Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CC-RCC) is the most lethal of all genitourinary cancers. The functional loss of the von Hippel-Lindau (VHL) gene occurs in 90% of CC-RCC, driving cancer progression. The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the library of pharmacologically active compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by small interfering RNA (siRNA) selectively reduced the colony-forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-27632 treatment, whereas downregulation of ROCK2 had no effect. In addition, two other ROCK inhibitors, RKI 1447 and GSK 429286, selectively targeted VHL-deficient CC-RCC. CC-RCC treatment with ROCK inhibitors is cytotoxic and cytostatic based on bromodeoxyuridine (BrdU) assay, propidium iodide (PI) staining and growth curves, and blocks cell migration based on transwell assay. On the one hand, knockdown of hypoxia-inducible factor (HIF) ß in the VHL-deficient CC-RCC had a protective effect against Y-27632 treatment, mimicking VHL reintroduction. On the other hand, CC-RCCVHL cells were sensitized to Y-27632 treatment in hypoxia (2% O2). These results suggest that synthetic lethality between ROCK inhibition and VHL deficiency is dependent on HIF activation. Moreover, HIF1α or HIF2α overexpression in CC-RCCVHL cells is sufficient to sensitize them to ROCK inhibition. Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 CC-RCC tumors in mice. Thus, ROCK inhibitors represent potential therapeutics for VHL-deficient CC-RCC.

'Dale': an interpretative phenomenological analysis of a service user's experience with a crisis resolution/home treatment team in the United Kingdom.

WHAT IS KNOWN ABOUT THE SUBJECT?: This paper describes crisis resolution/home treatment (CRHT) teams, which are part of mental health services in the United Kingdom. CRHT is expected to assist individuals in building resilience and work within a recovery approach. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This paper arises from an interview with one individual, Dale, as part of a larger study exploring service users' experiences of CRHT. It adds to the body of narrative knowledge in CRHT through Dale's co-authorship of this paper, reflecting on his original interview 4 years later, with co-authors providing critical interpretation of his experience, in turn supported by cognate literature. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Implications for practice are considered, themselves mediated through Dale's own descriptions of how CRHT interventions impacted upon him. These impacts are analysed with respect to three themes: Resilience, Recovery and Power. It is centrally contended that clinicians need to more clearly comprehend three core matters. First, what resilience 'is' for service users as well as the complex process through which these individuals move in developing resilience. Second, the distinction that service users might make between 'recovery' and 'functionality', and how this in turn can impact on individuals both in personal and socioeconomic sense. Finally, the mechanics of power within CRHT contexts and how these interpersonal dynamics can affect the relationship between service user and clinician in practice. ABSTRACT: Introduction and Aim The central purpose of this paper, part of a larger study exploring the experiences of Service Users (SUs) with CRHT, is to emphasise the importance of the SU voice itself within the domain. Following an interrogation of the historical contexts of CRHT. Method This paper uses interpretative phenomological approach around detailed thematic examination of an extended, semi-structured with a single SU: Dale. Moreover, four years after the interview was originally conducted, Dale was himself invited to reflect upon, and critically re-evaluate, his initial participation as a co-author of this paper. In this way, a genuinely participant-centred narrative on experiences with CRHT could be generated. Implications for Practice This resulted in Dale describing what 'crisis' meant to him, and his personal journey within that crisis. Although framing some experiences as negative, he primarily argues that the CRHT team was very personable, affirming his personal values and beliefs, and encouraging him to use coping skills that he had utilised effectively in prior periods of crisis. Analysis highlights three major themes permeating Dale's narrative: Resilience, Recovery and Power. It is contended that this analysis begins to demonstrate implications for practice and highlight that (and how) CRHT clinicians might more clearly engage with what resilience 'is' for SUs, and also the complex process through which these individuals move in developing it. Equally, it is proposed that practitioners should be mindful of the distinction that SUs might make between 'recovery' and 'functionality', and how this in turn can impact on individuals both in personal and socio-economic sense. Finally, the mechanics of power within CRHT contexts are foregrounded, and how these interpersonal dynamics can affect the working relationship between SU and clinician.

CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks the estrogen, progesterone and HER2 receptors and is resistant to targeted and hormone therapies. TNBCs express high levels of the transmembrane glycoprotein, complement C1r/C1s, Uegf, Bmp1 (CUB)-domain containing protein 1 (CDCP1), which has been correlated with the aggressiveness and poor prognosis of multiple carcinomas. Full-length CDCP1 (flCDCP1) can be proteolytically cleaved, resulting in a cleaved membrane-bound isoform (cCDCP1). CDCP1 is phosphorylated by Src family kinases in its full-length and cleaved states, which is important for its pro-metastatic signaling. We observed that cCDCP1, compared with flCDCP1, induced a dramatic increase in phosphorylation of the migration-associated proteins: PKCδ, ERK1/2 and p38 mitogen-activated protein kinase in HEK 293T. In addition, only cCDCP1 induced migration of HEK 293T cells and rescued migration of the TNBC cell lines expressing short hairpin RNA against CDCP1. Importantly, we found that only cCDCP1 is capable of dimerization, which can be blocked by expression of the extracellular portion of cCDCP1 (ECC), indicating that dimerization occurs through CDCP1's ectodomain. We found that ECC inhibited phosphorylation of PKCδ and migration of TNBC cells in two-dimensional culture. Furthermore, ECC decreased cell invasiveness, inhibited proliferation and stimulated apoptosis of TNBC cells in three-dimensional culture, indicating that the cCDCP1 dimer is an important contributor to TNBC aggressiveness. These studies have important implications for the development of a therapeutic to block CDCP1 activity and TNBC metastasis.

Global policies and practices for managing persons exposed to multidrug-resistant tuberculosis.

SETTING: In the 1960s, treatment for latent tuberculosis infection (LTBI) with isoniazid proved to be so effective, safe, and inexpensive that research into alternative treatments virtually ceased. Now that multidrug-resistant tuberculosis (MDR-TB) is widespread, no data are available to guide the management of persons exposed to MDR-TB (contacts). METHODS: We surveyed National TB Program directors and MDR-TB program managers about current practices for managing MDR-TB contacts in countries with an MDR-TB prevalence of >2% in new patients and those with programs for managing MDR-TB. RESULTS: Of 35 countries that met the survey criteria, 25 (71%) responded; 24 of these (96%) have a guideline for managing TB contacts. Of these, 19 (76%) usually or always evaluated contacts and treated LTBI. In contrast, 10 (40%) countries reported having a guideline for managing MDR-TB contacts, 11 (44%) usually or always evaluated MDR-TB contacts, and 9 (36%) treated LTBI. Only two (8%) used a regimen that has activity against MDR-TB. Lack of evidence or guidelines was the main reason for not treating MDR-TB contacts. CONCLUSIONS: Management of MDR-TB contacts is inconsistent and ineffective due to lack of evidence-based guidelines. There is an urgent need to generate evidence to guide policy.

United States law and managing the terminally ill fetus and newborn.

The article sets out the legal principles that govern practice in the US in relation to both the abnormal fetus and the terminally ill newborn. It also provides a view of the law relating to abortion more generally within the US.

Electronic tuberculosis surveillance systems: a tool for managing today's TB programs.

The World Health Organization (WHO) released the Stop TB Strategy in 2006, along with a revised version of the tuberculosis (TB) recording and reporting forms and register. These publications illustrate the need for an enhanced TB surveillance system that will include such key elements as rapid assessment of the quality of DOTS services; integration and response to the human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) epidemic; TB control challenges, such as increased smear-negative and extra-pulmonary TB and multidrug-resistant TB (MDR-TB); increased engagement of all care providers, such as private health care services and the community; and promotion of research to support program improvement. Electronic surveillance systems utilize computer technology to facilitate the capture, transfer and reporting of the WHO-recommended TB data elements. Electronic surveillance offers several potential advantages over the traditional paper-based systems used in many low-resource settings, such as improved data quality and completeness, more feasible links to other health care programs, quality-enhanced data entry and analysis features and increased data security. These advantages must, however, be weighed against the requirements and costs of electronic surveillance, including implementation and support of a quality paper-based surveillance system and the additional costs associated with infrastructure, training and human resources for the implementation and continuing support of an electronic system. Using examples from three different electronic TB surveillance systems that are being implemented in various resource-limited settings, this article demonstrates the feasibility, requirements and value of such systems to support the WHO-recommended enhancement of TB surveillance.

