The anterior medial hippocampus contributes to both recall and familiarity-based memory for scenes.

The hippocampus is usually associated with recall memory, whereas its contribution to familiarity-based memory is debated. Growing evidence support the idea that this structure participates to any cognitive process performed on scene representations. In parallel, differences in functional specialisation and cortical connectivity were found across the longitudinal and transverse axes of the hippocampus. Here we reanalysed functional MRI data from 51 participants showing stronger engagement of the hippocampus in recall, familiarity-based recognition and rejection, and visual discrimination, of scenes compared to single objects. A conjunction analysis between these four tasks revealed a set of occipital, medial temporal, posterior cingulate, and parietal regions, matching the scene construction network described in the literature. Crucially, we found that the anterior medial part of the hippocampus was consistently involved in all tasks investigated for scene stimuli. These findings support that the hippocampus can contribute to both recall and familiarity-based memory, depending on stimulus type. More generally, this bolsters the recent proposal that circumscribed regions within the hippocampus may underpin specific cognitive mechanisms.

Closed-loop optogenetic control of the dynamics of neural activity in non-human primates.

Electrical neurostimulation is effective in the treatment of neurological disorders, but associated recording artefacts generally limit its applications to open-loop stimuli. Real-time and continuous closed-loop control of brain activity can, however, be achieved by pairing concurrent electrical recordings and optogenetics. Here we show that closed-loop optogenetic stimulation with excitatory opsins enables the precise manipulation of neural dynamics in brain slices from transgenic mice and in anaesthetized non-human primates. The approach generates oscillations in quiescent tissue, enhances or suppresses endogenous patterns in active tissue and modulates seizure-like bursts elicited by the convulsant 4-aminopyridine. A nonlinear model of the phase-dependent effects of optical stimulation reproduced the modulation of cycles of local-field potentials associated with seizure oscillations, as evidenced by the systematic changes in the variability and entropy of the phase-space trajectories of seizures, which correlated with changes in their duration and intensity. We also show that closed-loop optogenetic neurostimulation could be delivered using intracortical optrodes incorporating light-emitting diodes. Closed-loop optogenetic approaches may be translatable to therapeutic applications in humans.

Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability.

Language processing is a highly integrative function, intertwining linguistic operations (processing the language code intentionally used for communication) and extra-linguistic processes (e.g., attention monitoring, predictive inference, long-term memory). This synergetic cognitive architecture requires a distributed and specialized neural substrate. Brain systems have mainly been examined at rest. However, task-related functional connectivity provides additional and valuable information about how information is processed when various cognitive states are involved. We gathered thirteen language fMRI tasks in a unique database of one hundred and fifty neurotypical adults (InLang [Interactive networks of Language] database), providing the opportunity to assess language features across a wide range of linguistic processes. Using this database, we applied network theory as a computational tool to model the task-related functional connectome of language (LANG atlas). The organization of this data-driven neurocognitive atlas of language was examined at multiple levels, uncovering its major components (or crucial subnetworks), and its anatomical and functional correlates. In addition, we estimated its reconfiguration as a function of linguistic demand (flexibility) or several factors such as age or gender (variability). We observed that several discrete networks could be specifically shaped to promote key functional features of language: coding-decoding (Net1), control-executive (Net2), abstract-knowledge (Net3), and sensorimotor (Net4) functions. The architecture of these systems and the functional connectivity of the pivotal brain regions varied according to the nature of the linguistic process, gender, or age. By accounting for the multifaceted nature of language and modulating factors, this study can contribute to enriching and refining existing neurocognitive models of language. The LANG atlas can also be considered a reference for comparative or clinical studies involving various patients and conditions.

A rare association between group A Streptococcus purpura fulminans and diffuse alveolar hemorrhage in a young girl: A case report.

