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1.  Transient improvement of poststroke apathy with zolpidem: a single-case, placebo-controlled double-blind study 
BMJ Case Reports  2013;2013:bcr2012007816.
We report the case of a 44-year-old patient with severe and disabling apathy nearly 2 years after a right hemisphere haemorrhagic stroke. The effect of a single dose of zolpidem was tested over a 2-week period, in alternation with either no treatment or a placebo in a double-blind randomised trial. Zolpidem was associated with a dramatic improvement in apathy, as assessed with the Apathy Inventory and the Behavioral Dysexecutive Syndrome Inventory. No adverse effect occurred during the trial.
doi:10.1136/bcr-2012-007816
PMCID: PMC3604023  PMID: 23396925
2.  Mucosal Imprinting of Vaccine-Induced CD8+ T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors 
Science translational medicine  2013;5(172):172ra20.
Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. We showed that the growth of orthotopic head and neck or lung cancers was inhibited when a cancer vaccine was delivered by the intranasal mucosal route but not the intramuscular route. This antitumor effect was dependent on CD8+ T cells. Indeed, only intranasal vaccination elicited mucosal-specific CD8+ T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8+ T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, dendritic cells from lung parenchyma, but not those from spleen, induced the expression of CD49a on cocultured specific CD8+ T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a, which supports the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8+ T cells that controlled their trafficking. Immunization route directly affected the efficacy of the cancer vaccine to control mucosal tumors.
doi:10.1126/scitranslmed.3004888
PMCID: PMC4086646  PMID: 23408053
3.  The Golgi Protein ACBD3, an Interactor for Poliovirus Protein 3A, Modulates Poliovirus Replication 
Journal of Virology  2013;87(20):11031-11046.
We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all of these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 [PVS2-3A(CV-A17)]. The small interfering RNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors and may thus be one of the factors favoring their emergence.
doi:10.1128/JVI.00304-13
PMCID: PMC3807280  PMID: 23926333
4.  Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells 
Vascular Cell  2014;6:1.
Netrins are secreted molecules involved in axon guidance and angiogenesis. We previously showed that Netrin-4 acts as an anti-angiogenic factor by inhibiting endothelial cell (EC) functions. In this study, we investigated the effects of Netrin-4 on vascular smooth muscle cell (VSMC) activity in vitro and in vivo. We show that exogenous Netrin-4 stimulated VSMC adhesion and migration, and increased their coverage on EC tubes (grown on a Matrigel substrate). siRNA knock-down of endogenous Netrin-4 expression in VSMC decreased their recruitment to EC tubes. VSMC expressed Netrin-4 and three of the six Netrin-1 cognate receptors: DCC, Neogenin, and Unc5B. Silencing of these receptors reduced Netrin-4 adhesion to VSMC, strongly suggesting that these receptors were involved in the recruitment process. We previously showed that Netrin-4 overexpression in PC3 cancer cells delayed tumor growth in a model of subcutaneous xenograft by reducing tumor vessel density. Here, we show that Netrin-4 overexpression improved tumor blood vessel structure and increased VSMC coverage. Thus, Netrin-4 induced mural cell recruitment may play a role in the inhibition of tumor growth. Our data suggest that Netrin-4 is important for blood vessel normalization through the regulation of both endothelial and perivascular cells.
doi:10.1186/2045-824X-6-1
PMCID: PMC3909532  PMID: 24472220
Netrin-4; Blood vessel; Mural cell; Angiogenesis; Basement membrane; Tumor growth
5.  Evidence for the High Importance of Co-Morbid Factors in HFE C282Y/H63D Patients Cared by Phlebotomies: Results from an Observational Prospective Study 
PLoS ONE  2013;8(12):e81128.
Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (n = 172) and C282Y/H63D (n = 58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients’ profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; p = 0.0454), overweight (66.7% vs. 39.4%; p = 0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice.
doi:10.1371/journal.pone.0081128
PMCID: PMC3855242  PMID: 24339903
6.  Placebo and other psychological interactions in headache treatment 
The Journal of Headache and Pain  2012;13(3):191-198.
