No abstract

Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr(-/-)Smpd1(+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.-1 - infection. These data suggest inhibition of Asm as a novel treatment strategy in CF. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis-4 -

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end-of-life care.This national conference affirmed the ethical propriety of DCD as not violating the dead donor rule. Further, by new developments not previously reported, the conference resolved controversy regarding the period of circulatory cessation that determines death and allows administration of pre-recovery pharmacologic agents, it established conditions of DCD eligibility, it presented current data regarding the successful transplantation of organs from DCD, it proposed a new framework of data reporting regarding ischemic events, it made specific recommendations to agencies and organizations to remove barriers to DCD, it brought guidance regarding organ allocation and the process of informed consent and it set an action plan to address media issues. When a consensual decision is made to withdraw life support by the attending physician and patient or by the attending physician and a family member or surrogate (particularly in an intensive care unit), a routine opportunity for DCD should be available to honor the deceased donor's wishes in every donor service area (DSA) of the United States. Key words: Deceased organ donation Received 25 July 2005, revised and accepted for publication 24 October 2005A national conference on organ donation after cardiac death (DCD) was convened in Philadelphia on April 7 and 8, 2005, to address the increasing experience of DCD and to affirm the ethical propriety of transplanting organs from such donors. Participants represented the broad spectrum of the medical community, including neuroscientists, critical care professionals and distinguished bioethicists (Appendix 1).Six work groups were assembled to address specific DCD issues and fulfill the conference objectives: (i) determining death by a cardiopulmonary criterion, (ii) assessing medical criteria that predict DCD candidacy following the withdrawal of life support, (iii) reviewing protocols for successful DCD organ recovery and subsequent transplantation, (iv) initiating DCD in donation service areas (DSAs), (v) discussing the allocation of DCD organs for transplantation and (vi) examining perceptions of DCD held by the media and the public. Work Group 1: Determining Death by a Cardiopulmonary CriterionA prospective organ donor's death may be determined by either cardiopulmonary (DCD) or neurologic criteria (donation after brain death [DBD]) (1). The term donation after cardiac death (DCD) clearly indicates that death precedes donation. Death determination in the DCD patient mandates the use of a cardiopulmonary criterion to prove the absence of circulation. The cardiopulmonary criterion may be used when the donor does not fulfill brain death criteria. The ethical axiom of organ donation necessitates adherence to the dead donor rule: the retrieval of organs for transplantation should not cause the death of a donor (2).In clinical situations that fulfill either brain death criteria ...

, 5.6a-i, 6.6a-i, 7.6a-i, 8.6a-i, 9.6a-i, 10.6a-i, 11.6a-i, 12.6a-i, 13.6a-i, 15.4a and b, 15.5a and b and 15.4-15.15. All of these tables may be found online at http://www.ustransplant.org. decline, reaching 13% for those who received a kidney in 2003, 48% of which cases were treated with antibodies.

No abstract