Unclear outcomes of heart rate variability following a concussion: a systematic review.

PURPOSE: : To systematically regroup articles that were published since the latest systematic search, but with specific inclusion criteria to help comparison that will offer a focused presentation of methods and results. This will offer a full overview of HRV's behavior at rest and during exercise in adults post-concussion. METHODS: : The systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method. A computer-based systematic search was conducted in December 2019 through the Pubmed, Scopus and SPORTDiscus databases. A manual search was performed through the reference list of all articles retained. The reliability of the systematic search was assured by having the article selection process entirely repeated by a second author. RESULTS: : The systematic search yielded a total of 15 articles to be further analyzed. Results show impairment of HRV during exercise for individuals with concussion, heterogenous studies with lack of control over confounding factors and only less than half of the results showing a significant difference between individuals with concussion and controls. CONCLUSION: : Further research should try standardizing HRV measurement protocols that control confounding factors to allow easier comparison between studies and allows the possibility for an eventual meta-analysis.

[Home blood transfusion in France: Benefits and development terms]. / Transfusion à domicile : intérêt et conditions de développement dans le contexte français.

OBJECTIVES: Patients with cancers or malignant homeopathies can suffer from chronic anemia and be regularly transfused in hospitals. Most of the time, their performance status is low. Few local structures currently provide blood transfusion services and patients have to go under difficult and costing transportation to the hospital. The objective of this work is to evaluate benefits and development terms of home blood transfusion for patients with chronic anemia and having to get transfused regularly. METHODS: A field investigation-mixing observations and interviews and a literature review were conducted. RESULTS: Home blood transfusion represented a little part of home health care activity. When it was practiced, its organization was heterogeneous: it was sometimes performed by a doctor, sometimes by a nurse. Home blood transfusion was benefic for patients: it was more comfortable and it allowed them to avoid harmful transportation to the hospital. Few adverse events occurred during various experiments, all were mild. Before its revaluation in March 2018, home blood transfusion was not enough funded by National health insurance. Home blood transfusion also suffered from a lack of framework until the publication of recommendations in April 2018. CONCLUSIONS: Lack of a framework and sufficient funding prevented home blood transfusion development until changes that occurred in 2018. Therefore, this activity should develop in years to come. Allowing reducing unnecessary hospitalizations, home blood transfusion fit into French health national strategy.

[Detection of Staphylococcus aureus resistant to methicillin (MRSA) by molecular biology (Cepheid GeneXpert IL, GeneOhm BD, Roche LightCycler, Hyplex Evigene I2A) versus screening by culture: Economic and practical strategy for the laboratory]. / Dépistage de Staphylococcus aureus résistant à la méthicilline (SARM) par biologie moléculaire (Cepheid GeneXpert IL, GeneOhm BD, LightCycler Roche, Hyplex Evigene I2A) versus dépistage par culture : stratégie économico-pratique pour le laboratoire.

OBJECTIVES: Patients admitted in cardiac surgery and cardiac ICU at the Clinic Saint-Gatien (Tours) are screened for MRSA at the entrance by nasal swab and culture on blood agar and selective chromogenic medium made by addition of cefoxitin: BBL CHROMagar MRSA-II BD (result obtained at Day +1). We wanted to assess the molecular biology techniques available to obtain a result at day 0 for the majority of patients and to define an economic and practical strategy for the laboratory. TECHNIQUES: We studied four molecular biology techniques: Cepheid GeneXpert (Cepheid) GeneOhm (BD), LightCycler (Roche) and Hyplex (I2A). Upon reception, nasal swabs were treated by culture, considered as reference, and one of the techniques of molecular biology, according to the manufacturer's notice. We conducted four studies between April 2008 and February 2009 to obtain a significant sample for each of them. METHODS: By screening we mean a method that allows us to exclude MRSA carriage for patients waiting for surgery, and not to change patient management: for example, lack of isolation measures specific to entrance, no modification of antibiotic prophylaxis during surgery and no isolation measures in the immediate postoperative period. RESULTS: The criteria we considered for this evaluation were: (1) technician time: time to perform one or a series of sample(s) n=10 or more (about 2h for all techniques except GeneXpert 75min), level of skilled competences (no specific training for GeneXpert); (2) results: turnaround time (all molecular biology techniques), ease of reading and results interpretations (no specialized training required for GeneXpert), failure or not (12% of failure of internal controls for GeneOhm); (3) economic: cost for one or a series of sample(s) (n=10 or more), if we considered X as the reference culture cost (10 X Hyplex and LightCycler, 20 X and 40 X for GeneXpert GeneOhm); (4) NPV: 100% for GeneXpert and LightCycler. CONCLUSION: At same sensitivity, no technique, including culture, can solve alone our problem, which is: (1) get results at day 0 for batch of samples (n<10): all molecular biology techniques; (2) beyond 10 samples: LightCycler (Roche) automated or Hyplex (I2A) manual; (3) when the result at day 1 is sufficient, the use of chromogenic agar with a reading of less than 18h as BBL CHROMagar MRSA II (BD) remains the most economical; (4) to be sure that a patient admitted at Day 0, even at night's emergency, is not carrier of MRSA: only Cepheid GeneXpert technology (IL). Furthermore, Cepheid GeneXpert (IL) allows performing several tests in parallel. The rapidity of this system can help control the transmission and make better use of antibiotics.

Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin.

Ras genes are commonly mutated in human cancers of the skin and other tissues. Oncogenic Ras signals through multiple effector pathways, including the Erk1/2 mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K) and the Ral guanine nucleotide exchange factor (RalGEF) cascades. In epidermis, the activation of oncogenic Ras induces hyperplasia and inhibits differentiation, features characteristic of squamous cell carcinoma. The downstream effector pathways required for oncogenic Ras effects in epidermis, however, are undefined. In this study, we investigated the direct contribution of Mek1 and Mek2 MAPKKs to oncogenic Ras signaling. The response of murine epidermis to conditionally active oncogenic Ras was unimpaired by deletion of either Mek1 or Mek2 MAPKKs individually. In contrast, Ras effects were entirely abolished by combined deletion of all Mek1/2 alleles, whereas epidermis retaining only one allele of either Mek1 or Mek2 showed intermediate responsiveness. Thus, the effects of oncogenic Ras on proliferation and differentiation in skin show a gene dosage-dependent requirement for the Erk1/2 MAPK cascade at the level of Mek1/2 MAPKKs.

Feelings of warmth correlate with neural activity in right anterior insular cortex.

The neural coding of perception can differ from that for the physical attributes of a stimulus. Recent studies suggest that activity in right anterior insular cortex may underlie thermal perception, particularly that of cold. We now examine whether this region is also important for the perception of warmth. We applied cutaneous warm stimuli on the left leg (warmth) in normal subjects (n = 7) during functional magnetic resonance imaging (fMRI). After each stimulus, subjects rated their subjective intensity of the stimulus using a visual analogue scale (VAS), and correlations were determined between the fMRI signal and the VAS ratings. We found that intensity ratings of warmth correlated with the fMRI signal in the right (contralateral to stimulation) anterior insular cortex. These results, in conjunction with previous reports, suggest that the right anterior insular cortex is important for different types of thermal perception.

Phosphorylation is involved in the activation of metal-regulatory transcription factor 1 in response to metal ions.

We have studied the role of phosphorylation in the activation of metal-regulatory transcription factor-1 (MTF-1) and metallothionein (MT) gene expression. We showed that MTF-1 is phosphorylated in vivo and that zinc stimulates MTF-1 phosphorylation 2-4-fold. Several kinase inhibitors were used to examine the possible involvement of kinase cascades in the activation of MTF-1. Metal-induced MT gene expression was abrogated by protein kinase C (PKC), c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase, and tyrosine-specific protein kinases inhibitors, as assayed by Northern analysis and by cotransfection experiments using a metal regulatory element-luciferase reporter plasmid. The extracellular signal-activated protein kinase and the p38 kinase cascades did not appear to be essential for the activation of MT gene transcription by metals. By using dominant-negative mutants of PKC, JNK, mitogen-activated kinase kinase 4 (MKK4), and MKK7, we provide further evidence supporting a role for PKC and JNK in the activation of MTF-1 in response to metals. Notably, increased MTF-1 DNA binding in response to zinc and MTF-1 nuclear localization was not inhibited in cells preincubated with the different kinase inhibitors despite strong inhibition of MTF-1-mediated gene expression. This suggests that phosphorylation is essential for MTF-1 transactivation function. We hypothesize that metal-induced phosphorylation of MTF-1 is one of the primary events leading to increased MTF-1 activity. Thus, metal ions such as cadmium could activate MTF-1 and induce MT gene expression by stimulating one or several kinases in the MTF-1 signal transduction pathway.

Inhibitory effects of T-cell stimulation and co-stimulation observed at high concentrations of plate-bound antibodies.