We report the case of a 7-year-old girl with septic shock and coagulopathy associated with purpura fulminans (PF) and diffuse alveolar hemorrhage (DAH) due to group A Streptococcus (GAS) infection identified with 16S ribosomal RNA analysis performed on the skin biopsy. GAS infection with PF associated with DAH is rare in healthy young children but pediatricians should be aware of this condition because of the poor prognosis. The initial treatment for circulatory failure and severe disseminated intravascular coagulation as well as the prompt initiation of antibiotic treatment may be crucial for the outcomes of S. pyogenes PF.

Fetal microchimerism by mode of delivery: a prospective cohort study.

OBJECTIVE: To compare fetal microchimerism (FMc) in pregnancies with uncomplicated vaginal delivery (VD) versus caesarean delivery (CD). DESIGN: Prospective cohort study. SETTING: University of Washington and Fred Hutchinson Cancer Research Center, USA. POPULATION: Women delivering singleton pregnancies without pertinent antenatal complications with uncomplicated deliveries (n = 36). METHODS: We collected maternal predelivery, postdelivery and umbilical cord blood for each mother-baby pair. Following maternal and fetal genotyping, FMc was measured with quantitative polymerase chain reaction assays targeting fetus-specific polymorphisms. Quantification of FMc is expressed as genome equivalents (gEq) of fetal DNA/100 000 total gEq tested. FMc detection was evaluated by logistic regression while controlling for total number of cell equivalents tested and clinically relevant covariates. FMc concentrations were compared using negative binomial regression while controlling for the same covariates and predelivery FMc positivity. MAIN OUTCOME MEASURE: Detection and concentration of FMc by mode of delivery. RESULTS: Twenty-four mother-baby pairs had a VD and 12 had a CD. Postdelivery FMc detection was higher following CD than after VD (58.3% versus 16.7%, P = 0.02). After controlling for covariates, the likelihood of postdelivery FMc detection was almost nine-fold higher after CD than VD (odds ratio 8.8, 95% CI 1.6-47.6; P = 0.01). With respect to postdelivery FMc concentration, the detection rate ratio for CD versus VD in the adjusted negative binomial regression model was 14.7 (95% CI 3.2-66.8; P = 0.001). CONCLUSION: Postdelivery peripheral FMc detection and concentration are significantly higher after CD than after VD. As FMc is associated with long-term maternal health, our findings suggest that the mode of delivery may impact this risk. TWEETABLE ABSTRACT: Greater fetal microchimerism found in maternal blood following caesarean delivery compared with vaginal delivery.

Urine collection methods used for non-toilet-trained children in pediatric emergency departments in France: A medical practice analysis.

INTRODUCTION: Since April 2015, the French Society of Pediatrics has encouraged suprapubic aspiration (SA) and urethral catheterization (UC) for urine collection in non-toilet-trained children suspected of having urinary tract infections (UTIs) and has tried to reduce the use of urine bag (UB). OBJECTIVE: To analyze the medical practices concerning urine collection methods used for non-toilet-trained children in pediatric emergency departments in France. METHODS: We conducted a descriptive medical practice study in October 2017. All members of the French Society of Pediatric Nephrology received two questionnaires about urine collection methods used for non-toilet-trained children, distinguishing between male and female patients, and about the corresponding analgesic protocols used in their pediatric emergency departments. RESULTS: In total, 26 centers completed questionnaires concerning female patients. UC was performed in cases of fever associated with urinary tract malformations in 14 of 26 centers (54%). UB was used in cases of fever of unknown origin lasting for more than 48h in 17 of 26 centers (65%), in cases of fever associated with UTI symptoms in 14 of 26 centers (54%), and in cases of fever in infants under 3 months of age in 16 of 26 centers (61%). The questionnaires concerning male patients were completed by 30 centers. UB was the initially used urine collection method in all situations with, respectively, 22 of 30 (73%), 27 of 30 (90%), 23 of 30 (77%), and 22 of 30 (73%) centers. The analgesic protocol for urine collection is not well established in France. CONCLUSION: UC for urine collection in pediatric emergency departments in France is underused despite the national recommendations and the greater diagnostic power of this method compared with UB.

