Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

ACID-SENSING ION CHANNELS: functional and molecular characterization in putative nociceptors, and modulation by nerve injury and serine protease

R��sum�� Les canaux ioniques ASICs (acid-sensing ion channels) appartiennent �� la famille des canaux ENaC/Degenerin. Pour l'instant, quatre g��nes (1 �� 4) ont ��t�� clon��s dont certains pr��sentent des variants d'��pissage. Leur activation par une acidification rapide du milieu extracellulaire g��n��re un courant entrant transitoire essentiellement sodique accompagn�� pour certains types d'ASICs d'une phase soutenue. Les ASICs sont exprim��s dans le syst��me nerveux, central (SNC) et p��riph��rique (SNP). On leur attribue un r��le dans l'apprentissage, la m��moire et l'isch��mie c��r��brale au niveau central ainsi que dans la nociception (douleur aigu�� et inflammatoire) et la m��chanotransduction au niveau p��riph��rique. Toutefois, les donn��es sont parfois contradictoires. Certaines ��tudes sugg��rent qu'ils sont des senseurs primordiaux impliqu��s dans la d��tection de l'acidification et la douleur. D'autres ��tudes sugg��rent plut��t qu'ils ont un r��le modulateur inhibiteur dans la douleur. De plus, le fait que leur activation g��n��re majoritairement un courant transitoire alors que les fibres nerveuses impliqu��es dans la douleur r��pondent �� un stimulus nocif avec une adaptation lente sugg��re que leurs propri��t��s doivent ��tre modul��s par des mol��cules endog��nes. Dans une premi��re partie de ma th��se, nous avons abord�� la question de l'expression fonctionnelle des ASICs dans les neurones sensoriels primaires aff��rents du rat adulte pour clarifier le r��le des ASICs dans les neurones sensoriels. Nous avons caract��ris�� leurs propri��t��s biophysiques et pharmacologiques par la technique du patch-clamp en configuration �� whole-cell ��. Nous avons pu d��montrer que pr��s de 60% des neurones sensoriels de petit diam��tre expriment des courants ASICs. Nous avons mis en ��vidence trois types de courant ASIC dans ces neurones. Les types 1 et 3 ont des propri��t��s compatibles avec un r��le de senseur du pH alors que le type 2 est majoritairement activ�� par des pH inf��rieurs �� pH6. Le type 1 est m��di�� par des homomers de la sous-unit�� ASIC1 a qui sont perm��ables aux Ca2+. Nous avons ��tudi�� leur co-expression avec des marqueurs des nocicepteurs ainsi que la possibilit�� d'induire une activit�� neuronale suite �� une acidification qui soit d��pendante des ASICs. Le but ��tait d'associer un type de courant ASIC avec une fonction potentielle dans les neurones sensoriels. Une majorit�� des neurones exprimant les courants ASIC co-expriment des marqueurs des nocicepteurs. Toutefois, une plus grande proportion des neurones exprimant le type 1 n'est pas associ��e �� la nociception par rapport aux types 2 et 3. Nous avons montr�� qu'il est possible d'induire des potentiels d'actions suite �� une acidification. La probabilit�� d'induction est proportionnelle �� la densit�� des courants ASIC et �� l'acidit�� de la stimulation. Puis, nous avons utilis�� cette classification comme un outil pour appr��hender les potentielles modulations fonctionnelles des ASICs dans un model de neuropathie (spared nerve injury). Cette approche fut compl��t��e par des exp��riences de ��quantitative RT-PCR ��. En situation de neuropathie, les courants ASIC sont dramatiquement chang��s au niveau de leur expression fonctionnelle et transcriptionnelle dans les neurones l��s��s ainsi que non-l��s��s. Dans une deuxi��me partie de ma th��se, suite au test de diff��rentes substances s��cr��t��es lors de l'inflammation et l'isch��mie sur les propri��t��s des ASICs, nous avons caract��ris�� en d��tail la modulation des propri��t��s des courants ASICs notamment ASIC1 par les s��rines prot��ases dans des syst��mes d'expression recombinants ainsi que dans des neurones d'hippocampe. Nous avons montr�� que l'exposition aux s��rine-prot��ases d��cale la d��pendance au pH de l'activation ainsi que la �� steady-state inactivation ��des ASICs -1a et -1b vers des valeurs plus acidiques. Ainsi, l'exposition aux serine prot��ases conduit �� une diminution du courant quand l'acidification a lieu �� partir d'un pH7.4 et conduit �� une augmentation du courant quand l'acidification alleu �� partir d'un pH7. Nous avons aussi montr�� que cette r��gulation a lieu des les neurones d'hippocampe. Nos r��sultats dans les neurones sensoriels sugg��rent que certains courants ASICs sont impliqu��s dans la transduction de l'acidification et de la douleur ainsi que dans une des phases du processus conduisant �� la neuropathie. Une partie des courants de type 1 perm��ables au Ca 2+ peuvent ��tre impliqu��s dans la neuros��cr��tion. La modulation par les s��rines prot��ases pourrait expliquer qu'en situation d'acidose les canaux ASICs soient toujours activables. R��sum�� grand publique Les neurones sont les principales cellules du syst��me nerveux. Le syst��me nerveux est form�� par le syst��me nerveux central - principalement le cerveau, le cervelet et la moelle ��pini��re - et le syst��me nerveux p��riph��rique -principalement les nerfs et les neurones sensoriels. Gr��ce �� leur nombreux "bras" (les neurites), les neurones sont connect��s entre eux, formant un v��ritable r��seau de communication qui s'��tend dans tout le corps. L'information se propage sous forme d'un ph��nom��ne ��lectrique, l'influx nerveux (ou potentiels d'actions). A la base des ph��nom��nes ��lectriques dans les neurones il y a ce que l'on appelle les canaux ioniques. Un canal ionique est une sorte de tunnel qui traverse l'enveloppe qui entoure les cellules (la membrane) et par lequel passent les ions. La