Compound heterozygosity for Hb S [ß6(A3)Glu→Val] and Hb Kenya (Aγ81Leu-ß86Ala) in a Ugandan woman.

Hb Kenya is a hemoglobin (Hb) tetramer composed of two normal α- and two non α-globin chains. The latter are the product of a fusion gene in which the 5' end is (A)γ and the 3' end is ß. The crossover point is between codon 81 of the (A)γ gene and codon 86 of the ß gene. Like the other non α genes, the hybrid protein product ((A)γ81Leu-ß86Ala) has 146 amino acids. The purpose of this report is to highlight the laboratory findings of Hb Kenya and to emphasize the pitfalls in misdiagnosis, particularly when associated with another variant such as Hb S [ß6(A3)Glu→Val].

Evaluation of potential factors predicting attainment of full gavage feedings in preterm infants.

BACKGROUND: The clinical measures of gastric residuals and abdominal distention are often used to guide feeding in preterm infants, but there are few data demonstrating their usefulness. Similarly, techniques are now available to investigate gastrointestinal (GI) function noninvasively and safely, but their ability to predict attainment of full gavage feedings and/or feeding volume in preterm infants is unclear. OBJECTIVE: We sought to determine prospectively the potential relationships of attainment of full gavage feedings and feeding volume with clinical measures and noninvasive GI tests. METHODS: Fifty preterm infants were followed prospectively. Daily tally was taken of gavage feeding intake, gastric residual volumes (GRVs; milliliters per day, number of GRVs >50% of the previous feeding volume, and number of GRVs >2 ml/kg), and abdominal distention. Infants underwent repeated measurement of lactase activity, GI permeability, fecal calprotectin concentration, and gastric emptying. RESULTS: The number of GRVs >2 ml/kg tended to decrease with postnatal age (p = 0.06). Lactase activity and feeding volume in milliliters per kilogram per day prior to achieving full feedings were correlated (p = 0.007, ß = 0.164). There was no correlation between feeding outcomes and GRV (ml/day), GRV >50%, GRV >2 ml/kg, small bowel, colonic, or whole bowel permeability, fecal calprotectin concentration, gastric emptying, or abdominal distention. CONCLUSIONS: GRV is unreliable in predicting attainment of full gavage feeding. Lactase activity is related to feeding volume. However, other noninvasive GI tests utilized were not predictive. These data cast doubt upon the utility of GRV in guiding feeding therapy. Randomized trials of different GRV management protocols are needed.

Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report.

PURPOSE: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state. PATIENTS AND METHODS: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique. RESULTS: Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed. CONCLUSIONS: VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors.

Effects of timing, sex, and age on site-specific gastrointestinal permeability testing in children and adults.

OBJECTIVES: Measurement of gastrointestinal (GI) permeability is commonly used in research and often used clinically. Despite its utility, little is known about sugar excretion timeframes or the potential effects of age and sex on GI permeability testing. We seek to determine the timeframes of sugar excretion and the potential effects of age and sex on urinary recovery of the sugars. SUBJECTS AND METHODS: Healthy adults (n = 17) and children (n = 15) fasted 4 hours after the evening meal and then ingested a solution of sucrose, lactulose, mannitol, and sucralose. Urine was collected at 30, 60, and 90 minutes after ingestion and then each time the subjects voided during the next 24 hours. Each urine void was collected separately. RESULTS: Median age for the adults was 47.5 years (range 21-57 years) and for children 10 years (range 5-17 years). There were no differences between children and adults in mean percent dose of sugar recovered. The time of peak urinary recovery of the sugars was generally similar between children and adults. Sucrose urinary recovery declined with age (P = 0.008; r2 = 0.19) unrelated to sex. Lactulose and sucralose urinary recovery declined with age in females (P = 0.05, r2 = 0.24 and P = 0.011, r2 = 0.41; respectively) but not in males. CONCLUSIONS: Overall, sugar urinary recovery is comparable in children and adults. Specific sugar urinary recovery may change as a function of age and/or sex. These results need to be taken into account when planning and interpreting gastrointestinal permeability studies.

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming.

Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34(+) cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal, and adult globin transcript and protein expression patterns were determined for comparison. Chromatin immunoprecipitation assays revealed RNA polymerase II occupancy and histone tail modifications consistent with transcriptional activation only in the high-HbF culture condition. Transcriptome profiling studies demonstrated reproducible changes in expression of nuclear transcription factors associated with high HbF. Among the 13 genes that demonstrated differential transcript levels, 8 demonstrated nuclear protein expression levels that were significantly changed by cytokine signal transduction. Five of the 8 genes are recognized regulators of erythropoiesis or globin genes (MAFF, ID2, HHEX, SOX6, and EGR1). Thus, cytokine-mediated signal transduction in adult erythroid cells causes significant changes in the pattern of globin gene and protein expression that are associated with distinct histone modifications as well as nuclear reprogramming of erythroid transcription factors.

A randomized, double-blind, placebo-controlled trial of rifaximin, a nonabsorbable antibiotic, in the treatment of tropical enteropathy.

OBJECTIVES: Tropical enteropathy is characterized by an increased urinary lactulose-to-mannitol (L:M) ratio on a site-specific sugar absorption test and is associated with increased intestinal permeability and decreased nutrient absorptive capacity. The etiology of tropical enteropathy is postulated to be intestinal bacterial overgrowth. This study tested the hypothesis that treatment with a nonabsorbable, broad-spectrum antibiotic, rifaximin, reduces the L:M ratio in rural Malawian children, among whom tropical enteropathy is common. METHODS: All children aged 3-5 years from one village were enrolled in a randomized, double-blind, placebo-controlled trial of treatment with rifaximin for 7 days. The L:M ratio was measured before and after treatment, and the change in the L:M ratio was the primary outcome. Secondary outcomes were changes in the urinary sucrose-to-lactulose (SUC:L) and sucralose-to-lactulose (SCL:L) ratios, as well as changes in the fractions of each test sugar recovered in the urine. RESULTS: A total of 144 children participated in this study, of whom 76% had an elevated L:M ratio on enrollment (L:M > or = 0.10). Children who received rifaximin did not show an improvement in their L:M ratio compared with those who received placebo (-0.01+/-0.12 vs. 0.02+/-0.16, respectively, P=0.51, mean+/-s.d.), nor were there significant differences between the two groups in excretion of lactulose, mannitol, sucralose, or sucrose, or in the SUC:L and SCL:L ratios. CONCLUSIONS: Rifaximin had no effect on the tropical enteropathy of 3-5-year-old Malawian children, suggesting that small-bowel bacterial overgrowth is not an important etiological factor in this condition.

Comparison of Sebia Capillarys capillary electrophoresis with the Primus high-pressure liquid chromatography in the evaluation of hemoglobinopathies.

The Sebia Capillarys (capillary zone electrophoresis [CE]) and the Primus Resolution high-pressure liquid chromatography (HPLC) were used to prospectively evaluate 297 samples for hemoglobinopathies. Hemoglobin (Hb) A levels were similar on both techniques (mean, 96.2% and SD, 5.7% by CE; mean, 96.8% and SD, 5.5% by HPLC), but HbA2 levels were higher by CE (mean, 2.8%; SD, 0.8%) than by HPLC (mean, 2.3%; SD, 0.8%). HbS had higher values by CE (mean, 40.6%; SD, 18.9%) than by HPLC (mean, 38.4%; SD, 18.9%). In cases with Hg S, HbA2 levels were greater by HPLC (mean, 4.0%; SD, 1.0%) than by CE (mean, 3.1%; SD, 0.8%). HbA2 was occasionally not separated sufficiently from HbC for measurement by CE, but did separate from HbE by CE. Both methods identified HbS, HbC, HbE, HbS, and HbC together, HbA2&prime, HbD-Los Angeles, HbF variant, HbG-Philadelphia, HbS-G Philadelphia, and Hb Lepore.

Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome.

OBJECTIVES: To determine gastrointestinal (GI) permeability and fecal calprotectin concentration in children 7 to 10 years of age with functional abdominal pain and irritable bowel syndrome (FAP/IBS) versus control subjects and ascertain potential relationships with pain symptoms and stooling. STUDY DESIGN: GI permeability and fecal calprotectin concentration were measured. Children kept a 2-week diary of pain episodes and stooling pattern. RESULTS: Proximal GI permeability was greater in the FAP/IBS group (n = 93) compared with control subjects (n = 52) (0.59 +/- 0.50 vs 0.36 +/- 0.26, respectively; mean +/- SD; P < .001) as was colonic permeability (1.01 +/- 0.67 vs 0.81 +/- 0.43, respectively; P < .05). Gastric and small intestinal permeability were similar. Fecal calprotectin concentration was greater in children with FAP/IBS compared with control children (65.5 +/- 75.4 microg/g stool vs 43.2 +/- 39.4, respectively; P < .01). Fecal calprotectin concentration correlated with pain interference with activities (P = .01, r(2) = 0.36). There was no correlation between GI permeability and pain related symptoms. Neither permeability nor fecal calprotectin correlated with stool form. CONCLUSIONS: Children with FAP/IBS have evidence of increased GI permeability and low-grade GI inflammation, with the latter relating to the degree to which pain interferes with activities.

Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates.

PURPOSE: Valproic acid (VPA), a widely used antiepileptic, also inhibits histone deacetylase (HDAC), and is undergoing evaluation as an anti-cancer agent. We studied the pharmacokinetics of VPA in the plasma and cerebrospinal fluid (CSF) in a non-human primate model that is highly predictive of human CSF penetration to determine if levels of VPA required to inhibit HDAC in in vivo models can be attained. METHODS: Oral VPA, 75 mg/kg, was administered to four non-human primates. Serial samples of blood (n = 4) and CSF (n = 3) were obtained for pharmacokinetic studies of total and free VPA. Plasma and CSF VPA concentrations were measured using the commercially available Abbott AxSYM VPA assay reagent system (Abbott Laboratories, Abbott Park, IL, USA). The resultant plasma and CSF data were evaluated using pharmacokinetic modeling methods. RESULTS: At a dose of 75 mg/kg, the maximum plasma concentration of VPA was 130.1 +/- 70.6 microg/ml (mean +/- standard deviation) for total drug and 53.3 +/- 44.4 microg/ml for free drug. The mean plasma area under the curve (AUC) for total drug was 680 +/- 233 microg/ml h and for free drug 146 +/- 89 microg/ml hr. The maximum CSF concentration occurred 2-3 h after administration and was 28.2 +/- 18.6 microg/ml. The CSF AUC for VPA was 108 +/- 52 microg/ml h. The CSF penetration of VPA was 12.9 +/- 5.1% for total drug and 57.0 +/- 8.7% for free drug. Disappearance from the plasma followed non-linear kinetics with a V (max) of 321.2 +/- 65.6 microg/kg/min and a K (m) of 17.2 +/- 13.7 mg/l. CONCLUSION: Valproic acid deserves further study for the treatment of CNS tumors given its high CSF penetration after oral dosing coupled with the anti-tumor activity observed in preclinical studies.

Concentrations of brain natriuretic peptide in the plasma predicts outcomes of treatment of children with decompensated heart failure admitted to the Intensive Care unit.

OBJECTIVES: It is known that levels of brain natriuretic peptide predict outcomes of treatment for adults with decompensated heart failure. We hypothesized that it could predict outcomes in children with this condition. METHODS: We divided retrospectively 82 patients with serial measurements of brain natriuretic peptide into 3 groups: those who survived and did not need readmission within less than 60 days; those who survived but needed readmission within less than 60 days; and those who died in hospital or within less than 60 days. Initial and final levels of the peptide correlated with adverse outcomes. RESULTS: The percent change in level of the peptide was minus 78 percent, minus 38 percent, and 138 percent in the readmission-free group, the readmitted, and nonsurviving groups, respectively. Final levels were significantly lower in the readmission-free group than in the readmitted and nonsurviving groups (p equals 0.013 and p is less than 0.00001, respectively) and in the readmitted group than in the nonsurvivors (p equals 0.013). On univariate analysis, the final level, the change in level, and the percentage change in level significantly predicted outcomes (p equals 0.0002, 0.0072 and 0.0005, respectively). On multivariate analysis, only the final level of the peptide significantly predicted outcomes (p equals 0.01). CONCLUSIONS: A final level of brain natriuretic peptide of greater than or equal to 760 picograms per millilitre strongly predicted an adverse outcome. Patients with higher final levels may be at higher risk of death and readmission, suggesting that this variable effectively predicts the response to treatment and prognosis in children with heart failure.

Validation of oxygen saturation monitoring in neonates.