Aging modulates fronto-temporal cortical interactions during lexical production. A dynamic causal modeling study.

In this dynamic causal modeling (DCM) study, we evaluated the effect of age on the effective connectivity of a cerebral network involved in lexical production. Younger and older adults performed an object naming task during fMRI. The DCM was used to explore the interactions between four regions of interest: the occipital cortex, OC; the lateral temporal cortex, LTC; the medial temporal cortex, MTC; and the inferior frontal cortex, IFC. We mainly focused on the modulation of the fronto-temporal interaction, according to the hypothesis that aging requires strategies that modulate the access to the semantic knowledge, either through a neural reserve mechanism (increased MTC-LTC connectivity) or through a neural compensation mechanism (supplementary IFC-MTC connectivity). For younger adults, our results indicated a bi-directional interaction between the left IFC and LTC suggesting a typical activation related to lexico-semantic representations. For older adults, our results reveal the existence of bi-directional interaction between the IFC and MTC, but not between the IFC and LTC - which in turn suggests that older adults adapt a new strategy, via supplemental access to conceptual access and semantic retrieval processes. This neural compensation strategy would be facilitated by a top-down mechanism from the IFC to the MTC. We discuss our results in the context of the possible additional strategies used by older compared to younger adults, to retrieve and produce words.

Neural correlates of the healthiness evaluation processes of food labels.

OBJECTIVES: This fMRI study evaluated the cognitive mechanisms and the cerebral substrates when evaluating the healthiness of food products from nutritional information displayed either with a traffic light (TL) system, a colored nutritional label, or with a guideline daily amount (GDA) system, a numeric label. We postulated that TL label would recruit emotional processes and activation of subjacent cerebral regions (e.g. insula and amygdala). On the contrary, the nutritional information presented in a GDA label, would recruit, due to its numeric format and higher complexity, supplementary cognitive processes and activation of related brain regions (e.g. middle and superior frontal as well as parietal cortices). METHODS: We examined 50 healthy participants during an evaluation task on the healthiness of real food products from nutritional information only. Per total, 60 food products nutritional labels have been presented, with either colored (TL) or numeric (GDA) nutritional information and three levels of complexity of nutritional information. RESULTS: In line with our predictions, evaluations based on GDA recruited prefrontal and parietal regions reported for analytic processes. Contrary to our predictions, the same network has been recruited when evaluations were based on TL. Finally, we found significant correlation between response time and the superior parietal lobule in the GDA condition. DISCUSSION: Our results suggested that TL did not have an effect on the used strategy compared to GDA, based on calculation and arithmetic processes. Correlations between response time and brain activations suggested a significant involvement of the arithmetic mechanisms in the evaluation of food healthiness.

Modulation of the inter-hemispheric processing of semantic information during normal aging. A divided visual field experiment.

We evaluated the effect of normal aging on the inter-hemispheric processing of semantic information by using the divided visual field (DVF) method, with words and pictures. Two main theoretical models have been considered, (a) the HAROLD model which posits that aging is associated with supplementary recruitment of the right hemisphere (RH) and decreased hemispheric specialization, and (b) the RH decline theory, which assumes that the RH becomes less efficient with aging, associated with increased LH specialization. Two groups of subjects were examined, a Young Group (YG) and an Old Group (OG), while participants performed a semantic categorization task (living vs. non-living) in words and pictures. The DVF was realized in two steps: (a) unilateral DVF presentation with stimuli presented separately in each visual field, left or right, allowing for their initial processing by only one hemisphere, right or left, respectively; (b) bilateral DVF presentation (BVF) with stimuli presented simultaneously in both visual fields, followed by their processing by both hemispheres. These two types of presentation permitted the evaluation of two main characteristics of the inter-hemispheric processing of information, the hemispheric specialization (HS) and the inter-hemispheric cooperation (IHC). Moreover, the BVF allowed determining the driver-hemisphere for processing information presented in BVF. Results obtained in OG indicated that: (a) semantic categorization was performed as accurately as YG, even if more slowly, (b) a non-semantic RH decline was observed, and (c) the LH controls the semantic processing during the BVF, suggesting an increased role of the LH in aging. However, despite the stronger involvement of the LH in OG, the RH is not completely devoid of semantic abilities. As discussed in the paper, neither the HAROLD nor the RH decline does fully explain this pattern of results. We rather suggest that the effect of aging on the hemispheric specialization and inter-hemispheric cooperation during semantic processing is explained not by only one model, but by an interaction between several complementary mechanisms and models.