We present a theory according which a headache treatment acts through a specific biological effect (when it exists), a placebo effect linked to both expectancy and repetition of its administration (conditioning), and a non-specific psychological effect. The respective part of these components varies with the treatments and the clinical situations. During antiquity, suggestions and beliefs were the mainstays of headache treatment. The word placebo appeared at the beginning of the eighteenth century. Controversies about its effect came from an excessive interpretation due to methodological bias, inadequate consideration of the variation of the measure (regression to the mean) and of the natural course of the disease. Several powerful studies on placebo effect showed that the nature of the treatment, the associated announce, the patients’ expectancy, and the repetition of the procedures are of paramount importance. The placebo expectancy is associated with an activation of pre-frontal, anterior cingular, accumbens, and periacqueducal grey opioidergic neurons possibly triggered by the dopaminergic meso-limbic system. In randomized control trials, several arms design could theoretically give information concerning the respective part of the different component of the outcome and control the natural course of the disease. However, for migraine and tension type headache attacks treatment, no three arm (verum, placebo, and natural course) trial is available in the literature. Indirect evidence of a placebo effect in migraine attack treatment, comes from the high amplitude of the improvement observed in the placebo arms (28% of the patients). This figure is lower (6%) when using the harder criterium of pain free at 2 h. But these data disregard the effect of the natural course. For prophylactic treatment with oral medication, the trials performed in the last decades report an improvement in 21% of the patients in the placebo arms. However, in these studies the duration of administration was limited, the control of attacks uncertain as well as the evolution of the co-morbid psycho-pathology. Considering the reviews and meta-analysis of complex prophylactic procedures, it must be concluded that their effect is mostly linked to a placebo and non-specific psychological effects. Acupuncture may have a slight specific effect on tension type headache, but not on migraine. Manual therapy studies do not exhibit difference between manipulation, mobilization, and controls; touch has no proven specific effect. A comprehensive efficacy review of biofeedback studies concludes to a small specific effect on tension type headache but not on migraine. A review of behavioral treatment conclude to an interesting mean improvement but did not demonstrated a specific effect with the exception of a four arm study including a pseudo meditation control group. Expectation-linked placebo, conditioning, and non-specific psychological effects vary according clinical situations and psychological context; likely low in RCT, high after anempathic medical contact, and at its maximum with a desired charismatic healer. The announcements of doctors strongly influence the beliefs of patients, and in consequence their pain and anxiety sensibilities; this modulates the amplitude of the placebo and the non-specific psychological effects and is therefore a major determinant of the therapeutic success. Furthermore, any repetitive contact, even through a placebo, may interfere positively with the psychopathological co-morbidity. One has to keep in mind that the non-specific psychological interactions play a major role in the improvement of the majority of the headache sufferers.
doi:10.1007/s10194-012-0422-0
PMCID: PMC3311834  PMID: 22367630
Migraine; Placebo; Headache treatment
7.  Placebo and other psychological interactions in headache treatment 
The Journal of Headache and Pain  2012;13(3):191-198.