Plate-bound monoclonal antibodies (mAb) are often used as a way of stimulating lymphocytes in vitro. Our observations show that the concentrations of mAb used in functional assays in vitro must be carefully assessed before conclusions are drawn about lymphocyte activation or co-activation.

Different host-cell shutoff strategies related to the matrix protein lead to persistence of vesicular stomatitis virus mutants on fibroblast cells.

Acute infection of fibroblastic cell lines by the Indiana strain of vesicular stomatitis virus (VSV) usually induces dramatic cytopathic effects and shutoff of cellular gene expression. We have compared a series of independent mutants with differences in shutoff induction and found that M was mutated either in the N-terminus (M(51)R) or C-terminus (V(221)F and S(226)R). Furthermore, only double mutants (M mutation and a ts mutation related or not to M) were able to persist on fibroblast cell lines at 39 degrees C. A more detailed investigation of the infection was performed for the mutants T1026, TP3 and G31, differing in their host shutoff effects related to M protein. Viral activity in persistently infected mouse L-929 and monkey Vero cell lines was followed by viral proteins detection, RNA synthesis throughout infection and finally detection of infectious particles. All three mutants cause extensive CPE followed by emergence of persistently infected cells on Vero cells. The same thing is seen on L-929 cells except for T1026 which causes little CPE. Taken together, the results form a basis of further studies to clarify how various viral and cellular factors interact in the establishment of a persistent infection by VSV mutants.

Thymic selection generates T cells expressing self-reactive TCRs in the absence of CD45.

The CD45 protein tyrosine phosphatase regulates Ag receptor signaling in T and B cells. In the absence of CD45, TCR coupling to downstream signaling cascades is profoundly reduced. Moreover, in CD45-null mice, the maturation of CD4+CD8+ thymocytes into CD4+CD8- or CD4-CD8+ thymocytes is severely impaired. These findings suggest that thymic selection may not proceed normally in CD45-null mice, and may be biased in favor of thymocytes expressing TCRs with strong reactivity toward self-MHC-peptide ligands to compensate for debilitated TCR signaling. To test this possibility, we purified peripheral T cells from CD45-null mice and fused them with the BWalpha-beta- thymoma to generate hybridomas expressing normal levels of TCR and CD45. The reactivity of these hybridomas to self or foreign MHC-peptide complexes was assessed by measuring the amount of IL-2 secreted upon stimulation with syngeneic or allogeneic splenocytes. A very high proportion (55%) of the hybridomas tested reacted against syngeneic APCs, indicating that the majority of T cells in CD45-null mice express TCRs with high avidity for self-MHC-peptide ligands, and are thus potentially autoreactive. Furthermore, a large proportion of TCRs selected in CD45-null mice (H-2b) were also shown to display reactivity toward closely related MHC-peptide complexes, such as H-2bm12. These results support the notion that modulating the strength of TCR-mediated signals can alter the outcome of thymic selection, and demonstrate that CD45, by molding the window of affinity/avidity for positive and negative selection, directly participates in the shaping of the T cell repertoire.

N-Myc shares cellular functions wiht c-Myc.

N-Myc is a member of the myc family of proto-oncogenes involved in initiation and progression of tumors. While c-MYC, the most characterized member of the family, is well known for its role in cellular proliferation and apoptosis, the function of N-MYC in differentiation and proliferation remains unclear. N-Myc mutant mice present a phenotype more consistent with a role of N-MYC protein in proliferation of precursor populations than in differentiation per se. Recent studies have also shown that N-MYC can enhance apoptosis and shorten the G1 phase of the cell cycle. However, the role of N-MYC in instigating cell-cycle progression has not been clearly demonstrated. Here, we demonstrate that overexpression of N-myc or activation of inducible N-MYC proteins is sufficient to induce apoptosis in serum-starved fibroblast cells, an effect that can be counteracted by overexpression of Bcl-2. Moreover, N-MYC can induce the reentry of quiescent cells into the cell cycle even in the absence of external stimuli. These results indicate that N-MYC and c-MYC share many properties, supporting the model that MYC-specific roles during embryonic development are mediated, at least in part, via their specific profile of expression rather than by their different protein functions.

Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta.