plupart de ces canaux sont normalement ferm��s et n��cessitent d'��tre activ��s pour s'ouvrire et g��n��rer un influx nerveux. Les canaux ASICs sont activ��s par l'acidification et sont exprim��s dans tout le syst��me nerveux. Cette acidification a lieu notamment lors d'une attaque c��r��brale (isch��mie c��r��brale) ou lors de l'inflammation. Les exp��riences sur les animaux ont montr�� que les canaux ASICs avaient entre autre un r��le dans la mort des neurones lors d'une attaque c��r��brale et dans la douleur inflammatoire. Lors de ma th��se je me suis int��ress�� au r��le des ASICs dans la douleur et �� l'influence des substances produites pendant l'inflammation sur leur activation par l'acidification. J'ai ainsi pu montrer chez le rat que la majorit�� des neurones sensoriels impliqu��s dans la douleur ont des canaux ASICs et que l'activation de ces canaux induit des potentiels d'action. Nous avons op��r�� des rats pour qu'ils pr��sentent les sympt��mes d'une maladie chronique appel��e neuropathie. La neuropathie se caract��rise par une plus grande sensibilit�� �� la douleur. Les rats neuropathiques pr��sentent des changements de leurs canaux ASICs sugg��rant que ces canaux ont une peut-��tre un r��le dans la gen��se ou les sympt��mes de cette maladie. J'ai aussi montr�� in vitro qu'un type d'enryme produit lors de l'inflammation et l'isch��mie change les propri��t��s des ASICs. Ces r��sultats confirment un r��le des ASICs dans la douleur sugg��rant notamment un r��le jusque l�� encore non ��tudi�� dans la douleur neuropathique. De plus, ces r��sultats mettent en ��vidence une r��gulation des ASICs qui pourrait ��tre importante si elle se confirmait in vivo de part les diff��rents r��les des ASICs. Abstract Acid-sensing ion channels (ASICs) are members of the ENaC/Degenerin superfamily of ion channels. Their activation by a rapid extracellular acidification generates a transient and for some ASIC types also a sustained current mainly mediated by Na+. ASICs are expressed in the central (CNS) and in the peripheral (PNS) nervous system. In the CNS, ASICs have a putative role in learning, memory and in neuronal death after cerebral ischemia. In the PNS, ASICs have a putative role in nociception (acute and inflammatory pain) and in mechanotransduction. However, studies on ASIC function are somewhat controversial. Some studies suggest a crucial role of ASICs in transduction of acidification and in pain whereas other studies suggest rather a modulatory inhibitory role of ASICs in pain. Moreover, the basic property of ASICs, that they are activated only transiently is irreconcilable with the well-known property of nociception that the firing of nociceptive fibers demonstrated very little adaptation. Endogenous molecules may exist that can modulate ASIC properties. In a first part of my thesis, we addressed the question of the functional expression of ASICs in adult rat dorsal root ganglion (DRG) neurons. Our goal was to elucidate ASIC roles in DRG neurons. We characterized biophysical and pharmacological properties of ASIC currents using the patch-clamp technique in the whole-cell configuration. We observed that around 60% of small-diameter sensory neurons express ASICs currents. We described in these neurons three ASIC current types. Types 1 and 3 have properties compatible with a role of pH-sensor whereas type 2 is mainly activated by pH lower than pH6. Type 1 is mediated by ASIC1a homomultimers which are permeable to Ca 2+. We studied ASIC co-expression with nociceptor markers. The goal was to associate an ASIC current type with a potential function in sensory neurons. Most neurons expressing ASIC currents co-expressed nociceptor markers. However, a higher proportion of the neurons expressing type 1 was not associated with nociception compared to type 2 and -3. We completed this approach with current-clamp measurements of acidification-induced action potentials (APs). We showed that activation of ASICs in small-diameter neurons can induce APs. The probability of AP induction is positively correlated with the ASIC current density and the acidity of stimulation. Then, we used this classification as a tool to characterize the potential functional modulation of ASICs in the spared nerve injury model of neuropathy. This approach was completed by quantitative RT-PCR experiments. ASICs current expression was dramatically changed at the functional and transcriptional level in injured and non-injured small-diameter DRG neurons. In a second part of my thesis, following an initial screening of the effect of various substances secreted during inflammation and ischemia on ASIC current properties, we characterized in detail the modulation of ASICs, in particular of ASIC1 by serine proteases in a recombinant expression system as well as in hippocampal neurons. We showed that protease exposure shifts the pH dependence of ASIC1 activation and steady-state inactivation to more acidic pH. As a consequence, protease exposure leads to a decrease in the current response if ASIC1 is activated by a pH drop from pH 7.4. If, however, acidification occurs from a basal pH of 7, protease-exposed ASIC1a shows higher activity than untreated ASIC1a. We provided evidence that this bi-directional regulation of ASIC1a function also occurs in hippocampal neurons. Our results in DRG neurons suggest that some ASIC currents are involved in the transduction of peripheral acidification and pain. Furthermore, ASICs may participate to the processes leading to neuropathy. Some Ca 2+-permeable type 1 currents may be involved in neurosecretion. ASIC modulation by serine proteases may be physiologically relevant, allowing ASIC activation under sustained slightly acidic conditions.