We present a theory according which a headache treatment acts through a specific biological effect (when it exists), a placebo effect linked to both expectancy and repetition of its administration (conditioning), and a non-specific psychological effect. The respective part of these components varies with the treatments and the clinical situations. During antiquity, suggestions and beliefs were the mainstays of headache treatment. The word placebo appeared at the beginning of the eighteenth century. Controversies about its effect came from an excessive interpretation due to methodological bias, inadequate consideration of the variation of the measure (regression to the mean) and of the natural course of the disease. Several powerful studies on placebo effect showed that the nature of the treatment, the associated announce, the patients’ expectancy, and the repetition of the procedures are of paramount importance. The placebo expectancy is associated with an activation of pre-frontal, anterior cingular, accumbens, and periacqueducal grey opioidergic neurons possibly triggered by the dopaminergic meso-limbic system. In randomized control trials, several arms design could theoretically give information concerning the respective part of the different component of the outcome and control the natural course of the disease. However, for migraine and tension type headache attacks treatment, no three arm (verum, placebo, and natural course) trial is available in the literature. Indirect evidence of a placebo effect in migraine attack treatment, comes from the high amplitude of the improvement observed in the placebo arms (28% of the patients). This figure is lower (6%) when using the harder criterium of pain free at 2 h. But these data disregard the effect of the natural course. For prophylactic treatment with oral medication, the trials performed in the last decades report an improvement in 21% of the patients in the placebo arms. However, in these studies the duration of administration was limited, the control of attacks uncertain as well as the evolution of the co-morbid psycho-pathology. Considering the reviews and meta-analysis of complex prophylactic procedures, it must be concluded that their effect is mostly linked to a placebo and non-specific psychological effects. Acupuncture may have a slight specific effect on tension type headache, but not on migraine. Manual therapy studies do not exhibit difference between manipulation, mobilization, and controls; touch has no proven specific effect. A comprehensive efficacy review of biofeedback studies concludes to a small specific effect on tension type headache but not on migraine. A review of behavioral treatment conclude to an interesting mean improvement but did not demonstrated a specific effect with the exception of a four arm study including a pseudo meditation control group. Expectation-linked placebo, conditioning, and non-specific psychological effects vary according clinical situations and psychological context; likely low in RCT, high after anempathic medical contact, and at its maximum with a desired charismatic healer. The announcements of doctors strongly influence the beliefs of patients, and in consequence their pain and anxiety sensibilities; this modulates the amplitude of the placebo and the non-specific psychological effects and is therefore a major determinant of the therapeutic success. Furthermore, any repetitive contact, even through a placebo, may interfere positively with the psychopathological co-morbidity. One has to keep in mind that the non-specific psychological interactions play a major role in the improvement of the majority of the headache sufferers.
doi:10.1007/s10194-012-0422-0
PMCID: PMC3311834  PMID: 22367630
Migraine; Placebo; Headache treatment
8.  GATE - Geant4 Application for Tomographic Emission: a simulation toolkit for PET and SPECT 
Physics in Medicine and Biology  2004;49(19):4543-4561.
Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols, and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document, and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at the address http://www-lphe.ep.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects toward the gridification of GATE and its extension to other domains such as dosimetry are also discussed.
PMCID: PMC3267383  PMID: 15552416
9.  Calcium Flux between the Endoplasmic Reticulum and Mitochondrion Contributes to Poliovirus-Induced Apoptosis▿  
Journal of Virology  2010;84(23):12226-12235.
We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca2+) concentration in neuroblastoma IMR5 cells, at least partly through Ca2+ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This leads to Ca2+ accumulation in mitochondria through the mitochondrial Ca2+ uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca2+ concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.
doi:10.1128/JVI.00994-10
PMCID: PMC2976416  PMID: 20861253
10.  Transient global amnesia caused by painless aortic dissection 
BMJ Case Reports  2009;2009:bcr09.2008.0935.
Neurological syndromes secondary to acute aortic dissection (AAD) are uncommon and usually consist of focal deficits after an embolic cerebral infarction. This article reports the observation of an AAD with the chief complaint of transient acute memory impairment–that is, a non-usual stroke-like symptom.
doi:10.1136/bcr.09.2008.0935
PMCID: PMC3027937  PMID: 21686553
11.  Abrupt onset of disturbed vigilance, bilateral third nerve palsy and masturbating behaviour: a rare presentation of stroke 
Emergency Medicine Journal : EMJ  2007;24(8):600-601.
