bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats
Authors: King J. N. , Maurer M. , Toutain P. L.
Published: May 2003

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous14C‐benazeprilat and oral14C‐benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin‐converting enzyme (ACE) activity.

Benazeprilat data were fitted to an equation corresponding to a single‐compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 ∼ 1.0 h;Cl ∼ 0.125 L/kg/h), elimination being principally biliary (∼85%) rather than urinary (∼15%). Nevertheless, inhibition of ACE was long‐lasting (t1/216–23 h) due to high affinity binding of benazeprilat to ACE (Kd ∼ 3.5 mmol/L, IC50 ∼ 4.3 mmol/L).

Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).
Variable absorption of clavulanic acid after an oral dose of 25 mg/kg of Clavubactin® and Synulox® in healthy dogs
Authors: Vree T. B. , Dammers E. , Van Duuren E.
Published: May 2003

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration–time curves of amoxicillin and clavulanic acid in dogs, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration–time curves obtained following a single dose in an open, randomized, two‐way crossover study involving 24 male Beagle dogs treated with two Amoxi–Clav formulations (A Clavubactin® and B Synulox®, each with 200/50 mg). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half‐life of elimination of amoxicillin was 1.5 h (t1/2 = 1.52 ± 0.19 h, Cmax = 11.4 ± 2.74 μg/mL), and that of clavulanic acid 0.76 h (t1/2 = 0.71 ± 0.23 h, Cmax = 2.06 ± 1.05 μg/mL). There was a fivefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varied by a factor of 2. The mean ratio of the AUCt amoxicillin : clavulanic acid was 12.7 ± 3.65 for formulation A and 11.8 ± 5.22 for formulation B (P = 0.51).
The efficacy of a single intraperitoneal injection of oxolinic acid in the treatment of bacterial infections in goldsinny wrasse (Ctenolabrus rupestris) and corkwing wrasse (Symphodus melops) studied under field and laboratory conditions
Authors: Samuelsen O. B. , Kvenseth P. G. , Andreassen J. H. , Torkildsen L. , Ervik A. , Bergh Ø.
Published: May 2003

The efficacy of a single intraperitoneal injection of oxolinic acid to control an outbreak of atypical Aeromonas salmonicida infection in goldsinny wrasse (Ctenolabrus rupestris) and in the treatment of systemic vibriosis in corkwing wrasse (Symphodus melops) was examined. In addition a field study was performed to examine the effect of medication on the survival rate of goldsinny wrasse in Atlantic salmon cages. Four groups of wild caught goldsinny wrasse, each of 50 fish, were treated with an intraperitoneal injection of propylene glycol:saline (50:50) (control) or 50 mg/kg oxolinic acid at a concentration of 50 mg/mL. Three days after medication the fish in all groups were treated by an intraperitoneal injection of prednisolone acetate and an increase in seawater temperature from 9.0 to 11.5 °C. Cumulative mortalities were 18% in the two groups treated with oxolinic acid and 94 and 100% in the unmedicated control groups, giving a ‘relative percentage survival’ (RPS) value of 82%. A laboratory maintained population of originally wild caught corkwing wrasse experiencing high daily mortality was treated with oxolinic acid (50 mg/kg) or propylene glycol:saline (control). Cumulative mortalities were 84% (control) and 42% (oxolinic acid medicated group) giving an RPS value of 50%. In a field investigation using goldsinny wrasse approximately 30% were medicated with oxolinic acid (50 mg/kg) prior to stocking in cages with Atlantic salmon. In two of three cages the cumulative mortality was significantly lower (P = 0.025 and P < 0.001) in the medicated groups.
Comparative Disposition Kinetics and Plasma Protein Binding of Gentamicin Sulphate in Three Juvenile Animal Species
Authors: EL‐Sooud K. Abo
Published: May 2003

The pharmacokinetics of gentamicin was studied in lambs, calves and foals, respectively after single intravenous (i.v.) injections of 5 mg kg−1 body weight. The plasma concentration–time curves of gentamicin sulphate were best fitted to follow a two‐compartment open model in calves and foals and a three‐compartment open model in lambs. Gentamicin showed high plasma level at 5 min post‐injection. Then its concentration decreased gradually until its minimum detectable level at 10 and 12 h post‐injection in foals and calves, respectively, was reached. In contrast, the plasma concentrations were much higher in lambs and persisted up to 48 h from the onset of injection. Values of pharmacokinetic parameters for gentamicin sulphate in different animals after i.v. injections were calculated. Pharmacokinetic data in lambs demonstrated a triphasic decline in plasma gentamicin concentration with slow terminal elimination phase (washout phase) with (t1/2γ) of 7.7 h. Gentamicin showed a small volume of distribution Vd(ss) (80.3 ml kg−1) in lambs indicating that the drug is slightly distributed in extra‐vascular tissues. The overall rate of total body clearance ClB in lambs was (0.46 ml kg−1) slower than in calves (1.5 ml kg−1) and foals (2.7 ml kg−1). In vitro protein binding per cent of gentamicin sulphate in plasma were 16.80, 11.03 and 7.98% in lambs, calves and foals. The results of this study emphasize the importance of determining the pharmacokinetics of gentamicin in each species of young animals separately.
Influence of Post‐ovulatory Insemination on Sperm Distribution, Pregnancy and the Infiltration by Cells of the Immune System, and the Distribution of CD2, CD4, CD8 and MHC Class II Expressing Cells in the Sow Endometrium
Authors: Kaeoket K. , Persson E. , Dalin A.‐M.
Published: May 2003

