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.).     

B cell reductive therapy in the treatment of autoimmune diseases: a focus on monoclonal antibody treatment of rheumatoid arthritis

The therapeutic approach to patients with autoimmune disorders is in the midst of a dramatic change. Monoclonal antibody technology has allowed us to dissect and now manipulate the human immune system with greater precision. It is now widely recognized that B lymphocytes play a role in the pathogenesis of many autoimmune diseases, though the extent and contribution is a matter of debate and active investigation. There is emerging data to suggest that both antibody-dependent and independent mechanisms contribute to disease pathogenesis. However, given the heterogeneous nature of autoimmune diseases, and the varied responses to B lymphocyte reduction, the role of B lymphocytes is likely disease-specific. The two clinical trials discussed in this review demonstrate remarkable consistency in the ability of B cell reduction to ameliorate the clinical manifestations of rheumatoid arthritis with minimal toxicity. B lymphocyte targeted approaches to autoimmune disease in general, and RA specifically, will not only provide an effective and potentially less toxic alternative treatment option, but also allow for a better understanding of the pathogenesis of these complex and morbid diseases.     

Ipsilateral hemiparesis caused by a corona radiata infarct after a previous stroke on the opposite side

Ipsilateral hemiparesis after a supratentorial stroke is rare. However, the role of the reorganization of the unaffected hemisphere in recovery after a stroke is poorly understood. Two patients developed ipsilateral hemiparesis after a left corona radiata infarct. Both of these patients had previously experienced contralateral hemiparesis after a right-sided supratentorial stroke. Functional magnetic resonance imaging demonstrated bilateral motor area activation during paretic left hand movement. This finding suggests that the ipsilateral hemiparesis was caused by a new stroke in the ipsilateral motor system that was functionally reorganized after the previous stroke.     

Retrograde study of hypocretin-1 (orexin-A) projections to subdivisions of the dorsal raphe nucleus in the rat

A retrograde tracer, WGA-apo-HRP-gold (WG), was injected into each subdivision of the dorsal raphe (DR) nucleus, and subsequent orexin-A immunostaining was performed for the tuberal region of the hypothalamus in order to investigate orexin projections to the DR. Similar to previous studies, the majority of orexin-single-labeled neurons were observed at the dorsal half of the lateral hypothalamus (LH), the circle around the fornix, i.e., perifornical nucleus (PeF), and the area dorsal to the fornix. The present study reports that hypothalamic neurons exhibited differential projections to each subdivision of the DR. Following WG injections into rostral DR, WG-single-labeled cells were observed at the dorsal half of the LH as well as dorsomedial hypothalamic nucleus. The major input to the intermediate DR originates from the ventromedial portion of the LH, PeF, and the area dorsal to the PeF, whereas one to lateral wing DR derived from PeF as well as the ventrolateral portion of the LH. Following WG injections into caudal DR, WG-single-labeled cells were located at ventromedial LH and the ventrolateral portion of the posterior hypothalamus. Following WG injections into each DR subdivision, WG/orexin-double-labeled neurons were observed at LH, PeF, and the area dorsal to the PeF. Only a few double-labeled cells were observed in dorsomedial and posterior hypothalamic nuclei. Our observations suggest that various hypothalamic neurons differentially project to each subdivision of the DR, a portion of which is orexin-immunoreactive. These orexin-immunoreactive DR-projecting hypothalamic neurons might have wake-related influences over a variety of brain functions subject to DR efferent regulation, including affective behavior, autonomic control, nociception, cognition, and sensorimotor integration.     

Does conversion of ATP to adenosine terminate ATP-stimulated vasopressin release from hypothalamo-neurohypophyseal explants?

