Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.

Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke.

Verification at the protein level of the PIF4-mediated external coincidence model for the temperature-adaptive photoperiodic control of plant growth in Arabidopsis thaliana.

Plant circadian clock controls a wide variety of physiological and developmental events, which include the short-days (SDs)-specific promotion of the elongation of hypocotyls during de-etiolation and also the elongation of petioles during vegetative growth. In A. thaliana, the PIF4 gene encoding a phytochrome-interacting basic helix-loop-helix (bHLH) transcription factor plays crucial roles in this photoperiodic control of plant growth. According to the proposed external coincidence model, the PIF4 gene is transcribed precociously at the end of night specifically in SDs, under which conditions the protein product is stably accumulated, while PIF4 is expressed exclusively during the daytime in long days (LDs), under which conditions the protein product is degraded by the light-activated phyB and also the residual proteins are inactivated by the DELLA family of proteins. A number of previous reports provided solid evidence to support this coincidence model mainly at the transcriptional level of the PIF 4 and PIF4-traget genes. Nevertheless, the diurnal oscillation profiles of PIF4 proteins, which were postulated to be dependent on photoperiod and ambient temperature, have not yet been demonstrated. Here we present such crucial evidence on PIF4 protein level to further support the external coincidence model underlying the temperature-adaptive photoperiodic control of plant growth in A. thaliana.

Sweet taste loss in myasthenia gravis: more than a coincidence?

Sweet dysgeusia, a rare taste disorder, may be encountered in severe anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG). A 42 year-old man reported progressive loss of sweet taste evolving for almost 10 weeks, revealing an AChRAb-positive MG with thymoma. Improvement of sweet perception paralleled reduction of the MG composite score during the 15 months follow up period, with immunosuppressive and surgical treatments. We suggest that sweet dysgeusia is a non-motor manifestation of MG that may result from a thymoma-dependent autoimmune mechanism targeting gustducin-positive G-protein-coupled taste receptor cells, in line with recent data from MRL/MpJ-Fas lpr/ (MRL/lpr) transgenic mice with autoimmune disease.

Strokes and TIAs during and after Carotid Artery Doppler: Cause or Coincidence?

The aim of the present study was to explore the prevalence of acute cerebrovascular symptoms temporally related to carotid Doppler examination (DEx), in order to increase the awareness and recording of such events and to discuss possible mechanisms. All adult patients who complained of acute onset neurologic symptoms during or shortly after a carotid DEx, between 01/2003 and 12/2011 in the University Hospital of Lausanne were prospectively collected. We identified four consecutive patients with acute onset neurologic symptoms during or shortly after a carotid DEx among approximately 13,500 patients who underwent carotid DEx in our facility during the nine-year period (0.015% of all examined carotids). Clinical data, imaging reports and CTA (CT angiography) or/and ultrasound images are presented for each patient. Ischemic cerebrovascular events during or immediately after cervical Doppler could be due to chance or to several physical factors. They should be promptly recognized by Doppler personnel and properly treated, but do not put into question the overwhelming benefits of Doppler in cerebrovascular patients.

Stimulated-echo acquisition mode (STEAM) MRI for black-blood delayed hyperenhanced myocardial imaging.

PURPOSE: To develop a breathhold method for black-blood viability imaging of the heart that may facilitate identifying the endocardial border. MATERIALS AND METHODS: Three stimulated-echo acquisition mode (STEAM) images were obtained almost simultaneously during the same acquisition using three different demodulation values. Two of the three images were used to construct a black-blood image of the heart. The third image was a T(1)-weighted viability image that enabled detection of hyperintense infarcted myocardium after contrast agent administration. The three STEAM images were combined into one composite black-blood viability image of the heart. The composite STEAM images were compared to conventional inversion-recovery (IR) delayed hyperenhanced (DHE) images in nine human subjects studied on a 3T MRI scanner. RESULTS: STEAM images showed black-blood characteristics and a significant improvement in the blood-infarct signal-difference to noise ratio (SDNR) when compared to the IR-DHE images (34 +/- 4.1 vs. 10 +/- 2.9, mean +/- standard deviation (SD), P < 0.002). There was sufficient myocardium-infarct SDNR in the STEAM images to accurately delineate infarcted regions. The extracted infarcts demonstrated good agreement with the IR-DHE images. CONCLUSION: The STEAM black-blood property allows for better delineation of the blood-infarct border, which would enhance the fast and accurate measurement of infarct size.

Successful embolization of a delayed splenic rupture following trauma in a child.

Delayed rupture of the spleen following trauma is an exceedingly rare phenomenon in children. In the case we have experienced, arterial embolization was successfully performed, surgery was avoided, and functional splenic tissue was preserved. Embolization is of value in the management of blunt splenic injuries in hemodynamically stable children, even after delayed rupture. The exact criteria for its use remain to be established.

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity.

A key feature of memory processes is to link different input signals by association and to preserve this coupling at the level of synaptic connections. Late-phase long-term potentiation (L-LTP), a form of synaptic plasticity thought to encode long-term memory, requires gene transcription and protein synthesis. In this study, we report that a recently cloned coactivator of cAMP-response element-binding protein (CREB), called transducer of regulated CREB activity 1 (TORC1), contributes to this process by sensing the coincidence of calcium and cAMP signals in neurons and by converting it into a transcriptional response that leads to the synthesis of factors required for enhanced synaptic transmission. We provide evidence that TORC1 is involved in L-LTP maintenance at the Schaffer collateral-CA1 synapses in the hippocampus.

Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures.

Xenobiotic exposure is a risk factor in the etiology of neurodegenerative disease. It was recently hypothesized that restricted exposure during brain development could predispose for a neurodegenerative disease later in life. As neuroinflammation contributes to progressive neurodegeneration, it is suspected that neurodevelopmental xenobiotic exposure could elicit a neuroinflammatory process, which over time may assume a detrimental character. We investigated the neurotoxic effects of paraquat (PQ) in three-dimensional whole rat brain cell cultures, exposed during an early differentiation stage, comparing immediate effects-directly post exposure-with long-term effects, 20 days after interrupted PQ-administration. Adverse effects and neuroinflammatory responses were assessed by measuring changes in gene- and protein-expression as well as by determining cell morphology changes. Differentiating neural cultures were highly susceptible to PQ and showed neuronal damage and strong astrogliosis. After the 20-day washout period, neurons partially recovered, whereas astrogliosis persisted, and was accompanied by microglial activation of a neurodegenerative phenotype. Our data shows that immediate and long-term effects of subchronic PQ-exposure differ. Also, PQ-exposure during this window of extensive neuronal differentiation led to a delayed microglial activation, of a character that could promote further pro-inflammatory signals that enable prolonged inflammation, thereby fueling further neurodegeneration.

Formes sévères d'hypersensibilité médicamenteuse retardée [Severe delayed drug hypersensitivity reactions].

Although most delayed drug hypersensitivity reactions are mild and show rapid improvement after drug discontinuation, there are severe systemic and/or cutaneous drug reactions which may be life-threatening. These entities are discussed here, namely DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Early detection of warning signs and symptoms may help to take appropriate measures precociously.