This study investigates the distribution of leucocytes, CD2+, CD4+, CD8+ lymphocyte subpopulations and MHC class II expressing cells in the sow endometrium following post‐ovulatory insemination in relation to clinical findings and pregnancy outcome. Crossbred multiparous sows were inseminated once either at 15–20 h after ovulation [experiment 1, slaughtered at 20–25 h (5–6 h after artificial insemination (AI), group 1‐A, n = 4), at 70 h after ovulation (group 1‐B, n = 4), on day 11 (group 1‐C, n = 4, first day of standing oestrus = day 1) or on day 19 (group 1‐D, n = 4)] or 30 h after ovulation [experiment 2, slaughtered at 5–6 h after AI (group 2‐A, n = 4) or on day 19 (group 2‐D, n = 3)]. The uterine horns were flushed to control for the presence of spermatozoa and neutrophils and/or for recovery of oocytes and/or embryos. Mesometrial uterine samples were plastic embedded and stained. Cryofixed uterine samples were analysed by immunohistochemistry using mAbs to lymphocyte subpopulations and MHC class II molecules. Light microscopy was used to examine surface (SE) and glandular epithelia (GE), and connective tissue layers, both subepithelially (SL) and glandular (GL). In experiment 1, group 1‐A, only one sow had spermatozoa in the utero‐tubal junction (UTJ). Marked/moderated numbers of neutrophils and spermatozoa were observed in the flushings of two sows. In group 1‐B, altogether 23 of 48 oocytes were cleaved. Day 11 (1‐C), embryos with small diameter were observed. Day 19 (1‐D), no embryos were found but small pieces of foetal membrane were observed in one of the sows. In group 1‐A, large numbers of neutrophils were found within the SE and SL but with high individual variation. For T lymphocyte subpopulations, in the SE, most CD2+ cells were found in group 1‐A. For both SE and GE in all groups, the number of CD8+ cells was significantly larger than that of CD4+ cells. In experiment 2, group 2‐A, no sow had spermatozoa in the UTJ or in the uterine flushings. At day 19, no sow was pregnant. In group 2‐A, large numbers of neutrophils were found within the SE and SL but with high individual variation. At day 19, high E2 levels showed a hormonal prooestrous stage but the endometrial neutrophil infiltration normally expected at pro‐oestrus was absent. In conclusion, post‐ovulatory insemination (about 18 h after ovulation) resulted in impaired spermatozoa transport within the uterus and embryonic degeneration. In sows post‐ovulatory inseminated at a later stage (30 h after ovulation), no sow was pregnant. In both experiments, disturbed immune cell patterns were observed in some individuals.
Risk factors for iron deficiency in a hospitalized urban New Zealand population
Authors: Grant CC , Wall CR , Wilson C , Taua N
Published: May 2003

Objective:  To determine which dietary practices and sociodemographic factors are associated with iron deficiency anaemia (IDA) and iron deficiency (ID) in hospitalized New Zealand children.

Methodology:  A prospective study of children 8−23 months of age hospitalized with an acute illness from 1997 to 1999. Iron deficiency was defined as abnormal values for two out of three of serum ferritin (< 10 µg/L), serum iron saturation (< 10%) and red cell distribution width (> 14.5%). Iron deficiency anaemia (IDA) was defined as ID + serum haemoglobin concentration <110 g/L. Those with IDA or ID were compared separately with those who were not iron deficient.

Results:  Three hundred and ninety‐one children were enrolled. Two hundred and twenty had IDA, 73 had ID and 98 were not iron deficient. In a multivariate analysis, those children who had a diagnosis of pneumonia (odds ratio 4.43, 95% CI 1.49, 13.13) were Pacific (odds ratio 6.31, 95% CI 2.14, 18.63), were currently drinking breast milk (odds ratio 10.22, 95% CI 2.95, 35.42), had a mother who restricted her meat intake during pregnancy (odds ratio 4.40, 95% CI 1.53, 12.64) or lived in a household with more than three children (odds ratio 7.42, 95% CI 1.88, 29.34) were at increased risk of IDA. Those children who were Pacific (odds ratio 5.44, 95% CI 1.37, 21.65) or who drank tea (odds ratio 7.88, 95% CI 1.10, 56.33) were at increased risk of ID. Those with a diagnosis of gastroenteritis (odds ratio 0.16, 95% CI 0.03, 0.75) were at decreased risk of ID.