BACKGROUND: Pulse oximetry is commonly used to monitor oxygenation in neonates, but cannot detect variations in hemoglobin. Venous and arterial oxygen saturations are rarely monitored. Few data are available to validate measurements of oxygen saturation in neonates (venous, arterial, or pulse oximetric). Purpose To validate oxygen saturation displayed on clinical monitors against analyses (with correction for fetal hemoglobin) of blood samples from neonates and to present the oxyhemoglobin dissociation curve for neonates. METHOD: Seventy-eight neonates, 25 to 38 weeks' gestational age, had 660 arterial and 111 venous blood samples collected for analysis. RESULTS: The mean difference between oxygen saturation and oxyhemoglobin level was 3% (SD 1.0) in arterial blood and 3% (SD 1.1) in venous blood. The mean difference between arterial oxygen saturation displayed on the monitor and oxyhemoglobin in arterial blood samples was 2% (SD 2.0); between venous oxygen saturation displayed on the monitor and oxyhemoglobin in venous blood samples it was 3% (SD 2.1) and between oxygen saturation as determined by pulse oximetry and oxyhemoglobin in arterial blood samples it was 2.5% (SD 3.1). At a Pao(2) of 50 to 75 mm Hg on the oxyhemoglobin dissociation curve, oxyhemoglobin in arterial blood samples was from 92% to 95%; oxygen saturation was from 95% to 98% in arterial blood samples, from 94% to 97% on the monitor, and from 95% to 97% according to pulse oximetry. CONCLUSIONS: The safety limits for pulse oximeters are higher and narrower in neonates (95%-97%) than in adults, and clinical guidelines for neonates may require modification.

Accurate measurements of fetal hemoglobin for neonates with different gestational ages.

The purposes of this study were to examine the accuracy of fetal hemoglobin (Hb F, alpha2gamma2) as quickly measured by a hemoximeter but verified by high performance liquid chromatography [HPLC, including Hb F total (Hb Ft), acetylated Hb F (Hb F1), and non acetylated Hb F ( Hb F*)], and to predict the Hb F levels for different gestational weeks of neonates. Thirty-nine neonates of predominantly Hispanic and African American ethnicity, with gestational ages ranging from 25 to 38 weeks, were investigated. Analyses were performed on 163 blood samples that were pure neonates' blood before the transfusion of any adult blood. Two neonates had increased Hb C [beta6(A3)Glu-->Lys, GAC-->AAG] levels (1.67-2.79%) and one neonate whose mother drank alcohol during pregnancy, had elevated Hb A2 levels (0.12-0.14%). After excluding these data points, the mean Hb F were overestimated by hemoximeter, 118.4 +/- 8.77% vs. 92.6 +/- 2.77% by HPLC (mean difference: 25.8 +/- 7.71%, p = <0.001). Mean Hb F1 was 10.5 +/- 2.28%. Hb F levels decreased as gestational age increased (p <0.001 for Hb Ft and Hb F*; p = <0.05 for Hb F1). A multivariate regression model for Hb F prediction was established with the best R2. The gestational age and post birth hours in the prediction of Hb Ft was included when Hb F could be determined at the clinical settings. Future studies may be needed to account for Hb F1 when measuring Hb F levels to assess oxygenation status in (pre term) neonates.

Valproic Acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts.

PURPOSE: To develop novel orthotopic xenograft models of medulloblastoma in severe combined immunodeficient mice and to evaluate the in vivo antitumor efficacy of valproic acid. EXPERIMENTAL DESIGN: Orthotopic xenografts were developed by injecting 10(3) to 10(5) tumor cells from four medulloblastoma cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right cerebellum of severe combined immunodeficient mice. Animals were then examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologic features. Tumor growth was monitored in vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks postinjection. Valproic acid treatment, administered at 600 microg/h for 2 weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of 10(5) medulloblastoma cells, and treated and untreated animals were monitored for differences in survival. Changes in histone acetylation, proliferation, apoptosis, differentiation, and angiogenesis in xenografts were also evaluated. RESULTS: Tumorigenicity was maintained at 100% in D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts displayed histologic features and immunohistochemical profiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to human medulloblastomas. Animal survival time was inversely correlated with injected tumor cell number. Treatment with valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the three models and was associated with induction of histone hyperacetylation, inhibition of proliferation and angiogenesis, and enhancement of apoptosis and differentiation. CONCLUSION: We have developed intracerebellar orthotopic models that closely recapitulated the biological features of human medulloblastomas and characterized their in vivo growth characteristics. Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity. These xenograft models should facilitate the understanding of medulloblastoma pathogenesis and future preclinical evaluation of new therapies against medulloblastoma.

The measurement of accurate fetal hemoglobin and related oxygen saturation by the hemoximeter.

