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)

Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development

DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia

BACKGROUND AND PURPOSE: The electric field and the concomitant heat (electrohyperthermia) can synergistically induce cell death in tumor tissue, due to elevated glycolysis, ion concentration, and permittivity in malignant compared with nonmalignant tissues. Here we studied the mechanism and time course of tumor destruction caused by electrohyperthermia. MATERIAL AND METHODS: Bilateral implants of HT29 colorectal cancer in the femoral regions of Balb/c (nu/nu) mice were treated with a single 30-min shot of modulated, 13.56-MHz, radiofrequency-generated electrohyperthermia (mEHT). Tumors at 0, 1, 4, 8, 14, 24, 48, and 72 h posttreatment were studied for morphology, DNA fragmentation, and cell death response-related protein expression using tissue microarrays, immunohistochemistry, Western immunoblots, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: Modulated EHT treatment induced significant tumor destruction in HT29 xenografts with a peak of a sevenfold increase compared with the untreated controls. The significant treatment-related elevation of DNA fragmentation-detected with TUNEL assay-and apoptotic bodies between 24 and 72 h posttreatment was proof of a programmed cell death response. This was associated with significant mitochondrial accumulation of bax and mitochondrial-to-cytoplasmic release of cytochrome c proteins between 8 and 14 h. Cleaved caspase-3 levels were low and mainly localized to inflammatory cells. The substantial cytoplasmic-to-nuclear translocation of apoptosis-inducing factor (AIF) and its 57-kDa activated fragment detected between 14 and 24 h after treatment indicated AIF as an effector for DNA fragmentation. CONCLUSION: Modulated EHT treatment can induce programmed cell death-related tumor destruction in HT29 colorectal adenocarcinoma xenografts, which dominantly follows a caspase-independent subroutine