Conclusions:  Both dietary and non‐dietary factors are associated with an increased risk of IDA and ID in New Zealand children. In this hospitalized sample, more non‐dietary than dietary factors were associated with poor iron status.
Hepatitis A vaccination options for Australia
Authors: MacIntyre CR , Burgess MA , Hull B , McIntyre PB
Published: May 2003

Abstract:  The epidemiology of hepatitis A is changing, with an increasing proportion of the population becoming susceptible to infection. The burden of hepatitis A is comparable to that of other vaccine‐preventable diseases for which new vaccines are available. Options for vaccination include selective programmes for high‐risk groups, which could involve screening prior to vaccination, or universal programmes for infants and/or adolescents. Selective programmes have been shown to be highly cost‐effective if well implemented, but there is evidence that they might be poorly implemented. If a universal vaccination programme were considered for Australia, an infant programme, with doses at 18 months and 2 years, possibly with an additional adolescent programme, would be the recommended option. Universal hepatitis A vaccination for infants and/or adolescents is of comparable cost‐effectiveness compared with other preventive strategies, but needs to be considered in the context of competing vaccination options.
Paediatric bronchiectasis in the twenty‐first century: Experience of a tertiary children's hospital in New Zealand
Authors: Edwards EA , Asher MI , Byrnes CA
Published: May 2003

Objective:  Despite its decline in developed countries, bronchiectasis appeared to be a common diagnosis in Auckland, New Zealand children. The aims of this study were: to document the number of children in Auckland with bronchiectasis, their severity, clinical characteristics and possible aetiologies; to assess whether there was a relationship between ethnicity and poverty; and to estimate a crude bronchiectasis prevalence rate for New Zealand.

Methods:  A retrospective review of the case histories of all children attending a tertiary children's hospital in Auckland with bronchiectasis diagnosed by high‐resolution chest computed tomography (CT) scan, during the period 1998−2000 was undertaken. Data collected included patient demographics, number of hospitalizations pre‐ and post‐diagnosis, lung function tests, radiology and investigations. The New Zealand deprivation 1996 index was applied to the data to obtain a measure of socio‐economic status.

Results:  Bronchiectasis was found to be common, with an estimated prevalence of approximately one in 6000 in the Auckland paediatric population. It was disproportionately more common in the Pacific Island and Maori children. In Pacific Island children, bronchiectasis not caused by cystic fibrosis was nearly twice as common in the general population than cystic fibrosis. Socio‐economic deprivation and low immunization rates may be significant contributing factors. The bronchiectasis seen was extensive. Ninety‐three percent had bilateral disease and 64% had involvement of four or more lobes on chest CT scan. A wide range of comorbidities and underlying aetiologies were evident.

Conclusions:  Paediatric bronchiectasis in Auckland, New Zealand, is common but underresourced. Only the most severe cases are being recognized, providing a significant challenge for paediatric health professionals.
Television, computer use and body mass index in Australian primary school children
Authors: Wake M , Hesketh K , Waters E
Published: May 2003

Objective:  To investigate relationships between children's body mass index (BMI) and parent reports of children's television and video game/computer habits, controlling for other potential risk factors for paediatric obesity.

Methods:  Child BMI was calculated from measured height and weight collected in 1997 as part of a large, representative, cross‐sectional study of children in Victoria, Australia. Parents reported the amount of time children watched television and used video games/computers, children's eating and activity habits, parental BMI and sociodemographic details.

Results:  A total of 2862 children aged 5−13 years participated. Child mean BMI z‐score was significantly related to television (F = 10.23, P < 0.001) but not video game/computer time (F = 2.23, P = 0.09), but accounted for only 1 and 0.2% of total BMI variance, respectively. When parental BMI, parental education, number of siblings, food intake, organized exercise and general activity level were included, television ceased to be independently significantly related to child BMI. Using adjusted logistic regression, the odds of being overweight and obese generally increased with increasing television viewing. No relationship was found for video game/computer use.

Conclusions:  A small proportion of variance in child BMI was related to television, but not video game/computer time. This was far outweighed by the influence of other variables. Causal pathways are likely to be complex and interrelated.
Diversity and dynamics of microbial communities in soils from agro‐ecosystems
Authors: Buckley Daniel H. , Schmidt Thomas M.
Published: May 2003

Soil microbial communities are integrally involved in biogeochemical cycles and their activities are crucial to the productivity of terrestrial ecosystems. Despite the importance of soil microorganisms, little is known about the distribution of microorganisms in the soil or the manner in which microbial community structure responds to changes in land management. We investigated the structure of microbial communities in the soil over two years in a series of replicated plots, that included, cultivated fields, fields abandoned from cultivation and fields with no history of cultivation. Microbial community structure was examined by monitoring the relative abundance of ribosomal RNA (rRNA) from seven of the most common bacterial groups in soil (the Alpha and Beta Proteobacteria, Actinobacteria, Cytophagales, Planctomycetes, Verrucomicrobia and the Acidobacteria) and the Eukarya. These data reveal that soil microbial communities are dynamic, capable of significant change at temporal scales relative to seasonal events. However, despite temporal change in microbial community structure, the rRNA relative abundance of particular microbial groups is affected by the local environment such that recognizable patterns of community structure exist in relation to field management.
Phylogeny and distribution of nitrate‐storing Beggiatoa spp. in coastal marine sediments
Authors: Mußmann Marc , Schulz Heide N. , Strotmann Bettina , Kjær Thomas , Nielsen Lars P. , Rosselló‐Mora Ramon A. , Amann Rudolf I. , Jørgensen Bo Barker
Published: May 2003

Filamentous sulphide‐oxidizing Beggiatoa spp. often occur in large numbers in the coastal seabed without forming visible mats on the sediment surface. We studied the diversity, population structure and the nitrate‐storing capability of such bacteria in the Danish Limfjorden and the German Wadden Sea. Their distribution was compared to the vertical gradients of O2, NO3– and H2S as measured by microsensors. The main Beggiatoa spp. populations occurred in a 0.5–3 cm thick intermediate zone, below the depth of oxygen and nitrate penetration but above the zone of free sulphide. The Beggiatoa spp. filaments were found to store nitrate, presumably in liquid vacuoles up to a concentration of 370 mM NO3–, similar to the related large marine sulphur bacteria, Thioploca and Thiomargarita. The observations indicate that marine Beggiatoa spp. can live anaerobically and conserve energy by coupling sulphide oxidation with the reduction of nitrate to dinitrogen and/or ammonia. Calculations of the diffusive nitrate flux and the potential sulphide oxidation by Beggiatoa spp. show that the bacteria may play a critical role for the sulphur cycling and the nitrogen balance in these coastal environments. 16S rDNA sequence analysis shows a large diversity of these uncultured, nitrate‐storing Beggiatoa spp. Smaller (9–17 µm wide) and larger (33–40 µm wide) Beggiatoa spp. represent novel phylogenetic clusters distinct from previously sequenced, large marine Beggiatoa spp. and Thioploca spp. Fluorescence in situ hybridization (FISH) of the natural Beggiatoa spp. populations showed that filament width is a conservative character of each phylogenetic species but a given filament width may represent multiple phylogenetic species in a mixed population.
Osteoporosis after liver transplantation
Authors: Compston Juliet E.
Published: May 2003

Osteoporosis remains a serious potential complication of liver transplantation, although its incidence may be significantly reduced by the use of lower doses of glucocorticoids. Additional factors likely to contribute to its pathogenesis include other immunosuppressive agents, particularly cyclosporin A and FK506, vitamin D insufficiency, secondary hyperparathyroidism, hypogonadism and pre-existing bone disease. Bone density assessment and spinal X-rays should be performed before transplantation to assess subsequent fracture risk and vitamin D and gonadal status assessed. Measures should be taken to optimise bone health prior to transplantation; in those with low bone mineral density and/or previous fragility fracture, prophylaxis against bone loss after transplantation should be considered. Although anti-fracture efficacy has not been established for any agent there is evidence, mainly in patients undergoing other forms of solid organ transplantation, that repeated infusions of pamidronate may be effective in preventing bone loss.
Effect of molecular adsorbent recirculating system in hepatitis C virus-related intractable pruritus
Authors: Doria Cataldo , Mandalá Lucio , Smith Jan , Vitale Claudio H. , Lauro Augusto , Gruttadauria Salvatore , Marino Ignazio R. , Foglieni Carlo Scotti , Magnone Mario , Scott Victor L.
Published: May 2003

Intractable pruritus is more common in cholestatic liver diseases and may be the presenting symptom and/or major complaint of hepatitis C and/or hepatitic C virus—related cirrhosis. From September 2000 to May 2002, three patients affected by intractable pruritus secondary to hepatitis C cirrhosis that failed medical treatment were treated with a molecular adsorbent recirculating system (MARS). MARS is an artificial liver support system that aims to clear the blood of metabolic waste products normally metabolized by the liver. Each patient underwent seven MARS sessions. Liver function tests, the 36-Item Short Form quality-of-life test, visual analog scale for itching, and bile acid measurement in the serum, albumin circuit and ultrafiltrate were performed before and after each MARS session. Moreover, at hospital admission, each patient underwent a psychological workup and abdominal imaging study. Subjective improvement in pruritus and quality of life, along with a decrease in serum bile acid concentration, was observed in every patient; no patient underwent retreatment and/or liver transplantation up to a 9-month follow-up. One patient died 201 days after MARS treatment. Although we observed a decreased level of serum bile acids, one cannot conclude that this was the mechanism of action for the reduction in pruritus intensity in patients in our series. Different toxins and/or a placebo effect might have had a role in this setting
A novel method for liver repopulation: Heterografting of micro-liver slices in a rat model
Authors: Gur Eyal , Deckel Roi , Zvibel Isabel , Brazovsky Eli , Kariv Revital , Brill Shlomo , Halpern Zamir , Oren Ran
Published: May 2003

The field of hepatocyte transplantation is developing, with encouraging results. However, current approaches are still unsuitable for human cell therapy, and safer and more applicable methods need to be developed. We recently successfully transplanted pieces of liver tissue (slices), cut from a wild-type Fischer 344 dipeptidyl peptidase IV (DPP IV)-positive rat and introduced into the liver of a DPP IV-deficient Fischer 344 rat. One month after the procedure, positive DPP IV enzymatic activity was detected in transplanted liver slices. These results suggest that transplantation of tissue slices is feasible and safe and could serve as a promising alternative to hepatocyte transplantation.
Duration of antiviral therapy for cholestatic HCV recurrence may need to be indefinite
Authors: Gopal Deepak V. , Rosen Hugo R.
Published: May 2003