Baseline evaluation of routine HIV testing among tuberculosis patients in Botswana.

In January 2004, the government of Botswana introduced a policy of routine, non-compulsory human immunodeficiency virus (HIV) testing to increase testing and access to antiretroviral treatment (ART) for individuals presenting for medical treatment. Before a systematic implementation of the policy, we conducted a cross-sectional survey of tuberculosis (TB) record data from 46 clinics in 10 districts to assess baseline HIV testing rates among TB patients. Recorded HIV results from the facility TB register and TB treatment card were reviewed. Of the 1242 TB patients entered in the register, 47% had a recorded HIV result and 84% of these were co-infected with HIV. TB treatment cards were available for 862 (69%) registered patients. Among the 411 (47%) with test results recorded on the treatment card, 341 (83%) were HIV-infected; of these, 12% were reported to be receiving ART.

Reported childhood tuberculosis treatment outcomes, Gaborone and Francistown, Botswana, 1998-2002.

SETTING: Botswana. OBJECTIVES: To estimate frequencies of tuberculosis (TB) treatment outcomes, assess the validity of reported treatment outcomes, and identify risk factors for death during TB treatment among children aged <15 years during 1998-2002. DESIGN: We examined TB treatment outcome frequencies using the national Electronic TB Registry (ETR) data. Treatment and medical records were reviewed to calculate predictive values (PV) for outcomes recorded in the ETR. We interviewed parents of children treated for TB and assessed risk factors for death during treatment via case-control study. RESULTS: Of 5483 patients, 3646 (67%) were cured or completed treatment and 577 (10.5%) died during treatment. The PV for ETR was 76% for death and 97% for cured or completed treatment. We interviewed parents of 91 children who died during treatment and 220 children who completed treatment. Human immunodeficiency virus (HIV) status was unknown for 76% of the children and 54% of the parents. Parent-reported adverse effects to anti-tuberculosis medication (adjusted odds ratio [aOR] 4.9, 95% confidence limit [CL] 2.2-9.2), and lower patient age (aOR 2.2, 95%CL 1.2-4.2) were associated with death during treatment. CONCLUSIONS: TB control programs in Botswana should assess for potential adverse effects of anti-tuberculosis medication and expand HIV testing among children with TB and their parents.

Population-based risk factors for tuberculosis and adverse outcomes among Tibetan refugees in India, 1994-1996.

SETTING: Tibetan refugees in India, 1994-1996. OBJECTIVE: To determine tuberculosis (TB) incidence, independent risk factors for TB, and predictors of adverse outcomes. DESIGN: Data from a house-to-house census/demographic survey were merged with TB patient data. Separate multivariable models for each birthplace were developed for outcomes of interest. RESULTS: From 1994 to 1996, 47,491 Tibetans were surveyed and 1197 TB cases confirmed (incidence 835/ 100,000). Risk factors for TB in separate multivariable models differed by place of birth. Independent predictors of death for Tibet-born refugees included age >50 years, extra-pulmonary TB, and second-line therapy, while for India-born refugees they included second-line therapy and no improvement at the end of treatment. No significant risk factors for default were identified for Tibet-born refugees, while region of residence and the absence of a BCG scar were independent predictors among those born in India. Predictors of receipt of second-line therapy among Tibet-born refugees included region, years in camps, and prior TB, while among those born in India they were region, age > or =20 years, sputum-positive at diagnosis, and previous TB. CONCLUSIONS: TB incidence in Tibetan refugee settlements exceeds the highest national TB rates, and country of birth determines risk factors. TB control efforts in India should include this population.

Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002.