Functional MRI evidence for the decline of word retrieval and generation during normal aging.

This fMRI study aimed to explore the effect of normal aging on word retrieval and generation. The question addressed is whether lexical production decline is determined by a direct mechanism, which concerns the language operations or is rather indirectly induced by a decline of executive functions. Indeed, the main hypothesis was that normal aging does not induce loss of lexical knowledge, but there is only a general slowdown in retrieval mechanisms involved in lexical processing, due to possible decline of the executive functions. We used three tasks (verbal fluency, object naming, and semantic categorization). Two groups of participants were tested (Young, Y and Aged, A), without cognitive and psychiatric impairment and showing similar levels of vocabulary. Neuropsychological testing revealed that older participants had lower executive function scores, longer processing speeds, and tended to have lower verbal fluency scores. Additionally, older participants showed higher scores for verbal automatisms and overlearned information. In terms of behavioral data, older participants performed as accurate as younger adults, but they were significantly slower for the semantic categorization and were less fluent for verbal fluency task. Functional MRI analyses suggested that older adults did not simply activate fewer brain regions involved in word production, but they actually showed an atypical pattern of activation. Significant correlations between the BOLD (Blood Oxygen Level Dependent) signal of aging-related (A > Y) regions and cognitive scores suggested that this atypical pattern of the activation may reveal several compensatory mechanisms (a) to overcome the slowdown in retrieval, due to the decline of executive functions and processing speed and (b) to inhibit verbal automatic processes. The BOLD signal measured in some other aging-dependent regions did not correlate with the behavioral and neuropsychological scores, and the overactivation of these uncorrelated regions would simply reveal dedifferentiation that occurs with aging. Altogether, our results suggest that normal aging is associated with a more difficult access to lexico-semantic operations and representations by a slowdown in executive functions, without any conceptual loss.

Treatment options for patients with mobile left ventricular thrombus and ventricular dysfunction: a case series.

INTRODUCTION: Little is known about the optimal management of large, mobile, pedunculated left ventricular clots. The management is particularly challenging in patients with advanced heart failure considered for left ventricular assist device implantation, because the clot may cause pump thrombosis. METHODS: We retrospectively reviewed the records of patients with left ventricular thrombi identified by echocardiography, and found three cases with large protruding mobile clots. RESULTS: In this paper, we are presenting three challenging cases where the clots were successfully treated surgically. In two cases, the removal of clot was performed simultaneously with the implantation of ventricular assist devices. In the third case, the patient underwent only thrombectomy. Overall, the early outcomes were good in all three patients, but one subsequently died from unrelated causes. CONCLUSIONS: These clinical cases give evidence for surgical treatment of large mobile clots without systemic embolism, even if ventricular assist device is implanted during the same operation.

An fMRI study of the social competition in healthy subjects.

Social interaction requires the ability to infer another person's mental state (Theory of Mind, ToM) and also executive functions. This fMRI study aimed to identify the cerebral correlates activated by ToM during a specific social interaction, the human-human competition. In this framework, we tested a conflict resolution task (Stroop) adapted to a virtual situation of competition. The participants were instructed to play in order to win either against a human-like competitor (human-human competition) or against a non-human competitor (human-machine competition). Only the human-human competition requires ToM as this type of competition is performed under social interaction. We identified first the classical network of executive regions activated by Stroop. Secondly, we identified the social (human-human) competition regions, represented by the bilateral superior and inferior frontal gyri, the anterior cingulate, the insula, the superior and anterior temporal, the hippocampus, the fusiform gyrus, the cuneus and the precuneus. Finally, we identified the executive regions that were modulated by the human-human competition, i.e., the executive control regions additionally activated when mentalizing in the context of social competition. They constituted a network predominant to the right and composed of the superior and middle frontal, anterior cingulate, insula and fusiform gyrus. We suggest that our experimental paradigm may be useful in exploration of the cerebral correlates of social adjustments in several situations such as psychiatric disorders presenting executive and social dysfunctions.

Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the Ludwigshafen Risk and Cardiovascular Health Study.

Two strongly correlated polymorphisms located within the gene of the glucokinase regulator protein (GKRP), rs780094 and rs1260326, are associated with increased plasma triglyceride levels and provide a genetic model for the long-term activation of hepatic glucokinase. Because pharmacological glucokinase activators are evaluated for the treatment of diabetes, the aim of the study was to assess if these polymorphisms could provide evidence for an increased cardiovascular risk of long-term glucokinase activation. Therefore, these polymorphisms were tested in 3 500 patients of the Ludwigshafen Risk and Cardiovascular Health study, which was designed to assess cardiovascular risk factors. The two variants were associated with a significant increase of both plasma triglycerides (p<0.0001) and VLDL triglyceride levels (p<0.0001). Plasma free fatty acid concentrations were also significantly elevated (p<0.0078). LDL and HDL cholesterol levels were unchanged. No association was found with respect to coronary stenosis, myocardial infarction, left ventricular wall hypertrophy, and hypertension. In conclusion, long-term genetic glucokinase activation by the GKRP polymorphisms was not associated with an increased cardiovascular risk in the study population.

Variations in the APP gene promoter region and risk of Alzheimer disease.

We genotyped five polymorphisms, including two polymorphisms with known effects on transcriptional activity, in a large cohort of 427 Alzheimer disease (AD) cases and 472 control subjects. An association between rs463946 (-3102 G/C) and AD was found and was confirmed in a replication sample of a similar size. By contrast, analysis of three recently described rare mutations influencing APP transcription did not confirm their association with AD risk.

Association studies in candidate genes: strategies to select SNPs to be tested.

OBJECTIVE: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. METHOD: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. RESULTS: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.

Expression and characterization of recombinant porcine plasminogen activator inhibitor-1.

Porcine models are, among other animal models, very suitable for in vivo investigations in the vascular field especially with respect to the possible relationship between atherosclerosis and thrombosis. In order to use this model to define the in vivo role of PAI-1, the characterization of porcine PAI-1 and its availability for the generation of immunological tools are a prerequisite. Porcine plasminogen activator inhibitor-1 (poPAI-1) cDNA was isolated from a cDNA library prepared from cultured porcine aortic cells and characterized in comparison with PAI-1 cDNA's from other species including human, bovine, rabbit, rat and murine. Subsequently the DNA sequence coding the mature protein was cloned into an appropriate vector for expression in Escherichia coli and recombinant porcine PAI-1 was purified and characterized. On SDS-PAGE the apparent molecular weight was estimated to be 45 kDa, identical to the molecular weight of human PAI-1. The purified recombinant porcine PAI-1 (rpoPAI-1) had a specific activity of 508,800 +/- 800 U/mg (mean +/- SD, n = 3) towards human tissue-type plasminogen activator (ht-PA) and a functional half-life in vitro of 2.1 +/- 0.8 h (n = 3). Incubation with a two fold molar excess of ht-PA (n = 3) or human urokinase-type plasminogen activator (hu-PA, n = 2) followed by analysis by SDS-PAGE revealed reaction products corresponding to active (71 +/- 7% resp. 96 +/- 3.6%), latent (12 +/- 0.4% resp. 2.6 +/- 2.4%) and substrate (16.6 +/- 6.8% resp. 1.5 +/- 1.3) forms. Inactivated samples of porcine PAI-1 could be reactivated with guanidinium chloride up to 52% of its original specific activity towards t-PA and u-PA. The second order rate constant of inhibition of ht-PA was 1.64 +/- 0.37 10(7)M-1 s-1 (n = 9). In gel filtration rpoPAI-1 in buffer eluted at a volume corresponding to 24 kDa, whereas in the presence of porcine plasma, the molecular form containing PAI-1 activity eluted at a volume corresponding to 330 kDa, presumably as a consequence of binding of active PAI-1 to vitronectin. Taken together, these data demonstrate that no obvious functional differences exist between human and porcine PAI-1.

Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries.

High plasma levels of plasminogen activator inhibitor type-1 (PAI-1), the principal inhibitor of the fibrinolytic system, have been associated with thrombotic and arterial disease. To study PAI-1 expression in healthy and atherosclerotic human arteries, a detailed analysis was made by light and electron microscopy immunocytochemistry and by in situ hybridization. In healthy arteries PAI-1 was found both at the level of endothelial cells and of smooth muscle cells (SMCs) of the arterial media. In early atherosclerotic lesions PAI-1 was also detected in intimal SMCs and in extracellular areas in association with vitronectin. Immunogold analysis by electron microscopy revealed PAI-1 in vesicular structures in endothelial cells and in SMCs with normal or foam cell characteristics. In advanced atheromatous plaques, PAI-1 mRNA expression in SMCs within the fibrous cap was increased compared with SMCs located in the adjacent media or in normal arterial tissue. PAI-1 mRNA was also detected in macrophages located at the periphery of the necrotic core. The increased synthesis of PAI-1 by cellular components of the atherosclerotic plaque and the extracellular accumulation of PAI-1 may contribute to the thrombotic complications associated with plaque rupture and possibly play a role in the accumulation of extracellular matrix deposits.

Regulatory elements involved in constitutive and phorbol ester-inducible expression of the plasminogen activator inhibitor type 2 gene promoter.

Gene transcription rates and mRNA levels of plasminogen activator inhibitor type 2 (PAI-2) are markedly induced by the tumor promoting agent phorbol 12-myristate 13-acetate (PMA) in human HT1080 fibrosarcoma cells. To identify promoter elements required for basal-, and phorbol ester-inducible expression, deletion mutants of the PAI-1 promoter fused to the chloramphenicol acetyl transferase (CAT) reporter gene, were transiently expressed in HT1080 cells. Constitutive CAT activity was expressed from constructs containing more than 215 bp of promoter sequence, whereas deletion to position -91 bp abolished CAT gene expression. Treatment of transfected cells with PMA resulted in a three- to ten-fold increase in CAT expression from all constructs except from the construct shortened to position -91. DNAse1 protection analysis of the promoter region between -215 and the transcription initiation site revealed numerous protected regions, including two AP1-like binding sites (AP1a and AP1b) and one CRE-like element. Site-directed mutagenesis of the AP1a site or of the CRE-like site resulted in the loss of basal CAT activity and abolished the PMA effect, whereas mutagenesis of AP1b only partially inhibited basal and PMA-mediated expression. Our results suggest that the PAI-2 promoter contains at least two elements required for basal gene transcription and PMA-mediated induction.

Plasminogen activator inhibitor 2. Isolation and characterization of the promoter region of the gene.

We have isolated the promoter region and part of the coding region of the human plasminogen activator inhibitor 2 gene. The first two exons (65 and 177 base pairs, respectively) are separated by a 3.6 kilo base pair intron. More than 2 kilo base pair of the promoter region was sequenced and analyzed. The promoter region is characterized by: a) a TATAAA box located 31 base pairs upstream of the transcription initiation site; b) a 123 base pair stretch (-598 to -720) that is homologous (greater than 90% identity) to the inverted sequence of -1268 to -1380; c) a 24 base pair inverted repeat at -276 to -299 and three direct repeats; and d) several sequences that are homologous (up to 1 mismatch) to the cAMP responsive element or to binding sites for the transcription factors AP1 and AP2.