BACKGROUND: The purposes of this study were to examine the accuracy of fetal hemoglobin (HbF) as quickly measured by the hemoximeter, verified by the high-performance liquid chromatography method, and to examine related oxygen saturation (SO(2)) measurements in neonates. METHODS: Thirty-nine neonates with gestational ages ranging from 25 to 38 weeks were investigated (n=280 blood samples). Twenty younger premature neonates had blood transfusions (n=188 blood samples, 72 before and 116 after transfusions), and 19 older neonates did not. RESULTS: The bias of the hemoximeter was 23% (+/-9.1) against the HPLC; 25% (+/-7.9) before, and 19% (+/-8.6) after blood transfusions (all P<0.001), for HbF measurements. A regression line (HbFt by the HPLC=8.46+0.7 x HbF by the hemoximeter) has been provided for the prediction. Oxyhemoglobin dissociation curves with the status of (before and after) blood transfusions were presented. In relation to oxygen tension values of 50-75 mm Hg, in addition to the right-shifted oxyhemoglobin dissociation curves, pulse oximeter ranged from 95 to 98% before the transfusions, but decreased to 94 to 96% after the blood transfusions. CONCLUSIONS: Accurate HbF and related oxygen saturation measurements need to be determined, especially for premature neonates, to minimize the risk of oxygen toxicity.

Effect of Lactobacillus GG on intestinal integrity in Malawian children at risk of tropical enteropathy.

BACKGROUND: Tropical enteropathy is an asymptomatic villous atrophy of the small bowel that is prevalent in the developing world and is associated with altered intestinal function and integrity. The histology of tropical enteropathy resembles that seen in small-bowel bacterial overgrowth. OBJECTIVE: This study tested the hypothesis that treatment of 3-5-y-old Malawian children with the probiotic Lactobacillus GG would improve their intestinal function and integrity. DESIGN: Clinically healthy children (n = 164) were enrolled in a placebo-controlled, randomized, double-blind trial. Intestinal function and integrity were measured by using the site-specific sugar-absorption test before and after 30 d of treatment with Lactobacillus GG or placebo. The primary outcomes were the ratios of urinary lactulose to mannitol (L:M) and of urinary sucrose to lactulose (S:L) excretion. RESULTS: Of the 161 children who completed the study, 119 (73%) had tropical enteropathy on enrollment (L:M > 0.10). Children receiving Lactobacillus GG did not differ significantly from the placebo group in the excretion (in % of dose administered) of mannitol (mean +/- SD: 8.9 +/- 4.4 and 8.9 +/- 3.9, respectively), lactulose (0.31 +/- 0.20 and 0.33 +/- 0.23, respectively), or sucrose (0.078 +/- 0.058 and 0.082 +/- 0.075, respectively). L:M and S:L also did not differ significantly between the Lactobacillus and placebo groups (0.19 +/- 0.13 and 0.20 +/- 0.12, respectively, for L:M; 0.58 +/- 0.46 and 0.65 +/- 0.57, respectively, for S:L). CONCLUSION: Administration of Lactobacillus GG for 30 d had no effect on the intestinal integrity of 3-5-y-old Malawian children.

Heterogeneity of the molecular biology of methemoglobinemia: a study of eight consecutive patients.

Congenital methemoglobinemia can be caused by mutations involving five different genes. We studied the etiology and molecular biology of eight consecutive patients with methemoglobinemia. Four had b5R mutations; two were novel. A novel intronic mutation caused markedly reduced mRNA resulting in type II methemoglobinemia. Three patients had acquired methemoglobinemia without any b5R mutations.

Accuracy in the alteration of acetaminophen suppositories.

Many pediatric anesthesiologists divide acetaminophen suppositories to achieve an approximate dose. In this three-part study we first surveyed pediatric anesthesiologists regarding their attitudes and frequency of this clinical practice. Second, acetaminophen suppositories were divided for analysis of acetaminophen content. Finally, the accuracy of pediatric anesthesiologists in dividing suppositories was assessed. The survey indicated 50% of anesthesiologists believed acetaminophen was nonuniform and 62% believed the alteration of suppositories was inaccurate. The laboratory investigation revealed uniform distribution of acetaminophen but poor accuracy in achieving the target dose. The findings suggest using only intact suppositories for improved accuracy.

Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death.

The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah(-/-)), protected from liver injury by the drug 2-(2- nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah(-/-) animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases.