Safety and efficacy of long-term nasobiliary drainage to treat intractable pruritus in cholestatic liver disease.

INTRODUCTION: Cholestasis related pruritus, secondary to intrahepatic and/or extrahepatic biliary obstruction is a common manifestation in chronic liver disease. Pruritus is difficult to treat, and results are often suboptimal. A stepwise medical approach is usually employed, followed by a trial molecular adsorbents recirculation system in medication resistant cases. Pruritus resulting in reduced quality of life is a variant syndrome eligible for liver transplantation in the setting of preserved synthetic function. AIM: This case series describes the use of long-term (LT) nasobiliary drainage (NBD) in three patients with intractable pruritus. This case series tests the hypothesis that LT-NBD could be successfully used to alleviate cholestasis related pruritus, and prevent or delay the need for liver transplantation. METHOD: LT-NBD was carried out in three female patients (mean age 43 years) with intractable pruritus secondary to primary biliary cirrhosis (PBC) (n=2), and benign recurrent intrahepatic cholestasis (n=1). NBD was carried out through the endoscopic placement of a 6 French Cook Medical nasobiliary catheter into the common bile duct. RESULTS: Symptomatic relief of pruritus was described by all three cases within 24 h of NBD placement. LT-NBD was stopped in the patient with benign recurrent intrahepatic cholestasis after 8 weeks due to complete resolution of pruritus. In one patient with PBC, LT-NBD was undertaken over 12 months, with complete resolution of pruritus. In the second patient with PBC, LT-NBD was carried out over 14 months, with complete resolution of pruritus. DISCUSSION: This case series supports the efficacy of LT-NBD in the treatment of intractable pruritus. We propose that NBD offers an accessible modality for the treatment of intractable pruritus in liver disease, potentially avoiding the need for liver transplantation.

Heterogeneous variances and genetics by environment interactions in genetic evaluation of crossbred lambs.

Accounting for environmental heteroscedasticity and genetics by environment interaction (G×E) in genetic evaluation is important because animals may not perform predictably across environments. The objectives of this study were to evaluate the presence and consequences of heteroscedasticity and G×E on genetic evaluation. The population considered was crossbred lambs sired by terminal sires and reared under commercial conditions in the UK. Data on 6325 lambs sired by Charollais, Suffolk and Texel rams were obtained. The experiment was conducted between 1999 and 2002 on three farms located in England, Scotland and Wales. There were 2322, 2137 and 1866 lambs in England, Scotland and Wales, respectively. A total of 89 sires were mated to 1984 ewes of two types (Welsh and Scottish Mules). Most rams were used for two breeding seasons with some rotated among farms to create genetic links. Lambs were reared on pasture and had their parentage, birth, 5 week, 10 week, and slaughter weights recorded. Lambs were slaughtered at a constant fatness, at which they were ultrasonically scanned for fat and muscle depth. Heteroscedasticity was evaluated in two ways. First, data were separated into three subsets by farm. Within-farm variance component estimates were then compared with those derived from the complete data (Model 1). Second, the combined data were fitted, but with a heterogeneous (by farm) environmental variance structure (Model 2). To investigate G×E, a model with a random farm by sire (F×S) interaction was used (Model 3). The ratio of the F×S variance to total variance was a measure of the level of G×E in the population. Heterogeneity in environmental variability across farm was identified for all traits (P<0.01). Rank correlations of sire estimated breeding value between farms differed for Model 1 for all traits. However, sires ranked similarly (rank correlation of 0.99) for weight traits with Model 2, but less so for ultrasonic measures. Including the F×S interaction (Model 3) improved model fit for all traits. However, the F×S term explained a small proportion of variation in weights (<2%) although more in ultrasonic traits (at least 10%). In conclusion, heteroscedasticity and G×E were not large for these data, and can be ignored in genetic evaluation of weight but, perhaps, not ultrasonic traits. Still, before incorporating heteroscedasticity and G×E into routine evaluations of even ultrasonic traits, their consequences on selection response in the breeding goal should be evaluated.

The management of the surgical complications of HELLP syndrome.