Mek is a dual-specificity kinase that activates the extracellular-signal-regulated (Erk) mitogen-activated protein (MAP) kinases upon agonist binding to receptors. The Erk MAP kinase cascade is involved in cell-fate determination in many organisms. In mammals, this pathway is proposed to regulate cell growth and differentiation. Genetic studies have shown that although a single mek gene is present in Caenorhabditis elegans, Drosophila and Xenopus, two mek homologs, Mek1 and Mek2, are present in the mammalian cascade. In the present study, we describe a mutant mouse line in which the mek1 gene has been disrupted by insertional mutagenesis. The null mutation was recessive lethal, as the homozygous mutant embryos died at 10.5 days of gestation. Histopathological analyses revealed a reduction in vascularization of the placenta that was due to a marked decrease of vascular endothelial cells in the labyrinthine region. The failure to establish a functional placenta probably explains the death of the mek1-/- embryos. Cell-migration assays indicated that mek1-/- fibroblasts could not be induced to migrate by fibronectin, although the levels of Mek2 protein and Erk activation were normal. Re-expression of Mek1 in the mutant mouse embryonic fibroblasts (MEFs) restored their ability to migrate. Our findings provide genetic evidence that establishes the unique role played by Mek1 in signal transduction. They also suggest that mek1 function is required for normal response to angiogenic signals that might promote vascularization of the labyrinthine region of the placenta.

Dissociation of hemispheric exploitation of rods and cones for simple detection.

Sergent (1982a, 1982b, 1982c) proposed that stimuli carrying high luminous energy will be better detected in the right field (left hemisphere) and stimuli carrying low energy in the left visual field (right hemisphere). A photoreceptor-based model could explain the same effects as well as several others (eccentricity effects, retinal adaptation effects). Braun, Mailloux, and Dufresne (1995) suggested that cones might favor right field stimuli and rods might favor left field stimuli. We implemented a series of near-threshold simple detection experiments comprising stimuli varying along four dimensions (color, eccentricity, duration, and size) in dark-adapted subjects. Consistent and significant right field advantages accrued for near-meridianal foveal red stimuli, but there were no field effects for eccentric blue stimuli. An alternative to Sergent's stimulus energy model and the photoreceptor-based model, namely a parvocellular-magnocellular model, is proposed.

Defective development of the embryonic liver in N-myc-deficient mice.

The mechanisms involved in the formation and the differentiation of the liver remain unclear despite extensive studies. To investigate these events in mouse hepatic development, we have taken advantage of the N-myc mutant mouse line which exhibits abnormal liver development. N-myc mutant embryos die between 11.5 and 12.5 days postcoitum most probably from heart failure. In the present study, we report that at 11.5 days of gestation, extensive apoptosis restricted to the hepatocytes occurred in N-myc mutant liver when compared to wild-type samples. Moreover, the number of hematopoietic cells is reduced in the mutant liver. During early liver organogenesis, the N-myc gene is expressed in tissues involved in the induction and the differentiation of the hepatocytes. At 11.5 days postcoitum, both c-myc and N-myc genes are expressed in the liver. While c-myc is expressed at a high level in the organ per se, N-myc expression is mostly confined to the peripheral layer of the liver which will generate the Glisson's capsule. Taken together, the expression pattern of N-myc in the liver and the specific apoptosis of hepatocytes observed in N-myc mutants indicate that N-myc is required for hepatocyte survival and suggest that it is involved in the genetic cascade leading to normal liver development.

Induction of thymocyte deletion by purified single peptide/major histocompatibility complex ligands.

We report a novel in vitro approach that allows study of the consequences of TCR ligation on thymocytes in the absence of thymic stromal cells. Hence, thymocytes were incubated either in the presence of recombinant antigenic peptide/MHC complexes, which represent ligands of physiologic affinities, or with anti-TCR mAb, a ligand of supraphysiologic affinity. Whereas TCR cross-linking with mAb led to thymocyte deletion, incubation with peptide/MHC ligands did not trigger cellular apoptosis. However, the addition of a costimulatory signal (provided by anti-CD28 mAb) allowed the induction of apoptosis following TCR binding to peptide/MHC ligands, and it increased the levels of cell death obtained through mAb-mediated TCR cross-linking. Requirement for accessory signals seen with TCR stimulation by peptide/MHC complexes argues in favor of qualitative differences between TCR engagement by ligands of either physiologic or supraphysiologic affinity.

Intermanual transfer of somaesthetic information: a two-point discrimination experiment.