The clinical presentation of stroke usually includes sensory–motor impairment, cranial nerve palsies, or cognitive dysfunction. Disorders in behaviour are less frequently seen. The case of a patient with a very disturbing presentation, which included a disturbance in vigilance, bilateral third nerve palsy and masturbating behaviour, is presented. The topography of the lesions and its implications on the deficits observed are discussed.
doi:10.1136/emj.2007.047662
PMCID: PMC2660103  PMID: 17652699
12.  Visual recognition memory differentiates dementia with Lewy bodies and Parkinson's disease dementia 
Objective
To compare cognitive impairments in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), to discriminate between the two entities.
Methods
10 DLB and 12 PDD consecutive patients performed a neuropsychological battery designed to assess several cognitive domains: verbal and visual memory (Delayed Matching to Sample (DMS)‐48), language, gnosia, praxia and executive functions.
Results
DLB patients had poorer performances in orientation (p<0.05), Trail Making Test A (p<0.05) and reading of names of colours in the Stroop Test (p<0.05). Their scores were also lower in the visual object recognition memory test (DMS‐48), in both immediate (p<0.05) and delayed recognition (p<0.05). No differences were observed in the other tests.
Conclusion
Despite global similarities in cognitive performances between DLB and PDD patients, we observed important differences: in particular, DMS‐48, a test of visual object recognition memory and visual storage capacity, was poorer in DLB patients.
doi:10.1136/jnnp.2006.104257
PMCID: PMC2117680  PMID: 17287240
13.  Psychopathology and quality of life burden in chronic daily headache: influence of migraine symptoms 
The Journal of Headache and Pain  2010;11(3):247-253.
The aim of this study is to compare the psychopathology and the quality of life of chronic daily headache patients between those with migraine headache and those with tension-type headache. We enrolled 106 adults with chronic daily headache (CDH) who consulted for the first time in specialised centres. The patients were classified according to the IHS 2004 criteria and the propositions of the Headache Classification Committee (2006) with a computed algorithm: 8 had chronic migraine (without medication overuse), 18 had chronic tension-type headache (without medication overuse), 80 had medication overuse headache and among them, 43 fulfilled the criteria for the sub-group of migraine (m) MOH, and 37 the subgroup for tension-type (tt) MOH. We tested five variables: MADRS global score, HAMA psychic and somatic sub-scales, SF-36 psychic, and somatic summary components. We compared patients with migraine symptoms (CM and mMOH) to those with tension-type symptoms (CTTH and ttMOH) and neutralised pain intensity with an ANCOVA which is a priori higher in the migraine group. We failed to find any difference between migraine and tension-type groups in the MADRS global score, the HAMA psychological sub-score and the SF36 physical component summary. The HAMA somatic anxiety subscale was higher in the migraine group than in the tension-type group (F(1,103) = 10.10, p = 0.001). The SF36 mental component summary was significantly worse in the migraine as compared with the tension-type subgroup (F(1,103) = 5.758, p = 0.018). In the four CDH subgroups, all the SF36 dimension scores except one (Physical Functioning) showed a more than 20 point difference from those seen in the adjusted historical controls. Furthermore, two sub-scores were significantly more affected in the migraine group as compared to the tension-type group, the physical health bodily pain (F(1,103) = 4.51, p = 0.036) and the mental health (F(1,103) = 8.17, p = 0.005). Considering that the statistic procedure neutralises the pain intensity factor, our data suggest a particular vulnerability to somatic symptoms and a special predisposition to develop negative pain affect in migraine patients in comparison to tension-type patients.
doi:10.1007/s10194-010-0208-1
PMCID: PMC3451907  PMID: 20383733
Psychopathology; Quality of life; Chronic daily headache; Migraine symptoms; Tension type headache symptoms
14.  Transient global amnesia caused by painless aortic dissection 
Neurological syndromes secondary to acute aortic dissection (AAD) are uncommon and usually consist of focal deficits after an embolic cerebral infarction. This article reports the observation of an AAD with the chief complaint of transient acute memory impairment—that is, a non‐usual stroke‐like symptom.
doi:10.1136/emj.2006.040881
PMCID: PMC2658161  PMID: 17183052
15.  A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock 
Critical Care  2009;13(2):R43.