INTRODUCTION: Complications from HELLP (Haemolysis, Elevated Liver enzymes and Low Platelet) syndrome may present as an emergency to any surgeon. We review the ten-year experience of a tertiary hepatobiliary centre managing HELLP patients. Three selected cases are described to highlight our management strategy and a systematic review of the recent literature is presented. METHODS: All patients with HELLP syndrome were identified from a prospectively maintained database and their details collated. Subsequently, a detailed search of PubMed was carried out to identify all case series of HELLP syndrome in the literature in the English language since 1999. RESULTS: On review of 1,002 cases, 10 patients were identified with surgical complications of HELLP syndrome. Seven of these patients had a significant liver injury. Only three of these required surgical intervention for liver injury although four other patients required surgical intervention for other complications. There was no maternal mortality in this series. Review of the literature identified 49 cases in 31 publications. The management approaches of these patients were compared with ours. CONCLUSIONS: We have presented a large series of patients with surgical complications resulting from HELLP syndrome managed without maternal mortality. This review has confirmed that haemodynamically stable patients with HELLP syndrome associated hepatic rupture can be conservatively treated successfully. However, in unstable patients, perihepatic packing and transfer to a specialist liver unit is recommended.

Genetic evaluation of days to harvest in crossbred lambs.

Days to harvest (DTH) is the number of days a lamb is fed before reaching a target level of fatness. Although economically relevant, this trait has not been thoroughly evaluated in sheep. Most lambs harvested in the United Kingdom are crossbreds sired by purebred terminal sires, with Charollais, Suffolk, and Texel most commonly used. Sires from these breeds were selected on an index designed to increase lean growth while constraining fat. The purpose of this research was to 1) evaluate the effects of index selection in terminal sires on DTH and 2) evaluate the feasibility of incorporating DTH into genetic evaluation programs. Charollais, Suffolk, and Texel sheep had participated in sire referencing schemes where genetic links among flocks were established by sharing rams. Rams with high or low index scores were chosen from these schemes and mated to crossbred ewes at 3 farms in the United Kingdom. Lambs were harvested at a target 11% subcutaneous fat. Records on DTH from 6,350 lambs were analyzed in 2 ways: 1) as time to harvest fitting a survival model and 2) as a normally distributed variable in a bivariate analysis with weight at harvest. The survival analysis was stratified by rearing type (single or twin). In both approaches, sires were fitted using a multivariate normal distribution with a relationship matrix. Regardless of model fitted, sire index did not affect DTH (P>0.10). However, Texel-sired lambs reached harvest faster (P<0.01) than either Charollais- or Suffolk-sired lambs although DTH in those 2 breed types did not differ (P>0.1). Ewe lambs reached harvest faster than wethers (P<0.01). Lambs from older ewes were harvested faster (P<0.001). The heritability of DTH was 0.21 from the survival model and 0.20 from the bivariate model. Rank correlation of sire EBV between methods was 0.9, suggesting strong agreement. The use of high or low index sires did not extend DTH in lambs harvested at a target fatness. Importantly, there is no antagonism between improving carcass merit and extending the grazing season. Furthermore, DTH is moderately heritable. If economically justified within a breeding program, it could be reduced through genetic selection.

Index selection in terminal sires improves lamb performance at finishing.

