Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in xenobiotic and endobiotic detoxification, including the clearance of toxic bilirubin. Previous studies have suggested both overlapping and preferential regulation of target genes by these receptors, but the mechanism of cross-talk remains elusive. Here we reveal a dual role of PXR in bilirubin detoxification in that both the loss and activation of PXR led to protection from hyperbilirubinemia induced by bilirubin infusion or hemolysis. The increased bilirubin clearance in PXR-null mice was associated with selective upregulation of detoxifying enzymes and transporters, and the pattern of regulation is remarkably similar to that of transgenic mice expressing the activated CAR. Interestingly, the increased bilirubin clearance and associated gene regulation were absent in the CAR-null or double-knockout mice. In cell cultures, ligand-free PXR specifically suppressed the ability of CAR to induce the multidrug resistance associated protein 2 (MRP2), a bilirubin-detoxifying transporter. This suppression was, at least in part, the result of the disruption of ligand-independent recruitment of coactivator by CAR. In conclusion, PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross-talk and the hierarchy of xenobiotic and endobiotic regulation. PXR is a potential therapeutic target for clinical treatment of jaundice. (HEPATOLOGY 2005;41:497-505.).     

Acute respiratory distress syndrome caused by pulmonary nocardiosis in a patient with systemic lupus erythematosus

Nocardia is a gram-positive bacillus that infects mainly immunodepressed patients. Its association with lupus erythematosus has been described only occasionally and we have found no reports in the literature of an association between lupus and acute respiratory distress syndrome due to pulmonary nocardiosis. We present such a case and discuss the mechanisms that make this lung infection so virulent as well as its epidemiological and microbiological characteristics, clinical presentation, diagnosis, and treatment.     

Disordered eating in Japanese and Chinese female runners, rhythmic gymnasts and gymnasts

Eating Attitude Test-26 (EAT-26) and self-administered questionnaires were used to survey eating attitudes and menstrual irregularity of Japanese (J) and Chinese (C) collegiate female runners (RUNs), rhythmic gymnasts (RGYMs), gymnasts (GYMs), and nonathletic controls (NAs). Athletes were recruited from several outstanding colleges for physical education and sport in each country. The prevalence of disordered eating (DE) was significantly higher in Japanese athletes (21% in JRUNs, 19% in JRGYMs, and 15% in JGYMs) than Chinese athletes (4% in CRUNs, 2% in CRGYMs, and none in CGYMs). Also, the prevalence of amenorrhea was very low in CRUNs (1%), CRGYMs (0%), and CGYMs (0%), as compared with their respective Japanese counterparts (JRUNs 22%, JRGYMs 10%, JGYMs 8%). There was no significant difference in the prevalence of DE and amenorrhea between Japanese and Chinese NAs. Multivariate logistic regression analysis using 10 independent variables regarding anthropometrics, athletics, weight and diet concern, and nationality indicated that high frequency of dieting during a lifetime, high athletic level and being Japanese were significant risks for the development of DE in athletes. It is concluded that the low prevalence of DE in the Chinese in this study is partly explained by the lack of socioculturally- and socioeconomically-imposed desire to be thin as well as by the low frequency of dieting during their lifetime.     

Elevated cardiac troponin I in a 9-week-old infant

Myocardial ischemia in children is generally not suspected when they present to an emergency department with congestive heart failure. However, the opposite holds true for an adult patient. Elevated cardiac troponin is a specific biochemical marker for myocardial damage for both adults and children, however, they have not been routinely used in children at risk for myocardial damage. A case is presented of an infant with a complex congenital heart defect with congestive heart failure who was found to have an elevated cardiac troponin. Infants at risk for myocardial damage should have an evaluation of cardiac markers, as infants with elevated levels are prone to dysrhythmias or worsening cardiac function and thus warrant closer observations and therapy.     

Unsuspected acetaminophen toxicity in a 58-day-old infant

Acetaminophen is frequently used by both physicians and parents for the relief of pain and fever in infants and children of all age groups. It has an excellent safety profile in therapeutic doses, but hepatotoxicity can develop following both intentional or unintentional overdoses. Repetitive doses of acetaminophen, usually in supratherapeutic amounts, but not always, in ill infants have been associated with hepatotoxicity. Acetaminophen toxicity may be very difficult to diagnose in young infants when suspicion for this entity is low. In addition, initial signs and symptoms are nonspecific and biochemical evidence of hepatic damage may not become evident for 24 to 36 hours. We report the case of an infant who received multiple doses of acetaminophen during an illness who developed hepatotoxicity.     

Long-term results of high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma patients: a report of the Spanish working party for BMT in children (Getmon)

The authors retrospectively analyzed the long-term outcome of 67 patients over 1 year of age at diagnosis with high-risk neuroblastoma (stage 4 or stage 3 with N-myc amplification) who were treated with megatherapy and stem cell rescue from 1984 to 1998. Median age at transplant was 4 years (range 1.6-15 years). The source of cells was peripheral stem cells in 29 and bone marrow in 38 patients. In 12 patients, an in vitro purging of bone marrow harvest was performed. Most patients were conditioned with melphalan, BCNU, and VM-26. After transplant 19 patients received complementary treatment with IL-2 (16) or 13-cis-retinoic acid (3). Six patients (8%) died from transplant-related toxicity and 39 from disease progression. Three patients were alive with active disease at the time of analysis. Nineteen patients are alive and disease-free at a median follow-up of 104 months. Five-year event-free survival is 0.30. Survival of patients who received a purged graft was not significantly better than the rest. Post-transplant complementary treatment significantly improved overall and event-free survival (p = .01 and p = .04, respectively).