Two surveys undertaken in Botswana in the 1990s have recorded low rates of antituberculosis drug resistance, despite a three-fold rise in tuberculosis since 1989. We undertook a third survey to determine both trends since 1995 and HIV prevalence in tuberculosis patients in Botswana. Sputum specimens were obtained from patients nationwide in 2002 who also underwent anonymous, rapid HIV testing by use of Oraquick. Of 2200 sputum smear-positive patients and 219 previously treated patients with suspected recurrent tuberculosis, 1457 (60%) were infected with HIV. Resistance to at least one drug in new patients rose from 16 (3.7%) isolates in 1995 to 123 (10.4%; p<0.0001) in 2002. Interventions for tuberculosis control are urgently needed in Botswana to prevent further emergence of drug resistance.

The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era.

The pre-chemotherapy literature represents an impressive body of evidence that clarifies important epidemiological concepts in childhood tuberculosis. Reports describe the major transitions in tuberculosis, from exposure to infection and from infection to disease (morbidity and mortality), without the influence of chemotherapy. Children with household exposure to a sputum smear-positive source case experienced the greatest risk of becoming infected and of developing subsequent disease. Household exposure to a sputum smear-negative source case or non-household exposure still posed an appreciable, although greatly reduced, risk. Infection in children less than 2 years of age indicated a probable household source case. The majority of older children who were infected did not have a household source identified, and presumably became infected in the community. The annual risk of infection (ARI) was not constant across all ages, but seemed to increase during periods of widening social contact. Infants and adolescents were the groups at highest risk for disease development and death following primary infection.

New international efforts in childhood tuberculosis: proceedings from the 2002 Workshop on Childhood Tuberculosis, Montreal, Canada, 6-7 October 2002.

On 6-7 October 2002, the International Union Against Tuberculosis and Lung Disease (IUATLD), the International Pediatrics Association (IPA), the United States Centers for Disease Control and Prevention (CDC), the United States National Institutes for Health (NIH), and the World Health Organization (WHO) co-sponsored and organized a Workshop on 'Tuberculosis in Children' to assess research needs in childhood tuberculosis (TB) in conjunction with the 33rd IUATLD World Conference on Lung Health. Participants included approximately 40 researchers from the sponsoring organizations as well as from academic institutions, and National Tuberculosis (TB) Programs from a number of countries in sub-Saharan Africa, Asia, Latin America, and Eastern Europe. The goals of the workshop were to highlight current gaps in knowledge about childhood TB, to assess research opportunities, and to begin to establish working partnerships and identify funding sources. The workshop focused on six key topics: the global epidemiology of TB among children, clinical practice including diagnosis and case management of childhood TB, basic research, programmatic aspects of the control of TB among children, ethics, and effects of human immunodeficiency virus (HIV) on TB in children. Review papers on these topics were presented as the foundation for the workshop. Participants were then divided into groups to deliberate on critical areas of research and programmatic needs, recommendations for addressing the needs, and strategic planning to increase international focus on childhood TB. The following summary, including data reported and referenced within the review papers presented at the workshop, represents the proceedings of the workshop.

Global epidemiology of childhood tuberculosis.

Tuberculosis (TB) in children has been less of a public health priority in recent years, despite the fact that TB is an important cause of childhood morbidity and mortality worldwide. Data on trends in childhood TB are scarce in the published literature. The diagnosis of TB in children is difficult, and rarely rests on bacteriologic confirmation. Surveillance data for children in many countries are lacking and there are few epidemiologic studies. However, in regions of the world such as sub-Saharan Africa where adult TB is increasing, this trend is likely occurring among children as well. This review documents an increase in childhood TB in many parts of the world. Risk factors vary by region. Improvements in global surveillance of childhood TB, investigation of the role of national TB programs (NTPs) in improving the control of childhood TB, and better identification of risk factors for childhood disease will be crucial to future control efforts for childhood TB. This might include assessment of optimal methods of contact investigations and an analysis of NTP data to assess risk factors for adverse outcomes (e.g., death, default, treatment failure) among children. Ultimately, these data will ensure the success of interventions to reduce the burden of childhood TB using strategies that specifically target this population. As children represent the future burden of TB disease, these efforts could significantly reduce the overall global burden of TB in years to come.

Correspondence of soldier defense secretion mixtures with cuticular hydrocarbon phenotypes for chemotaxonomy of the termite genus Reticulitermes in North America.