Transient suppression of Shigella flexneri type 3 secretion by a protective O-antigen-specific monoclonal IgA.

Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

Long-term monitoring of post-stroke plasticity after transient cerebral ischemia in mice using in vivo and ex vivo diffusion tensor MRI.

WE USED A MURINE MODEL OF TRANSIENT FOCAL CEREBRAL ISCHEMIA TO STUDY: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus.Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.

Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia

Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6mg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro speci���c binding of glibenclamide to microglia increased after pro-in���ammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome.

Wigner higher-order spectra: definition, properties, computation and application to transient signal analysis

The Wigner higher order moment spectra (WHOS)are defined as extensions of the Wigner-Ville distribution (WD)to higher order moment spectra domains. A general class oftime-frequency higher order moment spectra is also defined interms of arbitrary higher order moments of the signal as generalizations of the Cohen���s general class of time-frequency representations. The properties of the general class of time-frequency higher order moment spectra can be related to theproperties of WHOS which are, in fact, extensions of the properties of the WD. Discrete time and frequency Wigner higherorder moment spectra (DTF-WHOS) distributions are introduced for signal processing applications and are shown to beimplemented with two FFT-based algorithms. One applicationis presented where the Wigner bispectrum (WB), which is aWHOS in the third-order moment domain, is utilized for thedetection of transient signals embedded in noise. The WB iscompared with the WD in terms of simulation examples andanalysis of real sonar data. It is shown that better detectionschemes can be derived, in low signal-to-noise ratio, when theWB is applied.

Heat shock response in photosynthetic organisms: membrane and lipid connections.

The ability of photosynthetic organisms to adapt to increases in environmental temperatures is becoming more important with climate change. Heat stress is known to induce heat-shock proteins (HSPs) many of which act as chaperones. Traditionally, it has been thought that protein denaturation acts as a trigger for HSP induction. However, increasing evidence has shown that many stress events cause HSP induction without commensurate protein denaturation. This has led to the membrane sensor hypothesis where the membrane's physical and structural properties play an initiating role in the heat shock response. In this review, we discuss heat-induced modulation of the membrane's physical state and changes to these properties which can be brought about by interaction with HSPs. Heat stress also leads to changes in lipid-based signaling cascades and alterations in calcium transport and availability. Such observations emphasize the importance of membranes and their lipids in the heat shock response and provide a new perspective for guiding further studies into the mechanisms that mediate cellular and organismal responses to heat stress.

New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.