Introduction
We aimed to establish whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during evolving bacterial community-acquired infection in adults is associated with severe sepsis or septic shock.
Methods
We conducted a multicentre case-control study in eight intensive care units. Cases were all adult patients admitted for severe sepsis or septic shock due to a bacterial community-acquired infection. Control individuals were patients hospitalized with a mild community-acquired infection. Each case was matched to one control for age, presence of diabetes and site of infection.
Results
The main outcome measures were the proportions of cases and controls exposed to NSAIDs or aspirin during the period of observation. In all, 152 matched pairs were analyzed. The use of NSAIDs or aspirin during the observation period did not differ between cases and controls (27% versus 28; odds ratio = 0.93, 95% confidence interval [CI] = 0.52 to 1.64). If aspirin was not considered or if a distinction was made between acute and chronic drug treatment, there remained no difference between groups. However, the median time to prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02).
Conclusions
In this study, the use of NSAIDs or aspirin during evolving bacterial infection was frequent and occurred in one-quarter of the patients with such infection. Although the use of NSAIDs by patients with severe sepsis or septic shock did not differ from their use by those with mild infection at the same infected site, we observed a longer median time to prescription of effective antibiotic therapy in NSAID users.
doi:10.1186/cc7766
PMCID: PMC2689487  PMID: 19331665
16.  Early Phosphatidylinositol 3-Kinase/Akt Pathway Activation Limits Poliovirus-Induced JNK-Mediated Cell Death▿  
Journal of Virology  2008;82(7):3796-3802.
Poliovirus (PV)-induced apoptosis seems to play a major role in tissue injury in the central nervous system (CNS). We have previously shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. We showed here that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, limiting the extent of JNK activation and thereby cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the apoptosis signal-regulating kinase 1, which acts upstream from JNK in PV-infected IMR5 cells. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in the CNS.
doi:10.1128/JVI.02020-07
PMCID: PMC2268503  PMID: 18216097
17.  Poliovirus Induces Bax-Dependent Cell Death Mediated by c-Jun NH2-Terminal Kinase▿  
Journal of Virology  2007;81(14):7504-7516.
Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH2-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.
doi:10.1128/JVI.02690-06
PMCID: PMC1933371  PMID: 17494073
18.  Bax Is Activated during Rotavirus-Induced Apoptosis through the Mitochondrial Pathway▿  
Journal of Virology  2007;81(9):4457-4464.
Rotaviruses are the leading cause of infantile viral gastroenteritis worldwide. Mature enterocytes of the small intestine infected by rotavirus undergo apoptosis, and their replacement by less differentiated dividing cells probably leads to defective absorptive function of the intestinal epithelium, which, in turn, contributes to osmotic diarrhea and rotavirus pathogenesis. Here we show that infection of MA104 cells by the simian rhesus rotavirus strain RRV induced caspase-3 activation, DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase; all three phenomena are features of apoptosis. RRV induced the release of cytochrome c from mitochondria to the cytosol, indicating that the mitochondrial apoptotic pathway was activated. RRV infection of MA104 cells activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change. Most importantly, Bax-specific small interfering RNAs partially inhibited cytochrome c release in RRV-infected cells. Thus, mitochondrial dysfunction induced by rotavirus is Bax dependent. Apoptosis presumably leads to impaired intestinal functions, so our findings contribute to improving our understanding of rotavirus pathogenesis at the cellular level.
doi:10.1128/JVI.02344-06
PMCID: PMC1900143  PMID: 17301139
20.  ActA Is Required for Crossing of the Fetoplacental Barrier by Listeria monocytogenes▿  
Infection and Immunity  2006;75(2):950-957.