ATP stimulates vasopressin (VP) release from explants of the hypothalamo-neurohypophyseal system (HNS), but the response is not sustained for the duration of exposure to ATP. Since adenosine, a metabolite of ATP, inhibits VP release from neurohypophysial terminals and adenosine receptors (AR) are expressed in supraoptic nucleus (SON) neurons, we postulated that conversion of ATP to adenosine contributed to termination of ATP-stimulated VP release from HNS explants. This was tested using a non-selective AR antagonist, 5-amino-9-chloro-2-(2-furyl)-1, 2, 4-triazolo [1, 5-c] quinazoline (CGS-15943). CGS-15943 did not affect basal VP release and did not alter the initial response to ATP. A selective A1R antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), increased basal VP release at 1 microM, without altering the response to ATP. However, at a higher concentration of DPCPX (10 microM), VP release was enhanced by ATP for an extended period of time. Inhibition of the enzymatic conversion of ATP to adenosine using a combination of a potent ecto-5'-nucleotidase inhibitor, alpha,beta-methylene adenosine 5'-diphosphate (AMP-CP), and a competitive substrate for ecto-5'-nucleotidase (guanosine monophosphate, GMP) did not affect basal VP release. Enzymatic inhibition did slightly prolong the response to ATP, but it was not sustained for the duration of exposure to ATP. We conclude that an endogenous inhibitory influence of adenosine decreases basal VP release from HNS explants and that conversion of exogenously applied ATP to adenosine contributes to termination of ATP-induced stimulation of VP release, but additional mechanisms such as receptor desensitization also limit the response to extended exposure to ATP.     

Arthroscopic synovectomy in haemophilic arthropathy of the knee

From January 1996 to January 2001, arthroscopic synovectomies were performed in 28 knees with haemophilic arthropathy. The mean follow-up period was 5 years and 11 months. Six portals (two anterior, two suprapatellar, two posterior) and a posterior trans-septal portal were used in all cases. The average Hospital for Special Surgery (HSS) knee score increased from 56.4 to 71.5 points at the last follow-up. The average frequency of haemarthrosis reduced from five times per month before operation to once per month. The amount of factor replacement decreased from a mean of 4,633 U to 1,505 U. Progression of arthritis was observed radiographically in three cases at the last follow-up. An arthroscopic synovectomy of the knee using appropriate arthroscopic portals is a useful method in treating haemophilic patients as it decreases bleeding episodes, amount of factor replacement and knee pain.

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Résumé De janvier 1996 à janvier 2001, des synovectomies arthroscopiques ont été exécutées dans 28 genoux avec une arthropathie hémophilique. Le suivi moyen était 5 années et 11 mois. Six abords (deux antérieurs, deux supra-rotuliens, deux postérieurs) et un abord trans-septal postérieur ont été utilisé dans tous les cas. Le score moyen du genou de lHôpital pour Chirurgie Spéciale (HSS) a augmenté de 56,4 à 71,5 points au dernier examen. La fréquence moyenne dhémarthrose sest réduite de cinq fois par mois avant lopération à une fois par mois aprés. La quantité moyenne de remplacement de facteur a diminué de 4,633 à 1,505 unités. Dans lévaluation radiographique, la progression de larthrite a été observée dans trois cas au dernier suivi. Une synovectomie arthroscopique du genou qui utilise des abords arthroscopiques appropriés est une méthode utile pour traiter les malades hémophiliques, diminuant les épisodes de saignement, la quantité de facteur et les douleurs du genou.

     

The application of the Six Sigma program for the quality management of the PACS

OBJECTIVE: We implemented a Six Sigma-based quality management program for the PACS to improve the quality of and lessen the necessary resources for its management. CONCLUSION: With the Six Sigma-based PACS quality management program, we were able to reduce resource requirements while maintaining quality.     

Pulmonary parenchymal involvement of low-grade lymphoproliferative disorders

Lymphoid tissue is a normal component of the lung. The various lymphoproliferative diseases affect the lung parenchyma. The purpose of this article is to classify various lymphoproliferative diseases and to understand their computed tomography features of pulmonary involvement. The examples include follicular bronchiolitis, lymphocytic interstitial pneumonia, plasma cell granuloma, Castleman disease, lymphomatoid granulomatosis, and mucosa-associated lymphoid tissue lymphoma. Pathologic correlation is helpful for understanding imaging findings and their pathophysiology.