Lamb meat is often perceived by consumers as fatty, and consumption has decreased in recent decades. A lean growth index was developed in the UK for terminal sire breeds to increase carcass lean content and constrain fat content at a constant age end point. The purposes of this study were 1) to evaluate the effects of index selection of terminal sires on their crossbred offspring at finishing and 2) to evaluate its effectiveness within terminal sire breeds. Approximately 70% of lambs marketed in the UK have been sired by rams of breeds typically thought of as specialized terminal sires. The most widely used are Charollais, Suffolk, and Texel. These breeds participated in sire referencing schemes from the early 1990s by sharing rams among flocks selected on the lean growth index. From 1999 to 2002 approximately 15 "high" and 15 "low" lean growth index score rams were selected from within their sire referencing schemes and mated to Welsh and Scottish Mule ewes. Their crossbred offspring were commercially reared on 3 farms in the UK. Lambs were finished to an estimated 11% subcutaneous fat by visual evaluation. At finishing, lambs were weighed, ultrasonically scanned, and assessed for condition score and conformation. Records were obtained for 6356 lambs on finishing BW (FWT), ultrasonic muscle depth (UMD), ultrasonic fat depth, overall condition score (OCS), and conformation of gigot, loin, and shoulder. Ultrasonic fat depth was log transformed (logUFD) to approach normality. High-index-sired lambs were heavier at finishing (1.2±0.2 kg) with thicker UMD (0.7±0.2 mm) and less logUFD (0.08±0.01 mm; P<0.05). There were no differences in OCS or conformation based on the sire index or breed (P>0.08). Suffolk-sired lambs were heavier than Charollais (1.0±0.3 kg), which were heavier than Texel (0.9±0.3 kg; P<0.001). Texel-sired lambs had thicker UMD than Charollais (0.7±0.2 mm; P<0.001) but were not different than Suffolk. Charollais-sired lambs had greater logUFD than both Texel (0.098±0.016 mm) and Suffolk (0.061±0.017 mm) sired lambs (P<0.001). Within a breed, high- and low-index-sired lambs differed in performance with the exceptions of FWT and UMD in Suffolks. Index selection produced heavier and leaner lambs at finishing. Producers have flexibility in choosing the terminal sire that best fits their production system.

Index selection in terminal sires improves early lamb growth.

The use of terminal sires (TS) for crossbreeding is integral to the UK sheep industry where approximately 71% of market lambs are sired by TS rams. Early growth of these crossbred lambs affects profitability. The objectives of this study were i) to evaluate the effectiveness of index selection among TS on BW and ADG of their crossbred offspring; and ii) to compare the efficacy of that selection within TS breeds. The most widely used TS breeds in the United Kingdom are Charollais, Suffolk, and Texel. These participated in sire referencing schemes in which they were evaluated on a lean growth index designed to increase carcass lean weight at a given age. From 1999 to 2002, approximately 15 high and 15 low lean growth index rams per breed (93 in total, differing in index on average by 4.6 SD) were selected from within their sire referencing schemes and mated to Welsh and Scottish Mule ewes. Their crossbred offspring were reared commercially on 3 experimental farms in England, Scotland, and Wales. A total of 6,515 lambs were born between 2000 and 2003. Lambs were weighed at birth (BWT), 5 wk (5WT), and 10 wk (10WT), and their ADG from birth to 10 wk was calculated. Lambs sired by high index rams were on average, across breeds, heavier at all ages (P < 0.01) with 0.07 ± 0.03, 0.3 ± 0.1, and 0.4 ± 0.1 kg greater BWT, 5WT, and 10WT, respectively. Their ADG was 5.1 ± 1.9 g/d greater than low-index-sired lambs (P < 0.01). Suffolk-sired lambs were on average heavier at all ages, with greater ADG, whereas Charollais-sired lambs were lightest with smallest ADG. Overall, there was no significant interaction between sire index and sire breed (P > 0.10). Within Suffolk-sired lambs, there was little difference between high and low index sires for the traits studied (P > 0.3). High and low index Charollais-sired lambs differed in BWT (0.09 ± 0.04 kg) and 5WT (0.3 ± 0.1 kg), and Texel-sired lambs differed in 5WT (0.5 ± 0.1 kg), 10WT (0.9 ± 0.2 kg), and ADG (10.2 ± 3.3 g/d; P < 0.01). Lambs from Scottish Mule dams were heavier, with greater ADG, than lambs born to Welsh Mules (P < 0.01). Lambs reared in Scotland were heavier at all ages (P < 0.01). The results suggest that using index selection in TS can improve the growth of their commercial offspring reared on grass.

Comparison of repeatability and multiple trait threshold models for litter size in sheep using observed and simulated data in Bayesian analyses.

Bayesian analyses were used to estimate genetic parameters on 5580 records of litter size in the first four parities from 1758 Mule ewes. To examine the appropriateness of fitting repeatability (RM) or multiple trait threshold models (MTM) to litter size of different parities, both models were used to estimate genetic parameters on the observed data and were thereafter compared in a simulation study. Posterior means of the heritabilities of litter size in different parities using a MTM ranged from 0.12 to 0.18 and were higher than the heritability based on the RM (0.08). Posterior means of the genetic correlations between litter sizes of different parities were positive and ranged from 0.24 to 0.71. Data sets were simulated based on the same pedigree structure and genetic parameters of the Mule ewe population obtained from both models. The simulation showed that the relative loss in accuracy and increase in mean squared error (MSE) was substantially higher when using the RM, given that the parameters estimated from the observed data using the opposite model are the true parameters. In contrast, Bayesian information criterion (BIC) selected the RM as most appropriate model given the data because of substantial penalty for the higher number of parameters to be estimated in the MTM model. In conclusion, when the relative change in accuracy and MSE is of main interest for estimation of breeding values of litter size of different parities, the MTM is recommended for the given population. When reduction in risk of using the wrong model is the main aim, the BIC suggest that the RM is the most appropriate model.

Genetic relationship between longevity and objectively or subjectively assessed performance traits in sheep using linear censored models.

Genetic parameters of longevity in crossbred Mule ewes, and genetic relationships among longevity, growth, body composition, and subjectively assessed traits on Mule lambs and ewes have been estimated using Bayesian linear censored models. Additionally, the genetic associations between longevity and culling reasons were examined. Data comprised 1,797 observations of Mule ewes for longevity, culling reasons, growth, body composition, mouth scores, and type traits. Longevity was defined as the time (in years) from 2 yr of age (the age at first lambing of most ewes) to culling or death. Censored data (i.e., observations for which only the lower bound of the true longevity is known, such as when the animals are still alive) comprised 24% of all observations for longevity. Bivariate analyses were used to analyze the longevity of the ewe with each performance trait by fitting linear Bayesian models considering censored observations. Longevity was split into 3 different sub-traits: age at culling due to teeth/mouth conditions, age at culling due to udder conditions, and age at culling due to other culling reasons. These sub-traits and their aggregation into the overall trait of longevity were analyzed in a multiple-trait model. The heritability of longevity was moderate at 0.27, whereas heritabilities of the growth and body composition traits ranged from 0.11 for average of shoulder, loin, and gigot conformation to 0.36 for ewe BW at first premating. Mouth scores and type traits had heritabilities ranging from 0.13 for jaw position to 0.39 for fleece quality. All analyzed traits showed low genetic correlations with longevity, ranging from -0.20 for average conformation scores in live animals to 0.18 for tooth angle. Teeth/mouth conditions resulted in the greatest heritability (0.15) among the sub-traits based on the separate culling reasons. Genetic correlations between separate culling reasons were low to high (0.12 to 0.63 for teeth/mouth conditions with udder conditions and other culling reasons, respectively). Longevity may be preferred as a selection criterion because of (i) its moderate heritability compared with its component sub-traits based on specific culling reasons, and (ii) its moderate to high genetic correlation with these component sub-traits. The moderate heritability for longevity reflects the potential of this trait for genetic improvement, especially when longevity is based on clearly defined culling reasons.

Spread of marker bacteria from the hides of cattle in a simulated livestock market and at an abattoir.

The spread of microbial contamination on the hides of beef was investigated at two stages in the meat chain: (i) in a simulated livestock market ("the market") using 33 animals, and (ii) in the unloading-to-skinning area of a commercial abattoir using 18 animals. At both stages, harmless bacterial markers (nalidixic acid-resistant Escherichia coli K-12; rifampicin- and nalidixic acid-resistant Pseudomonas fluorescens; and a tetracycline-resistant E. coli) were inoculated on the hides of a small number of selected animals, and their transfer to other animals and the environment was examined. At the market, the initial prevalence of animals positive for the hide markers (9.1% in each phase) introduced in the presale pen, sale ring, and postsale pen changed to 39.4, 15.1, and 54.5%, respectively, by the end of the market process. In addition, widespread contamination of the market environment with the hide markers was observed. At the abattoir, the initial prevalence of animals positive for the hide marker (11.1%) inoculated at unloading increased to 100% (hide before skinning) and 88.8% (skinned carcass). In addition, another marker inoculated on environmental surfaces in lairage pens, races, and stunning box was detected on 83.3% (hide before skinning) and 88.8% (skinned carcass). These results, although obtained with a relatively small number of animals, demonstrate that both the livestock market process and the unloading-to-skinning process at abattoirs can facilitate the extensive spread of microbial contamination on hides not just within, but also between, batches of animals.

Cost-effectiveness of N-butyl-2-cyanoacrylate (histoacryl) glue injections versus transjugular intrahepatic portosystemic shunt in the management of acute gastric variceal bleeding.

UNLABELLED: The management of bleeding gastric varices has not been standardized. Although transjugular intrahepatic portosystemic shunt (TIPS) is used in most centers, endoscopic treatment with N-butyl-2-cyanoacrylate (cyanoacrylate) glue has recently been shown to be effective. Cost-effectiveness analyses of these methods are lacking. METHODS: We performed a retrospective review of patients with bleeding gastric varices treated either by TIPS or cyanoacrylate glue injection. Economic analysis was based on direct costs for a fixed financial year. The two groups were compared for a period of 6 months follow-up, to liver transplantation, or death for each patient. RESULTS: Between January, 1995 and December, 1999, 20 patients with bleeding gastric varices had TIPS; 23 patients had cyanoacrylate glue injection from January, 2000 to October, 2001. There were no significant differences between the two groups in patient characteristics, transfusion requirement, and gastric variceal anatomy. In the TIPS group, 15/20 patients had the procedure performed within 24 h of hemorrhage, and 90% of stent insertions were successful. Complications consisted of two cases of pulmonary edema, two cases of severe encephalopathy, and a 15% stenosis rate at 6 months. In the glue group, there were 3 +/- 1.5 endoscopies and 2 +/- 1 injections per patient, with a 96% initial hemostasis. There was one case of (glue) pulmonary embolism and one blocked front endoscope lens, which required repair. The initial rebleed rate was significantly lower in patients who had TIPS (15% vs 30%, p = 0.005). The inpatient stay was shorter in the glue group (13 +/- 1 vs 18 +/- 2 days, p = 0.05), but there was no difference in the overall mortality rate. The median cost within 6 months of initial gastric variceal bleeding was $4,138 US dollars ($3,009-$8,290 US dollars) for glue versus $11,906 US dollars ($8,200-$16,770 US dollars) for TIPS (p < 0.0001). CONCLUSION: In this comparable group of patients, cyanoacrylate glue injection was more cost effective than TIPS in the management of acute gastric variceal bleeding. A prospective, randomized trial would be required to confirm our analysis.

Treatment of metastatic breast cancer with liver transplantation.

Resection of liver metastases is accepted as an appropriate treatment for colorectal metastases in suitable patients. Liver transplant is not often used for malignant disease as there is a high incidence of undetectable micrometastases elsewhere and recurrence is likely. The effects of immunosuppression may also enhance the growth of malignant cells at other sites. We report a case where a young patient with undiagnosed breast cancer with axillary and liver metastases underwent liver transplantation and is effectively leading a normal life 33 months after transplant.

The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats.

Efavirenz, a potent nonnucleoside reverse transcriptase inhibitor widely prescribed for the treatment of HIV infection, produces renal tubular epithelial cell necrosis in rats but not in cynomolgus monkeys or humans. This species selectivity in nephrotoxicity could result from differences in the production or processing of reactive metabolites, or both. A detailed comparison of the metabolites produced by rats, monkeys, and humans revealed that rats produce a unique glutathione adduct. The mechanism of formation and role of this glutathione adduct in the renal toxicity were investigated using both chemical and biochemical probes. Efavirenz was labeled at the methine position on the cyclopropyl ring with the stable isotope deuterium, effectively reducing the formation of the cyclopropanol metabolite, an obligate precursor to the glutathione adduct. This substitution markedly reduced both the incidence and severity of nephrotoxicity as measured histologically. Further processing of this glutathione adduct was also important in producing the lesion and was demonstrated by inhibiting gamma-glutamyltranspeptidase with acivicin pretreatment (10 mg/kg, IV) prior to dosing with efavirenz. Again, both the incidence and severity of the nephrotoxicity were reduced, such that four of nine rats given acivicin were without detectable lesions. These studies provide compelling evidence that a species-specific formation of glutathione conjugate(s) from efavirenz is involved in producing nephrotoxicity in rats. Mechanisms are proposed for the formation of reactive metabolites that could be responsible for the renal toxicity observed in rats.