The facultative intracellular bacterial pathogen Listeria monocytogenes induces severe fetal infection during pregnancy. Little is known about the molecular mechanisms allowing the maternofetal transmission of bacteria. In this work, we studied fetoplacental invasion by infecting mice with various mutants lacking virulence factors involved in the intracellular life cycle of L. monocytogenes. We found that the placenta was highly susceptible to bacteria, including avirulent bacteria, such as an L. monocytogenes mutant with an hly deletion (ΔLLO) and a nonpathogenic species, Listeria innocua, suggesting that permissive trophoblastic cells, trapping bacteria, provide a protective niche for bacterial survival. The ΔLLO mutant, which is unable to escape the phagosomal compartment of infected cells, failed to grow in the trophoblast tissue and to invade the fetus. Mutant bacteria with inlA and inlB deletion (ΔInlAB) grew in the placenta and fetus as well as did the wild-type virulent stain (EGDwt), indicating that in the murine model, internalins A and B are not involved in fetoplacental invasion by L. monocytogenes. Pregnant mice were then infected with an actA deletion (ΔActA) strain, a virulence-attenuated mutant that is unable to polymerize actin and to spread from cell to cell. With the ΔActA mutant, fetal infection occurs, but with a significant delay and restriction, and it requires a placental bacterial load 2 log units higher than that for the wild-type virulent strain. Definitive evidence for the role of ActA was provided by showing that a actA-complemented ΔActA mutant was restored in its capacity to invade fetuses. ActA-mediated cell-to-cell spreading plays a major role in the vertical transmission of L. monocytogenes to the fetus in the murine model.
doi:10.1128/IAI.01570-06
PMCID: PMC1828513  PMID: 17118980
21.  Identification of the agr Locus of Listeria monocytogenes: Role in Bacterial Virulence  
Infection and Immunity  2003;71(8):4463-4471.
Listeria monocytogenes is a gram-positive facultative intracellular food-borne pathogen that can cause severe infections in humans and animals. We have recently adapted signature-tagged transposon mutagenesis (STM) to identify genes involved in the virulence of L. monocytogenes. A new round of STM allowed us to identify a new locus encoding a protein homologous to AgrA, the well-studied response regulator of Staphylococcus aureus and part of a two-component system involved in bacterial virulence. The production of several secreted proteins was modified in the agrA mutant of L. monocytogenes grown in broth, indicating that the agr locus influenced protein secretion. Inactivation of agrA did not affect the ability of the pathogen to invade and multiply in cells in vitro. However, the virulence of the agrA mutant was attenuated in the mouse (a 10-fold increase in the 50% lethal dose by the intravenous route), demonstrating for the first time a role for the agr locus in the virulence of L. monocytogenes.
doi:10.1128/IAI.71.8.4463-4471.2003
PMCID: PMC166014  PMID: 12874326
23.  Identification of New Genes Involved in the Virulence of Listeria monocytogenes by Signature-Tagged Transposon Mutagenesis 
Infection and Immunity  2001;69(4):2054-2065.
Listeria monocytogenes is a gram-positive, facultative intracellular pathogen that can cause severe food-born infections in humans and animals. We have adapted signature-tagged transposon mutagenesis to L. monocytogenes to identify new genes involved in virulence in the murine model of infection. We used transposon Tn1545 carried on the integrative vector pAT113. Forty-eight tagged transposons were constructed and used to generate banks of L. monocytogenes mutants. Pools of 48 mutants were assembled, taking one mutant from each bank, injected into mice, and screened for those affected in their multiplication in the brains of infected animals. From 2,000 mutants tested, 18 were attenuated in vivo. The insertions harbored by these mutants led to the identification of 10 distinct loci, 7 of which corresponded to previously unknown genes. The properties of four loci involving putative cell wall components were further studied in vitro and in vivo. The data suggested that these components are involved in bacterial invasion and multiplication in the brain.
doi:10.1128/IAI.69.4.2054-2065.2001
PMCID: PMC98130  PMID: 11254558

Results 1-24 (24)