Soldier defense secretions from samples of Reticulitermes collected in California, Nevada, Arizona, New Mexico, and Georgia were characterized and correlated with cuticular hydrocarbon phenotypes. Twenty-seven cuticular hydrocarbon phenotypes have been defined, and soldier defense secretion (SDS) phenotypes have been described for 25 of these. Forty-five terpenoid compounds were found, including monoterpenes, sesquiterpenes, and a few diterpenes. The monoterpenes include (-)-alpha-pinene, (-)-beta-pinene, (-)-camphene, myrcene, (Z)- and (E)-ocimene, and (-)-limonene. The major sesquiterpenes produced are (+)-gamma-cadinene, (+)-gamma-cadinene aldehyde, (-)-germacrene A, germacrene B, gamma-himachalene, and beta-bisabolene. Some SDS phenotypes pair with more than one cuticular hydrocarbon phenotype; however, with two exceptions, each hydrocarbon phenotype is associated with only one SDS phenotype. These chemical characterizations lend support to the conclusion that there are numerous undescribed species of Reticulitermes in North America.

The simulated microgravity environment maintains key metabolic functions and promotes aggregation of primary porcine hepatocytes.

The high aspect ratio vessel allows the culture of primary porcine hepatocytes in an environment of low shear stress and simulated microgravity. Primary porcine hepatocytes have been difficult to maintain in culture long term while preserving their metabolic functions. This study was carried out in order to characterise key metabolic functions of cell aggregates formed by primary porcine hepatocytes cultured in a high aspect ratio vessel for a predetermined period of 21 days. 10(8) porcine hepatocytes were loaded into the high aspect ratio vessel and continuously rotated during the experiments. 0.7 ml of the culture medium was sampled on days 1, 2, 4, 7, 10, 14 and 21. 1H nuclear magnetic resonance spectroscopy of the culture medium, using the presaturation technique, assessed the following: glucose metabolism, glutamine synthesis and ketogenesis. There was glucose breakdown anaerobically during the first 10 days as manifested by lactate production and pyruvate and threonine consumption. After day 10 there was significantly smaller lactate production (day 1 vs day 10 P < 0.01), and significantly smaller pyruvate (day 1 vs day 14 P < 0.03) and threonine consumption (day 1 vs day 10 P < 0.002), indicative of an aerobic metabolic pattern. Significantly more glutamate was produced after day 10 (day 1 vs day 10 P < 0.031), and more glutamine was consumed after day 14. There was a steadily diminishing production of acetate which reached a minimum on day 14 (day 2 vs day 14 P < 0.00014). After an initial 10 day period of acclimatisation cell aggregates formed in the high aspect ratio vessel switched from the anaerobic pattern of metabolism to the more efficient aerobic pattern, which was exhibited until the experiments were terminated. The high aspect ratio vessel is suitable for long-term culture of porcine hepatocytes and it is worthwhile carrying out scale-up feasibility studies.

Novel wax esters and hydrocarbons in the cuticular surface lipids of the red harvester ant, Pogonomyrmex barbatus.

The cuticular surface lipids of the red harvester ant, Pogonomyrmex barbatus, were found to contain minor amounts of novel wax esters, in addition to the major components, hydrocarbons. The wax esters ranged in carbon number from C19 to C31 and consisted of esters of both odd- and even-numbered alcohols and acids. Each wax ester with a given carbon number eluted at several different retention times indicating possible methyl branching in either the fatty acid or alcohol moiety, or in both moieties. Each eluting peak of wax esters consisted of a mixture of wax esters of the same carbon number in which the fatty acid moiety ranged from C8 to C18, and the alcohol moiety ranged from C8 to C17. Some wax esters were largely found on the head indicating they may be of a glandular origin. The hydrocarbons consisted of: n-alkanes, C23 to C33; odd-numbered n-alkenes, C27 to C35; and the major components, methyl-branched alkanes, C26 to over C49. Notable components of the methyl-branched alkanes were 2-methyltriacontane, and the novel trimethylalkanes with a single methylene between the first and second branch points, 13,15,19-trimethylhentriacontane and 13,15,21-trimethyltritriacontane.

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems.