Progressive liver allograft injury related to hepatitis C virus (HCV) recurrence occurs in 20% to 30% of liver transplant recipients within the first 5 years. In particular, the subset of patients who develop the severe cholestatic variant has an extremely high mortality. We report our center’s experience with 7 cholestatic patients who were treated with interferon alfa-2b (3 million IU three times per week initially) in combination with ribavirin. In 4 of the 7 patients, HCV-RNA in serum became undetectable, and in an additional patient, normalization of serum bilirubin was achieved despite persistent viremia. Discontinuation of antiviral therapy by patient choice, intolerance of side effects, or occurrence of infection were followed temporally by rapid relapses of the cholestatic syndrome, allograft failure, and death. The only 2 patients alive in remission of this syndrome have been maintained on antiviral therapy for an average of 32 months. Thus, based on our experience, we recommend that duration of antiviral therapy in the subset of patients with cholestatic HCV recurrence should be indefinite.
Liver transplantation for HCV-associated liver cirrhosis: Predictors of outcomes in a population with significant genotype 3 and 4 distribution
Authors: Zekry A , Whiting P , Crawford D H , Angus P W , Jeffrey G P , Padbury R T , Gane E J , McCaughan G W
Published: May 2003

End-stage liver disease associated with hepatitis C virus (HCV) infection is now the leading indication for liver transplantation in adults. However, reinfection of the graft is universal. We aimed to determine predictors of outcome of HCV-liver transplant recipients in the Australian and New Zealand communities. The following variables were analysed: demographic factors, coexistent pathology at the time of transplantation, HCV genotype, and donor age. Outcomes measures were: 1. mortality; 2. development of HCV-related complications, which were stage 3 or 4 fibrosis, or mortality from HCV-related graft failure, or both. Between January 1989 and December 30, 1999, 182 patients were transplanted for HCV-associated cirrhosis. The median follow-up period was 4 years (range, 0 to 13 years). Genotype data were available on 157 patients. The distribution of genotypes among the 157 patients was as follows: 36 (23%) genotype 1a, 30 (19%) genotype 1b, 4 (9%) genotype 1, 17 (11%) genotype 2, 41 (26%) genotype 3a, and 16 (10%) genotype 4. Eight (5%) patients were HCV-polymerase chain reaction (PCR)-negative (but HCV-antibody-positive). Donor age and genotype 4 were associated with an increased risk of retransplantation or death (P < .001 and .05, respectively). Meanwhile, donor age, genotype 4, and pretransplant excess alcohol were risk factors for the development of HCV-related complications (P = .004, .008, and .02, respectively). In contrast, patients with genotype 3a were less likely to develop HCV-related complications (P = .05). In a population of HCV liver transplant recipients with a heterogeneous genotype distribution, donor age, and genotype 4, were predictors of a worse outcome, whereas genotype 3 was associated with a more favorable outcome.
Tumor necrosis factor-α promoter polymorphisms and the risk of rejection after liver transplantation: A case control analysis of 210 donor-recipient pairs
Authors: Jazrawi Saad F. , Zaman Atif , Muhammad Zafaruddin , Rabkin John M. , Corless Christopher L. , Olyaei Ali , Biggs Amy , Ham John , Chou Sunwen , Rosen Hugo R.
Published: May 2003

After orthotopic liver transplantation (OLT), allograft rejection remains an important problem and is the major reason that immunosuppressive therapy must be administered. Tumor necrosis factor-α (TNF-α) is a proinflammatory mediator that is central to the immune response, and intragraft expression of this cytokine is increased during acute cellular rejection (ACR). Polymorphisms within the TNF promoter have been identified and correlated with alterations in production. The aims of this study were to determine if an individual patient’s propensity to develop ACR is related to the presence of these genetic polymorphisms (either alone or in combination) within donor and recipient tissue and to determine if these polymorphisms affect patient survival after OLT. The study group consisted of 210 patients who underwent OLT between 1989 and 1999 with at least 6 months survival, including 42 cases who had evidence of acute cellular rejection (biopsy-proven, elevated enzymes, and response to increased immunosuppression) and were matched 4:1 to controls (n = 168) with similar age, gender, underlying liver disease, date of transplant, and baseline immunosuppression. The underlying liver diseases were hepatisis C virus (HCV)/alcohol (70), HCV alone (50), alcohol (30), primary biliary cirrhosis (15), primary sclerosing cholangitis (15), autoimmune hepatitis/cirrhosis (10), cryptogenic (15), and hepatitis B virus (HBV) (5). DNA was extracted from paraffin-embedded donor and recipient liver tissue (total 420 samples), amplified, and sequenced for TNF single-nucleotide polymorphisms (TNFA-308 A/G and TNFA-238 A/G). We found no differences between the TNF allelic distributions among donors without liver disease (presumably representative of a normal control population) and patients with end-stage liver disease undergoing OLT. Multivariate analysis revealed no association with TNF polymorphisms (within donor or recipient tissue) and rejection risk or patient survival after transplantation. In this large case control analysis of patients undergoing liver transplantation for diverse etiologies, TNF promoter polymorphisms were not independently associated with rejection or survival.
Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution
Authors: Wyllie Samuel , Seu Philip , Gao Feng Q. , Goss John A.
Published: May 2003