Twenty-four men and 24 women, all university students, judged whether two-point aesthesiometric applications, either both to the same palm (intramanual condition) or one to each palm (intermanual condition) were of the "same" or "different" spans. The main question was to determine the extent to which there is a loss of accuracy during intermanual comparisons, and by inference, interhemispheric relay. A second question, the extent to which this loss is a function of the difficulty of the task, was to be answered by the inclusion of span-differences above, at, and below threshold. Difficult trials were associated with a highly significant intramanual advantage of 4.74%, and easy trials with a non-significant intramanual advantage of 1.16%. For both intra- and intermanual conditions, subjects made more errors as a function of decreasing "span-difference". The two hands performed equally well, and the order of stimulation between the two hands made no difference in the results. The intramanual advantage could not be construed as an effect of response set (i.e., an artefact of subject's inherent bias for "same" or "different" judgements), nor as a scaling effect (e.g., of span scales relating to receptive field properties, relating in turn to interhemispheric relay). There was no evidence of a sex difference in basic ability, nor in the cost of hemispheric relay. It was concluded that there is a loss of precision in interhemispheric relay of somaesthetic discrimination, but this can only be detected close to threshold.

Generation of normal lymphocytes derived from N-myc-deficient embryonic stem cells.

Myc family proteins are thought to be transcription factors involved in regulation of cell growth and differentiation. N-myc is expressed at the pre-B cell stage of B cell differentiation and is dramatically induced by the pre-B cell growth factor, IL-7. To test the idea that N-myc plays an important role in lymphocyte development, we assayed the effect of a null N-myc mutation on the differentiation of B and T lineage cells. Homozygous, mutant embryonic stem (ES) cells were injected into blastocysts derived from recombination activating gene (RAG-2)-deficient mice. Since RAG-2 mutant mice fail to develop mature lymphocytes, later-stage lymphocytes that are present in chimeric mice are ES cell derived. Surprisingly, nearly normal numbers of mature T and B cells derived from N-myc-deficient ES cells were found in peripheral lymphoid organs of chimeric mice. Lymphocytes were judged to be functional based on responses to mitogens and production of serum IgM and multiple IgG isotypes in chimeric animals. We discuss these findings in relation to N-myc function in lymphocyte development and possible redundancy with other myc genes.

Specification of axial identity in the mouse: role of the Hoxa-5 (Hox1.3) gene.

Numerous lines of study have suggested that the Hox genes, encoding putative transcription factors, are key genes in the establishment of the body plan of the mammalian embryo. To examine the role of Hoxa-5 (Hox1.3) gene during development, we have used targeted mutagenesis in embryonic stem cells to produce a strain of mice carrying a disrupted Hoxa-5 allele. The viability of homozygous mutant mice is markedly reduced, with 50% of the mutant animals dying at birth or shortly thereafter. Analysis of the skeleton of Hoxa-5 mutants reveals a number of homeotic transformations restricted to the cervical and thoracic regions. Of these, one of the most frequent morphological abnormalities is the posterior transformation of the seventh cervical vertebra into the likeness of a thoracic vertebra complete with a pair of ribs. These results demonstrate that the Hoxa-5 gene has an important role in the establishment of the skeleton during development and contributes to the process whereby the axial structures are determined.

Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene.

The N-myc gene encodes a putative transcription factor that is thought to function in the regulation of gene expression during cell differentiation and/or growth. To examine the role of N-myc during development, we have used targeted mutagenesis in embryonic stem cells to produce a mouse line that carries an N-myc null allele. Mice homozygous for the mutation died between 10.5 and 12.5 days of gestation. Histological analysis of mutant embryos revealed that organs and tissues expected at these stages of development were present. However, multiple defects were observed, primarily in tissues and organs that normally express N-myc. In particular, mutant hearts were underdeveloped, often retaining the S-shape more typical of 9-day-old embryos. In addition, cranial and spinal ganglia were reduced in size and/or cellularity. Most of the noted defects were more consistent with a role of N-myc in proliferation of precursor populations than with a block in differentiation per se, at least at these early stages. These results demonstrate that N-myc plays an essential role during development and clearly confirm that N-myc has a physiological function that is distinct from that of the other myc-family genes.

RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.

We have generated mice that carry a germline mutation in which a large portion of the RAG-2 coding region is deleted. Homozygous mutants are viable but fail to produce mature B or T lymphocytes. Very immature lymphoid cells were present in primary lymphoid organs of mutant animals as defined by surface marker analyses and Abelson murine leukemia virus (A-MuLV) transformation assays. However, these cells did not rearrange their immunoglobulin or T cell receptor loci. Lack of V(D)J recombination activity in mutant pre-B cell lines could be restored by introduction of a functional RAG-2 expression vector. Therefore, loss of RAG-2 function in vivo results in total inability to initiate V(D)J rearrangement, leading to a novel severe combined immune deficient (SCID) phenotype. Because the SCID phenotype was the only obvious abnormality detected in RAG-2 mutant mice, RAG-2 function and V(D)J recombinase activity, per se, are not required for development of cells other than lymphocytes.