Liver failure, notwithstanding advances in medical management, remains a cause of considerable morbidity and mortality in the developed world. Although bioartificial liver (BAL) support systems offer the potential of significant therapeutic benefit for such patients, many issues relating to their use are still to be resolved. In this review, these issues are examined in terms of the functions required, the cells of choice in such a system, and the most appropriate environment to optimize the function of such cells. The major functions identified to date for a BAL are ammonia detoxification and biotransformation of toxic compounds, although this somewhat belies the complexity of the functions required. Two practical choices for cell type within such a system are xenogenic hepatocytes and immortalized human hepatocyte lines. Both these choices have drawbacks, such as the transmission of zoonoses and malignant infiltration, respectively. Finally, improvements in culture conditions, such as supplemented media, biodegradable scaffolds, and coculture, offer the possibility of prolonging the differentiated function of hepatocytes in a BAL.

An improved ex vivo method of primary porcine hepatocyte isolation for use in bioartificial liver systems.

INTRODUCTION: Primary porcine hepatocytes are commonly, used in bioartificial liver devices and for in vitro studies of hepatocyte function. Although in vivo isolation of porcine hepatocytes can give high yield and viability, such methods are time-consuming and expensive, requiring specialist surgical facilities. AIM: To develop a simple, low-cost, high viability, high yield, reproducible ex vivo method for obtaining functional porcine hepatocytes for use in bioartificial liver systems. METHODS: Weanling piglets (12 kg) were killed with pentobarbitone sodium, the infra-hepatic inferior vena cava was clamped and the supra-hepatic inferior vena cava cannulated. The whole liver was retrogradely perfused in situ with cold saline and excised, followed by an ex vivo open-loop and re-circulating perfusion method (at 37 degrees C) in five steps. The liver was disrupted, sequentially filtered in washing buffer, purified by centrifugation and resuspended in Williams E medium. Viability and cell number were assessed using trypan blue exclusion. The cells were subsequently cultured in serum-free chemically-defined medium and function was assessed. RESULTS: The time interval from when the animals were killed to the final cell wash was 105+/-5 min (n = 20). Cell viability was 85+/-6% with a yield of (2.4+/-0.5) x 10(10) from 12+/-1 kg piglets using 0.03% (w/v) collagenase (n = 20). Hepatocytes from all isolations were successfully plated and grown in monolayer culture. In freshly isolated hepatocytes (day 0) total protein content (TP) was 1.2+/-0.1 mg/10(6) cells (n = 5) and 1.2+/-0.3 mg/10(6) cells (n = 5) for day 2 monolayer cultures, corresponding to approximately 9x10(6) hepatocytes per dish. The percentage of total LDH released into the medium was 13+/-4% for day 0 and 8+/-4% at day 2; conversely, intracellular LDH activities were 87+/-4% and 92+/-4% of the total, respectively. The urea synthesis rate was 196+/-36 nmol/h/mg total protein at day 0 (n = 5) and 292+/-62 nmol/h/mg protein (n = 9) at day 2. The total P450 content was 99+/-11 pmol/mg total protein for fresh cells (n = 5) and maintained at 89+/-35 pmol/mg total protein in day 2 cultures. CONCLUSIONS: This ex vivo method provides a high viability, high yield, cost-effective and rapid technique for isolating functional porcine hepatocytes with high plating efficiency, which compares favourably with results obtained using complex in vivo techniques.

Animal models of fulminant hepatic failure: a critical evaluation.

Few conditions in medicine are more dramatic or more devastating than acute liver failure. Our understanding and treatment of this condition have been limited by the lack of satisfactory animal models. The most widely used models consist of surgical anhepatic and devascularization procedures and hepatotoxins, such as galactosamine and acetaminophen. Potential disadvantages with surgical models are their inability to recreate the inflammatory milieu that exists in acute liver failure and their reliance on surgical expertise. Models using hepatotoxins are free of such constraints. Galactosamine-induced hepatotoxicity is more predictable than acetaminophen, but its cost and lack of a human equivalent clinical syndrome has restricted its use. Acetaminophen-based models offer the greatest potential but have proven the most difficult to develop because of difficulties with reproducibility and refractory anemia. Although progress has been made, research must continue in this area to establish an animal model with minimal disadvantages that would accurately reflect the clinical syndrome seen in humans.