Hepatocellular carcinoma in the cirrhotic liver: double-contrast MR imaging for diagnosis.

PURPOSE: To measure the sensitivity and accuracy of double-contrast magnetic resonance (MR) imaging for the diagnosis of hepatocellular carcinoma (HCC) in the cirrhotic liver. MATERIALS AND METHODS: Twenty-seven patients with MR features of dysplastic nodules and/or HCC were examined. T2-weighted spin-echo and T1-weighted gradient-echo imaging was performed before and after superparamagnetic iron oxide (SPIO) administration and immediately followed by T1-weighted gradient-echo imaging at 10, 40, and 120 seconds after bolus injection of a gadolinium-based contrast material. Nonenhanced, nonenhanced plus SPIO-enhanced, and nonenhanced plus SPIO-enhanced plus gadolinium-enhanced images were reviewed. Alternative-free response receiver operating characteristic (ROC) methodology was used to analyze the results, which were correlated with histopathologic findings after transplantation in 15 patients and at biopsy in 12. Lesions visualized with all three techniques were characterized as a dysplastic nodule or HCC, and ROC analysis was performed. RESULTS: For all observers, SPIO-enhanced MR imaging (mean accuracy, 0.76) was more accurate than nonenhanced MR imaging (mean accuracy, 0.64) (P <.04), and double-contrast MR imaging (mean accuracy, 0.86) was more accurate than SPIO-enhanced imaging (P <.05). Both types of lesions were correctly characterized with all three techniques, although observer confidence for lesion characterization was greatest with double-contrast MR imaging. CONCLUSION: Double-contrast MR imaging significantly improves the diagnosis of HCC compared with SPIO-enhanced and nonenhanced imaging (P <.01).

Production factors that influence the hygienic condition of finished beef cattle.

A survey was conducted at five UK abattoirs to trace the source of dirty beef cattle and identify factors in the production chain that contributed to their dirtiness. The Meat Hygiene Service Clean Livestock score categories were used and the animals' histories were traced back to their farm of origin. Comprehensive information was collected relating to the farm, transport and lairage phases for 675 cattle from 85 batches. The mean score of the animals on arrival at the abattoir was 1.57, with 2.8 per cent in categories 3 and 4, and none in category 5. Regression analysis, blocking the data by farm of origin, revealed that age, feed type, coat length, clipping, journey distance and time, and abattoir were the six principal factors that affected the scores. Cattle under 20 months of age were cleaner than older cattle. Dry diets resulted in lower scores than wet diets. 'Shorthair' cattle were cleaner than 'medium' or 'longhair' cattle, and cattle which had been clipped were cleaner than unclipped animals. The cattle which had travelled over 150 miles (15 per cent) were dirtier than the others. Within each abattoir there were variations in score between 1 and 4, and the mean scores of the five abattoirs ranged from 1.19 to 1.76. A significant part of this variation could only be accounted for by unmeasured variables such as abattoir management practice, assessors' categorisations and climate.

Pretransplant prediction of prognosis after liver transplantation in primary sclerosing cholangitis using a Cox regression model.

Liver transplantation remains the only treatment for patients with end-stage primary sclerosing cholangitis (PSC); however, selection criteria for the procedure and its timing remains uncertain. The aim of this study was to identify pretransplant variables associated with survival after transplantation and to devise a Cox regression model for prediction of post-transplant survival. We studied 118 patients transplanted for PSC at the Queen Elizabeth Hospital, Birmingham, UK, being followed for up to 91/4 years after the procedure. The association between pretransplant data and the post-transplant survival up to 1 year was studied using the logrank test (univariate analyses) and Cox multiple regression analysis. Univariate analyses showed the following variables to be associated with a decreased post-transplant survival: high serum creatinine, high serum bilirubin, biliary tree malignancy, previous upper abdominal surgery, hepatic encephalopathy, ascites, and Crohn's disease, whereas ulcerative colitis was associated with increased post-transplant survival (all P