BACKGROUND: Lactate protects mice against the ischaemic damage resulting from transient middle cerebral artery occlusion (MCAO) when administered intracerebroventricularly at reperfusion, yielding smaller lesion sizes and a better neurological outcome 48 h after ischaemia. We have now tested whether the beneficial effect of lactate is long-lasting and if lactate can be administered intravenously. METHODS: Male ICR-CD1 mice were subjected to 15-min suture MCAO under xylazine + ketamine anaesthesia. Na L-lactate (2 ��l of 100 mmol/l) or vehicle was administered intracerebroventricularly at reperfusion. The neurological deficit was evaluated using a composite deficit score based on the neurological score, the rotarod test and the beam walking test. Mice were sacrificed at 14 days. In a second set of experiments, Na L-lactate (1 ��mol/g body weight) was administered intravenously into the tail vein at reperfusion. The neurological deficit and the lesion volume were measured at 48 h. RESULTS: Intracerebroventricularly injected lactate induced sustained neuroprotection shown by smaller neurological deficits at 7 days (median = 0, min = 0, max = 3, n = 7 vs. median = 2, min = 1, max = 4.5, n = 5, p < 0.05) and 14 days after ischaemia (median = 0, min = 0, max = 3, n = 7 vs. median = 3, min = 0.5, max = 3, n = 7, p = 0.05). Reduced tissue damage was demonstrated by attenuated hemispheric atrophy at 14 days (1.3 �� 4.0 mm(3), n = 7 vs. 12.1 �� 3.8 mm(3), n = 5, p < 0.05) in lactate-treated animals. Systemic intravenous lactate administration was also neuroprotective and attenuated the deficit (median = 1, min = 0, max = 2.5, n = 12) compared to vehicle treatment (median = 1.5, min = 1, max = 8, n = 12, p < 0.05) as well as the lesion volume at 48 h (13.7 �� 12.2 mm(3), n = 12 vs. 29.6 �� 25.4 mm(3), n = 12, p < 0.05). CONCLUSIONS: The beneficial effect of lactate is long-lasting: lactate protects the mouse brain against ischaemic damage when supplied intracerebroventricularly during reperfusion with behavioural and histological benefits persisting 2 weeks after ischaemia. Importantly, lactate also protects after systemic intravenous administration, a more suitable route of administration in a clinical emergency setting. These findings provide further steps to bring this physiological, commonly available and inexpensive neuroprotectant closer to clinical translation for stroke.

Neuronal survival induced by neurotrophins requires calmodulin

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.

Cerebral Hypoperfusion in Posterior Reversible Encephalopathy Syndrome is Different from Transient Ischemic Attack on CT Perfusion.

BACKGROUND: PRES is a reversible neurotoxic state presenting with headache, altered mental status, visual loss, and seizures. Delayed diagnosis can be avoided if radiological patterns could distinguish PRES from cerebral ischemia. METHODS: Clinical and radiological data were collected on all hospitalized patients who had (1) discharge diagnosis of PRES and (2) acute CTP/CTA. Data were compared with 10 TIA patients with proven cytotoxic edema on MRI. RESULTS: Of the four PRES patients found, three were correlated with acute blood pressure and one with chemotherapy. At the radiological level, quantitative analyses of the CTP parameters showed that 2 out of 4 patients had bilaterally reduced CBF-values (23.2-47.1��ml/100g/min) in occipital regions, as seen in the pathological regions of TIA patients (27.3������13.5 ml/100g/min). When compared with TIA patients, the pathological ROI's demonstrated decreased CBV-values (3.4-5.6��ml/100g). Vasogenic edema on MRI FLAIR imaging was seen in only one PRES patient, and cytotoxic edema on DWI-imaging was never found. CT angiography showed in one PRES patient a vasospasm-like unilateral posterior cerebral artery. CONCLUSIONS: If confirmed by other groups, CTP and CTA imaging in patients with acute visual loss and confusion may help to distinguish PRES from bi-occipital ischemia. These radiological parameters may identify PRES patients at risk for additional tissue infarction.

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Protein loop compaction and the origin of the effect of arginine and glutamic acid mixtures on solubility, stability and transient oligomerization of proteins

Addition of a 50 mM mixture of l-arginine and l-glutamic acid (RE) is extensively used to improve protein solubility and stability, although the origin of the effect is not well understood. We present Small Angle X-ray Scattering (SAXS) and Nuclear Magnetic Resonance (NMR) results showing that RE induces protein compaction by collapsing flexible loops on the protein core. This is suggested to be a general mechanism preventing aggregation and improving resistance to proteases and to originate from the polyelectrolyte nature of RE. Molecular polyelectrolyte mixtures are expected to display long range correlation effects according to dressed interaction site theory. We hypothesize that perturbation of the RE solution by dissolved proteins is proportional to the volume occupied by the protein. As a consequence, loop collapse, minimizing the effective protein volume, is favored in the presence of RE.