertechnetate scintigraphy was performed before surgery, 5 days after surgery, and 8 to 10 weeks after surgery. Dogs with continued portosystemic shunting were evaluated further by laparotomy or portography. Clinical outcome and complications were recorded.

Results—Mean (± SD) portal pressure increased from 6 ± 3 to 19 ± 6 mm Hg with PSS occlusion; in all 10 dogs, the increase in portal pressure was greater than 8 mm Hg. There were no intraoperative complications, and, after creation of the portocaval shunt, the intrahepatic PSS could be completely ligated in 8 of 10 dogs. The final portal pressure was 9 ± 4 mm Hg. Postoperative complications included coagulopathy and death (1 dog), ascites (3 dogs), and incisional discharge (3 dogs). Five of 8 dogs had continued portosystemic shunting at 8 to 10 weeks after surgery. Multiple extrahepatic PSS were demonstrated in 4 of these dogs. Clinical outcome was excellent in all 9 surviving dogs.

Conclusions and Clinical Significance—The surgical technique resulted in a high incidence of multiple extrahepatic PSS. Short‐term clinical results were promising, but long‐term outcome must be evaluated further.
Effects of 3.3‐MHz Ultrasound on Caudal Thigh Muscle Temperature in Dogs
Authors: Levine David , Millis Darryl L. , Mynatt Trevor
Published: August 2002

Objective—To examine the tissue‐temperature changes that occur at various depths during 3.3‐MHz ultrasound (US) treatments of the caudal thigh muscles in dogs.

Study Design—A prospective, randomized, experimental study.

Animals—Ten mixed‐breed research dogs.

Methods—Two US treatments, one at an intensity of 1.0 W/cm2and one at 1.5 W/cm2, were administered to the caudal thigh region of 10 adult male and female hound‐type dogs weighing 20.5 to 25.0 kg. Needle thermistors were inserted in the caudal thigh muscles below the skin surface at depths of 1.0, 2.0, and 3.0 cm, directly under the US treatment area. Both intensities of US treatment were performed on each dog over a 10‐cm2area for 10 minutes using a sound head with an effective radiating area of 5 cm2. Treatments were administered in random order. Tissue temperature was measured before, during, and after US treatment until tissue temperature returned to baseline.

Results—At the completion of the 10‐minute US treatment, the temperature rise at an intensity of 1.0 W/cm2was 3.0°C at the 1.0‐cm depth, 2.3°C at 2.0‐cm depth, and 1.6°C at 3.0‐cm depth. At an intensity of 1.5 W/cm2, temperatures rose 4.6°C at the 1.0‐cm depth, 3.6°C at 2.0‐cm depth, and 2.4°C at 3.0‐cm depth. Tissue temperatures returned to baseline within 10 minutes or sooner after treatment in all dogs.

Conclusions—This study demonstrates that significant heating occurs in the superficial thigh muscle of dogs during 3.3‐MHz US.

Clinical Relevance—3.3‐MHz US can be used to increase superficial tissue temperature in dogs, although the amount of time that tissue temperature remains elevated is relatively short.
Serosal Injury in the Equine Jejunum and Ascending Colon After Ischemia‐Reperfusion or Intraluminal Distention and Decompression
Authors: Dabareiner Robin M. , Sullins Kenneth E. , White Nathaniel A. , Snyder Jack R.
Published: August 2002

Objective—To document morphologic changes that occur in equine intestinal serosa after experimentally induced ischemia and subsequent reperfusion (jejunum, ascending colon) or after intraluminal distention and decompression (jejunum).

Study Design—Morphologic effects of ischemia‐reperfusion or intraluminal distention‐decompression determined on the serosal layer of the equine jejunum. The large colon serosa was evaluated after ischemia‐reperfusion injury.

Animals or Sample Population—Seven adult horses.

Methods—After induction of general anesthesia and ventral median celiotomy, ischemia was created by arteriovenous (AVO) and lumen occlusion of a 20‐cm segment of jejunum and ascending colon for 70 minutes, followed by a 60‐minute reperfusion period. Intraluminal distention (25 cm H2O) was created in a second 20‐cm jejunal segment and maintained within the abdomen for 120 minutes, followed by a 120‐minute decompression period. Seromuscular biopsies were obtained upon entering the abdomen and after the ischemic and reperfusion periods, and after the distention and decompression periods along with corresponding control seromuscular biopsies. Samples were processed and examined by light microscopy, transmission electron, and scanning electron microscopy.