Very little is known about iron metabolism and the mediators of iron metabolism in liver subjected to cold storage before transplantation. Therefore, in this study, we investigated the effect of cold storage on iron homeostasis in the rat liver. When livers were stored at 4°C in University of Wisconsin solution for up to 6 and 24 hours, significant increases occurred in the labile iron pool, ferritin protein, and heme oxygenase activity. Significant decreases in heme content and iron regulatory protein 1 and 2 binding activities occurred by 24 hours. Liver injury indicated by significant increases in University of Wisconsin solution transaminase activity and liver lipid hydroperoxide levels occurred by 6 and 24 hours. Taken together, these results suggest that during pretransplantation cold storage of the liver, an aberrant iron homeostasis develops that contributes to preservation injury, and predisposes the liver to reperfusion injury by iron-dependent reactive oxygen species/Fenton reaction.
The safety and outcome of joint replacement surgery in liver transplant recipients
Authors: Levitsky Josh , Te Helen S. , Cohen Stanley M.
Published: May 2003

A small group of patients may require total hip arthroplasty, total knee arthroplasty, or other joint replacement surgery after OLT for osteoporotic fractures, osteonecrosis, and osteoarthritis. Although arthroplasty is safe in the general population, its safety in liver transplant recipients is unclear. The aim of the study was to determine the safety and outcome of joint replacement surgery in our liver transplant recipients. A retrospective analysis was performed on all liver transplant recipients who had total joint arthroplasty at a single teaching institution between 1986 and 2002. Data regarding major intraoperative and postoperative complications was obtained from the medical charts and a hospital-based computer system. Of over 1,200 liver transplant recipients, we identified 7 patients who underwent 12 total arthroplasties (8 knee, 3 hip, 1 ankle). Joint replacements were performed electively for osteonecrosis (5 of 12) and osteoarthritis (5 of 12), whereas two hip arthroplasties were performed emergently for fractures. All patients with osteonecrosis or hip fracture had been treated with prolonged corticosteroids. There were no deaths or major complications in the intraoperative and postoperative periods. On long-term follow-up, no patients have had pain, dislocation, or infection in the postsurgical joint. No joint revision surgery has been required. In conclusion, a small number of stable liver transplant recipients at our institution underwent joint replacement surgery without major short-term or long-term complications. Our study suggests that joint replacement surgery may be safely and successfully performed in this population, although larger, randomized, prospective trials are needed to confirm our findings.
Treatment of recurrent hepatitis C in liver transplant recipients: Is there any histologic benefit?
Authors: Nair Satheesh , Khan Saad , Loss George , Eason James , Blazek Jamie , Lipscomb Jeanie , Mason Andrew
Published: May 2003

The benefit of antiviral treatment in recurrent hepatitis C after liver transplantation remains unclear. The aim of this study was to determine whether antiviral treatment improved histologic outcome in recurrent hepatitis C. All patients who were transplanted for hepatitis C from January, 1998 to December, 2000 were offered treatment with interferon alpha 2b (3 million units three times per week) and ribavirin (800 mg/d) for 1 year. All patients underwent liver biopsy before and after treatment. Virologic assay was performed at 3 months and at 1 year. Among the 33 patients, 13 managed 80% of total doses of both interferon and ribavirin. Dose reduction or discontinuation was necessary in others. In an intention to treat analysis, the overall virologic response at 3 months and 1 year was 27% and 12%, respectively. On an intention to treat basis, the overall histologic response showed little benefit. In the subgroup of patients who received full treatment, there was a trend towards benefit in regard to inflammation (per histologic activity index [HAI] score). However, the fibrosis score was comparable in both groups, and complete antiviral treatment did not improve the fibrosis score or prevent progression of fibrosis. In the posttransplant setting, it is often extremely difficult to give a full course of treatment with existing antiviral regimes. In an intention to treat analysis, the overall benefit of antiviral treatment in recurrent hepatitis C is disappointing, with little impact on the progression of fibrosis.
Small hepatocellular carcinoma in Child A cirrhotic patients: Hepatic resection versus transplantation
Authors: Bigourdan Jean-Marc , Jaeck Daniel , Meyer Nicolas , Meyer Carole , Oussoultzoglou Elie , Bachellier Philippe , Weber Jean-Christophe , Audet Maxime , Doffoël Michel , Wolf Philippe
Published: May 2003

