Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

BACKGROUND: Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. HYPOTHESIS: We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. TESTING THE HYPOTHESIS: Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy. IMPLICATIONS OF THE HYPOTHESIS: We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome

Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure?

Mitochondrial functions include production of energy, activation of programmed cell death, and a number of cell specific tasks, e.g., cell signaling, control of Ca2+ metabolism, and synthesis of a number of important biomolecules. As proper mitochondrial function is critical for normal performance and survival of cells, mitochondrial dysfunction often leads to pathological conditions resulting in various human diseases. Recently mitochondrial dysfunction has been linked to multiple organ failure (MOF) often leading to the death of critical care patients. However, there are two main reasons why this insight did not generate an adequate resonance in clinical settings. First, most data regarding mitochondrial dysfunction in organs susceptible to failure in critical care diseases (liver, kidney, heart, lung, intestine, brain) were collected using animal models. Second, there is no clear therapeutic strategy how acquired mitochondrial dysfunction can be improved. Only the benefit of such therapies will confirm the critical role of mitochondrial dysfunction in clinical settings. Here we summarized data on mitochondrial dysfunction obtained in diverse experimental systems, which are related to conditions seen in intensive care unit (ICU) patients. Particular attention is given to mechanisms that cause cell death and organ dysfunction and to prospective therapeutic strategies, directed to recover mitochondrial function. Collectively the data discussed in this review suggest that appropriate diagnosis and specific treatment of mitochondrial dysfunction in ICU patients may significantly improve the clinical outcome

SIRIUS is a state-of-the-art detector system for nuclear decay spectroscopy that will be mounted at the focalplane of S3 (Super Separator Spectrometer), which is part of the new SPIRAL2 facility at GANIL, Caen in France. Such a systemrequires high performance as it is dedicated to the study of very exotic nuclei. It is the result of collaboration between GANILCSNSM, IRFU, and IPHC It is composed of a succession of detectors (Trackers, Silicon detector DSSD and Tunnel plus anarray of five clover Germanium detectors). This set-up is mounted in a compact geometry. The energy measurement variesfrom 50 keV to over 500 MeV with high precision (2 x 10-3) at low energies and 1 % for the detection of heavy ions. A majorchallenge has been the development of new electronics with a very large dynamic range maintaining an adequate energyresolution for the measured particles (with energies from a few hundred keV up to 500 MeV).

International audienceSIRIUS is a state-of-the-art detector system for nuclear decay spectroscopy that will be mounted at the focal plane of S$^3$ (Super Separator Spectrometer), which is part of the new SPIRAL2 facility at GANIL, Caen in France. Such a systemrequires high performance as it is dedicated to the study of very exotic nuclei. It is the result of collaboration between GANILCSNSM, IRFU, and IPHC It is composed of a succession of detectors (Trackers, Silicon detector DSSD and Tunnel plus anarray of five clover Germanium detectors). This set-up is mounted in a compact geometry. The energy measurement variesfrom 50 keV to over 500 MeV with high precision (2 x 10$^{-3}$) at low energies and 1 % for the detection of heavy ions. A majorchallenge has been the development of new electronics with a very large dynamic range maintaining an adequate energyresolution for the measured particles (with energies from a few hundred keV up to 500 MeV)