Results—Ischemia and reperfusion, and intraluminal distention and decompression, resulted in severe morphologic changes in the seromuscular layer of equine jejunum. A similar period of ischemia‐reperfusion caused minimal changes in the ascending colon serosa.

Conclusion—Adult equine jejunum sustains more serosal damage than the ascending colon after similar periods of ischemia‐reperfusion injury. Intraluminal distention and subsequent decompression causes serosal damage in the equine jejunum.

Clinical Relevance—The small intestine is more susceptible to seromuscular layer damage than the ascending colon.
An in Vitro Biomechanical Comparison of Two Interlocking‐Nail Systems for Fixation of Ostectomized Equine Third Metacarpal Bones
Authors: Lopez Mandi J. , Wilson David G. , Trostle Steven S. , Markel Mark D.
Published: August 2002

Objective—To compare the mechanical properties of 2 interlocking‐nail systems for fixation of ostectomized equine third metacarpi (MC3): (1) a standard interlocking nail with 2 parallel screws proximal and distal to a 1‐cm ostectomy; and (2) a modified interlocking nail with 2 screws proximal and distal to a 1‐cm ostectomy with the screws offset by 30°.

Animal or Sample Population—Twelve pairs of adult equine forelimbs intact from the midradius distally.

Methods—Twelve pairs of equine MC3 were divided into 2 test groups (6 pairs each): torsion and caudocranial 4‐point bending. Standard interlocking nails (6‐hole, 13‐mm diameter, 230‐mm length) were placed in 1 randomly selected bone from each pair. Modified interlocking nails (6‐hole, 13‐mm, 230‐mm length, screw holes offset by 30°) were placed in the contralateral bone from each pair. All bones had 1‐cm mid‐diaphyseal ostectomies. Six construct pairs were tested in caudocranial 4‐point bending to determine stiffness and failure properties. The remaining 6 construct pairs were tested in torsion to determine torsional stiffness and yield load. Mean values for each fixation method were compared using a pairedttest within each group. Significance was set atP< .05.

Results—Mean (±SEM) values for the MC3‐standard interlocking‐nail composite and the MC3‐modified interlocking‐nail composite, respectively, in 4‐point bending were: composite rigidity, 3,119 ± 334.5 Nm/rad (newton · meter/radian) and 3,185 ± 401.2 Nm/rad; yield bending moment, 205.0 ± 18.46 Nm and 186.7 ± 6.17 Nm; and failure bending moment, 366.4 ± 21.82 Nm and 378.1 ± 20.41 Nm. There were no significant differences in the biomechanical values for bending between the 2 fixation methods. In torsion, mean (±SEM) values for the MC3‐standard interlocking‐nail composite and the MC3‐modified interlocking‐nail composite were: composite rigidity, 135.5 ± 7.128 Nm/rad and 112.5 ± 7.432 Nm/rad; gap stiffness, 207.6 ± 10.57 Nm/rad and 181.7 ± 12.89 Nm/rad; and yield load, 123.3 ± 2.563 Nm and 107.5 ± 8.353 Nm, respectively. Composite rigidity and gap stiffness for standard interlocking‐nail fixations were significantly higher than the modified interlocking‐nail fixation technique in torsion. Yield load had a tendency to be higher for the standard interlocking‐nail fixation (P= .15).

Conclusions—No significant differences in biomechanical properties were identified between a standard interlocking nail and one with the screw holes offset by 30° in caudocranial 4‐point bending. The standard interlocking nail was superior to the modified interlocking nail in torsional gap stiffness and composite rigidity. The torsional yield load also tended to be higher for the standard interlocking nail.

Clinical Relevance—The standard interlocking nail with parallel screw holes is superior to a modified interlocking nail with the screw holes offset by 30° in ostectomized equine MC3 bones in vitro when tested in torsion.