Hepatic resection (HR) is the treatment of choice for small hepatocellular carcinoma (HCC) in a noncirrhotic liver, whereas liver transplantation (LT) offers better results in patients with impaired hepatic function (Child B and C). However, it is still debated whether HR or LT is the best strategy for patients with Child A cirrhosis. We conducted a retrospective study on 37 consecutive patients with Child A cirrhosis and small HCC, treated between 1991 and 1999. Seventeen of these patients, who underwent LT, were compared with 20 patients who underwent HR, and prognostic factors for survival and tumor recurrence were analyzed. The primary endpoints were the intention-to-treat, 3- and 5-year survival, and 3- and 5-year recurrence-free survival. Three- and 5-year patient survival rate both were significantly (P = .04) higher in the LT group (87% and 71%, respectively) than in the HR group (67 and 36% respectively). Similarly, the 3- and 5- year recurrence-free survival rates were 87% and 80% for the LT group, and 52% and 40% for the HR group (P = .03). Absence of microscopic vascular invasion was the only other prognostic factor correlated with significantly better recurrence-free survival (P = .02). Therefore, we concluded that in patients with Child A cirrhosis and small HCC, liver transplantation resulted in better overall and disease-free survival than HR.
Bone mineral density in long-term survivors following pediatric liver transplantation
Authors: Guthery Stephen L. , Pohl John F. , Bucuvalas John C. , Alonso Maria H. , Ryckman Frederick C. , Balistreri William F. , Heubi James E.
Published: May 2003

We sought to estimate the prevalence of reduced bone mass, defined by lumbar spine bone mineral density (LS-BMD) (z-score < −2.0), and to determine the factors associated with LS-BMD after liver transplantation in children and adolescents. LS-BMD z-scores were measured in a sample of subjects who had undergone liver transplantation in childhood or adolescence using dual energy x-ray absorptiometry (DXA). One hundred nine patients underwent DXA. The mean age at transplantation was 4.3 years (median, 1.8 years), and mean duration since transplantation was 6.2 years (median, 5.8 years). The mean weight z-score was −0.130 (SD, 1.26). The mean LS-BMD z-score was −0.243 (SD, 1.27). Eight patients, or 7.3% (95% confidence interval [CI], 2.4% to 12.2%), had reduced bone mass. Compared with those without reduced bone mass, subjects with reduced bone mass were more likely to have been treated for rejection at least once (87.5% versus 51.5%; P = .07), and had greater cumulative exposure to prednisone during the year before DXA (92.3 versus 26.2 mg/kg/y; P = .001). Multiple linear regression determined that LS-BMD z-score was positively associated with time since transplantation and weight z-score and negatively associated with cumulative prednisone exposure. Serum 25-OH vitamin D was measured and reduced (< 15 ng/mL) in 5 of 87 patients, one of whom had reduced bone mass. In conclusion, the prevalence of reduced bone mass was 7.3% in our population. Only certain patients appear to be at risk for low BMD, including those with a history of rejection. Screening for reduced bone mass may be appropriate for these patients.
Steroid Hormone Synthesis by Vaccinia Virus Suppresses the Inflammatory Response to Infection
Authors: Reading Patrick C. , Moore Jeffrey B. , Smith Geoffrey L.
Published: May 2003

The 3β-hydroxysteroid dehydrogenase (3β-HSD) isoenzymes play a key role in cellular steroid hormone synthesis. Vaccinia virus (VV) also synthesizes steroid hormones with a 3β-HSD enzyme (v3β-HSD) encoded by gene A44L. Here we examined the effects of v3β-HSD in VV disease using wild-type (vA44L), deletion (vΔA44L), and revertant (vA44L-rev) viruses in a murine intranasal model. Loss of A44L was associated with an attenuated phenotype. Early (days 1–3) after infection with vΔA44L or control viruses the only difference observed between groups was the reduced corticosterone level in lungs and plasma of vΔA44L-infected animals. Other parameters examined (body weight, signs of illness, temperature, virus titres, the pulmonary inflammatory infiltrate, and interferon [IFN]-γ levels) were indistinguishable between groups. Subsequently, vΔA44L-infected animals had reduced weight loss and signs of illness, and displayed a vigorous pulmonary inflammatory response. This was characterized by rapid recruitment of CD4+ and CD8+ lymphocytes, enhanced IFN-γ production and augmented cytotoxic T lymphocyte activity. These data suggest that steroid production by v3β-HSD contributes to virus virulence by inhibiting an effective inflammatory response to infection.
Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis
Authors: Hegen Martin , Sun Linhong , Uozumi Naonori , Kume Kazuhiko , Goad Mary E. , Nickerson-Nutter Cheryl L. , Shimizu Takao , Clark James D.
Published: May 2003

Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2α (cPLA2α) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2α plays a key role in the development of CIA, we backcrossed cPLA2α-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2α-deficient mice compared with wild-type littermates. At completion of the study, >90% of the wild-type mice had developed disease whereas none of the cPLA2α-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2α-deficient mice. Although the disease scores differed significantly between cPLA2α mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2α in the pathogenesis of CIA.
A Human Minor Histocompatibility Antigen Resulting from Differential Expression due to a Gene Deletion
Authors: Murata Makoto , Warren Edus H. , Riddell Stanley R.
Published: May 2003

Minor histocompatibility antigens (minor H antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte antigen identical hematopoietic stem cell transplantation. Only a few human minor H antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human minor H antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and antigen-presenting cells. In contrast to previously defined human minor H antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating minor H antigens in humans.
AID Mediates Hypermutation by Deaminating Single Stranded DNA
Authors: Dickerson Sarah K. , Market Eleonora , Besmer Eva , Papavasiliou F. Nina
Published: May 2003

Activation-induced deaminase (AID) is a protein indispensable for the diversification of immunoglobulin (Ig) genes by somatic hypermutation (SHM), class switch recombination (CSR), and gene conversion. To date, the precise role of AID in these processes has not been determined. Here we demonstrate that purified, tetrameric AID can deaminate cytidine residues in DNA, but not in RNA. Furthermore, we show that AID will bind and deaminate only single-stranded DNA, which implies a direct, functional link between hypermutation and transcription. Finally, AID does not target mutational hotspots, thus mutational targeting to specific residues must be attributed to different factors.
Default Bayesian Priors for Regression Models with First‐Order Autoregressive Residuals
Authors: Ghosh Malay , Heo Jungeun
Published: May 2003

Abstract.The objective of this paper is to develop default priors when the parameter of interest is the autocorrelation coefficient in normal regression models with first‐order autoregressive residuals. Jeffreys’ prior as well as reference priors are found. These priors are compared in the light of how accurately the coverage probabilities of Bayesian credible intervals match the corresponding frequentist coverage probabilities. It is found that the reference priors have a definite edge over Jeffreys’ prior in this respect. Also, the credible intervals based on these reference priors seem superior to similar intervals based on certain divergence measures.
First‐Order Autoregressive Processes with Heterogeneous Persistence
Authors: JASIAK JOANN
Published: May 2003

Abstract.We propose a semi‐nonparametric method of identification and estimation for Gaussian autoregressive processes with stochastic autoregressive coefficients. The autoregressive coefficient is considered as a latent process with either a moving average or regime switching representation. We develop a consistent estimator of the distribution of the autoregressive coefficient based on nonlinear canonical decomposition of the observed process. The approach is illustrated by simulations.
Gaussian Semi‐parametric Estimation of Fractional Cointegration
Authors: Velasco Carlos
Published: May 2003

Abstract. We analyse consistent estimation of the memory parameters of a nonstationary fractionally cointegrated vector time series. Assuming that the cointegrating relationship has substantially less memory than the observed series, we show that a multi‐variate Gaussian semi‐parametric estimate, based on initial consistent estimates and possibly tapered observations, is asymptotically normal. The estimates of the memory parameters can rely either on original (for stationary errors) or on differenced residuals (for nonstationary errors) assuming only a convergence rate for a preliminary slope estimate. If this rate is fast enough, semi‐parametric memory estimates are not affected by the use of residuals and retain the same asymptotic distribution as if the true cointegrating relationship were known. Only local conditions on the spectral densities around zero frequency for linear processes are assumed. We concentrate on a bivariate system but discuss multi‐variate generalizations and show the performance of the estimates with simulated and real data.
Book Reviews
Authors: Porfiriev Boris
Published: May 2003

Pandora's Poison: Chlorine, Health, and a New Environmental Strategy, Joe Thornton, MIT Press, Cambridge, MA (2000), 599 pp.
Is a Two‐State Solution Still Viable?
Authors: Cohen Stephen P. , Hudson Michael C. , Guttman Nathan , Jahshan Khalil E.
Published: May 2003

The following is an edited transcript of the thirty‐second in a series of Capitol Hill conferences convened by the Middle East Policy Council. The meeting was held on April 11, 2003, in the Dirksen Senate Office Building with Chas. W. Freeman, Jr., moderating.
Social Vulnerability to Environmental Hazards*
Authors: Cutter Susan L. , Boruff Bryan J. , Shirley W. Lynn
Published: May 2003

Objective.County‐level socioeconomic and demographic data were used to construct an index of social vulnerability to environmental hazards, called the Social Vulnerability Index (SoVI) for the United States based on 1990 data.

Methods.Using a factor analytic approach, 42 variables were reduced to 11 independent factors that accounted for about 76 percent of the variance. These factors were placed in an additive model to compute a summary score—the Social Vulnerability Index.

Results.There are some distinct spatial patterns in the SoVI, with the most vulnerable counties clustered in metropolitan counties in the east, south Texas, and the Mississippi Delta region.

Conclusion.Those factors that contribute to the overall score often are different for each county, underscoring the interactive nature of social vulnerability—some components increase vulnerability; others moderate the effects.
Is Combat Pay Effective? Evidence from Operation Desert Storm*
Authors: Dunn Lucia F.
Published: May 2003

Objective. To determine whether combat pay for U.S. Army officers has been adequate to maintain troop strength during wartime in the all‐volunteer military.

Methods. Data from a panel survey of 3,800 officers collected one year prior to Operation Desert Storm and again during the Iraqi engagement are used. The primary economic indicator of work disutility—the marginal rate of substitution (MRS) or tradeoff of time for money—is estimated; and the MRS‐hourly pay relationship in both time periods is determined.

Results. Combat pay was found to be generally adequate to offset increases in wartime disutility. Additional payment was required for male officers in only two branch groups, and these involved relatively small numbers of personnel compared to the larger Combat Arms branches.

Conclusions. We find no evidence that a market‐oriented volunteer army could not maintain adequate troop strength during wartime, at least in environments similar to that of the early 1990s when these data were collected.