Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility.
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Atorvastatin↗
Biomedical subjects
V Bernard
Publications and source records attributed to V Bernard.
The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons.
Before their exocytotic release during stimulation of nerve terminals, nonpeptide neurotransmitters are loaded into synaptic vesicles by specific transporters. Recently, a protein initially identified as brain-specific Na(+)-dependent inorganic phosphate transporter I (BNPI) has been shown to represent a vesicular glutamate transporter (VGLUT1). In this study, we investigated whether a highly homologous "differentiation-associated Na(+)-dependent inorganic phosphate transporter" (DNPI) is involved in glutamatergic transmission. Vesicles isolated from BON cells expressing recombinant DNPI accumulated l-glutamate with bioenergetical and pharmacological characteristics identical to those displayed by VGLUT1 and by brain synaptic vesicles. Moreover, DNPI localized to synaptic vesicles, at synapses exhibiting classical excitatory features. DNPI thus represents a novel vesicular glutamate transporter (VGLUT2). The distributions of each VGLUT transcript in brain were highly complementary, with only a partial regional and cellular overlap. At the protein level, we could only detect either VGLUT1- or VGLUT2-expressing presynaptic boutons. The existence of two VGLUTs thus defines distinct subsets of glutamatergic neurons.
Amino Acid Transport Systems↗
Symbiotic performance of herbaceous legumes in tropical cover cropping systems.
Increasing use of herbaceous legumes such as mucuna ( Mucuna pruriens var. utilis [Wright] Bruck) and lablab ( Lablab purpureus [L.] Sweet) in the derived savannas of West Africa can be attributed to their potential to fix atmospheric nitrogen (N2). The effects of management practices on N2 fixation in mucuna and lablab were examined using 15N isotope dilution technique. Dry matter yield of both legumes at 12 weeks was two to five times more in in situ mulch (IM) than live mulch (LM) systems. Land Equivalent Ratios, however, showed 8 to 30% more efficient utilization of resources required for biomass production under LM than IM systems. Live mulching reduced nodule numbers in the legumes by one third compared to values in the IM systems. Similarly, nodule mass was reduced by 34 to 58% under LM compared to the IM systems. The proportion of fixed N2 in the legumes was 18% higher in LM than IM systems. Except for inoculated mucuna, the amounts of N fixed by both legumes were greater in IM than LM systems. Rhizobia inoculation of the legumes did not significantly increase N2 fixation compared to uninoculated plots. Application of N fertilizer reduced N2 fixed in the legumes by 36 to 51% compared to inoculated or uninoculated systems. The implications of cover cropping, N fertilization, and rhizobia inoculation on N contributions of legumes into tropical low-input systems were discussed.
Crops, Agricultural↗
In vivo internalization of the somatostatin sst2A receptor in rat brain: evidence for translocation of cell-surface receptors into the endosomal recycling pathway.
To determine whether cellular compartmentalization of somatostatin receptors can be regulated in vivo, we examined the immunocytochemical distribution of the sst2A receptor (sst2AR) after stereotaxical injections of somatostatin analogs into the rat parietal cortex. Whereas CH-275, a sst1R agonist, failed to induce changes in the diffuse sst2AR immunostaining pattern characteristic of control animals, somatodendritic profiles displaying intracytoplasmic immunoreactive granules became apparent short-term after injection of either somatostatin or the sst2R agonist octreotide. Confocal microscopy revealed that 90% of sst2AR-immunoreactive endosome-like organelles displayed transferrin receptor immunoreactivity. At the electron microscopic level, the percentage of sst2AR immunoparticles dramatically decreased at the plasmalemma of perikarya and dendrites after octreotide injection. Conversely, it significantly increased in endosomes-like organelles. These results demonstrate that sst2ARs undergo, in vivo, rapid and massive internalization into the endocytic recycling compartment in response to acute agonist stimulation and provide important clues toward elucidating somatostatin receptor signaling in the mammalian brain.
Animals↗
Tuning of pulmonary arterial circulation evidenced by MR phase mapping in healthy volunteers.
Magnetic resonance (MR) phase mapping was used to noninvasively assess both blood flow and cross-sectional area (CSA) in the main pulmonary artery (MPA) of 12 healthy volunteers. Flow and CSA patterns exhibited two positive peaks: high systolic and small diastolic. This finding can be explained using a simple "distributed" theoretical model that takes into account the role of a reflected pressure wave from pulmonary vascular impedance in generating a diastolic flow. The mean reflection coefficient of pressure wave, MPA input impedance, and pulmonary vascular impedance were assessed. We verified, in this series, that pressure wave velocity appears to be age-dependent. MR phase mapping has been used to observe the tuning (resonance) of the right cardiovascular system at rest under physiological conditions. MR phase mapping could be used to assess pathological modifications of the tuning that occurs in cases of pulmonary arterial hypertension.
Adult↗
Noninvasive assessment of pulmonary arterial hypertension by MR phase-mapping method.
We describe a magnetic resonance (MR) imaging method that emphasizes pressure wave velocity to noninvasively assess pulmonary arterial hypertension. Both the blood flow and the corresponding vessel cross-sectional area (CSA) were measured by MR phase mapping in the main pulmonary artery (MPA) in 15 patients. MPA pressures were also measured, in the same patients, by right-side heart catheterization. Two significant relationships were established: 1) between the pressure wave velocity in the MPA and the mean pressure in the MPA (Ppa) writing pressure wave velocity = 9.25 Ppa - 202.51 (r = 0.82) and 2) between the ratio of pressure wave velocity to the systolic blood velocity peak in the MPA (R) and the mean pressure in the MPA writing R = 0.68 Ppa - 4.33 (r = 0.89). Using these relationships, we estimated two pressure values to frame the actual Ppa value in each patient from the present series with a reasonable reliability percentage (87%).
Adult↗
Transplantation of normal and DMD myoblasts expressing the telomerase gene in SCID mice.
The limited proliferative capacity of dystrophic human myoblasts severely limits their ability to be genetically modified and used for myoblast transplantation. The forced expression of the catalytic subunit of telomerase can prevent telomere erosion and can immortalize different cell types. We thus tested the ability of telomerase to immortalize myoblasts and analyzed the effect of telomerase expression on the success of myoblast transplantation. Telomerase expression did not significantly extend the human myoblast life span. The telomerase expressing myoblasts were nonetheless competent to participate in myofiber formation after infection with the retroviral vector. Although the new fibers obtained are less numerous than after the transplantation of normal myoblasts, these results demonstrate that the forced expression of telomerase does not block the ability of normal or dystrophic myoblasts to differentiate in vivo. It will be now necessary to determine the factors that prevent telomerase from extending the life span of human myoblasts before the potential of this intervention can be fully examined.
Animals↗
Detection of coronary stenoses by stress echocardiography using a previously implanted pacemaker for ventricular pacing: preliminary report of a new method.
BACKGROUND: The number of patients with pacemakers has been increasing and a large number of them will present with chest pain or symptoms suggesting angina pectoris. Myocardial ischemia and presence of coronary artery disease are difficult to detect and assess by noninvasive methods in patients with a pacemaker; the electrocardiogram (ECG) at rest and during exercise is usually very difficult to analyze in terms of ischemia or even presence of an acute myocardial infarction. HYPOTHESIS: To detect significant coronary stenosis in patients with previously implanted pacemakers, we tested a new stress echocardiography method using incremental ventricular pacing by already implanted pacemakers. METHODS: We studied prospectively 25 consecutive patients who underwent stress echocardiography with increasing ventricular pacing up to either 85% of the age-predicted maximal heart rate or chest pain. Positive tests were defined by new hypokinesia or worsening of a preexisting alteration in wall motion in at least two adjacent territories. All patients underwent coronary angiograms to define the presence and severity of coronary stenoses. RESULTS: Among the 25 tests, 11 (44%) were stopped for chest pain. 1 (4%) for moderate discomfort, 1 (4%) for a drop in blood pressure, and the target pacing rate was achieved in the tests of the remaining 12 patients (48%). There were no complications. Thirteen patients had significant stenoses. In 10 cases, stress echocardiography was a true positive test with respect to coronary angiography. There were 11 true negative, 1 false positive, and 3 false negative tests. The sensitivity was 77%, specificity was 90%, the positive predictive value was 91%, and the negative predictive value 79%. The accuracy was 84%. CONCLUSIONS: This new stress echocardiography method appears feasible, easy, safe, and effective for detection of significant coronary stenoses in patients with pacemakers.
Aged↗
Synaptic localization of ionotropic glutamate receptors in the rat substantia nigra.
Glutamatergic neurotransmission in the substantia nigra pars compacta and pars reticulata is mediated through N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxaline propionic acid/kainate (AMPA) type receptors as well as other glutamate receptors and is critical for basal ganglia functioning. A major glutamatergic input to the substantia nigra originates in the subthalamic nucleus, and the long-lasting stimulation of the dopaminergic cells of the substantia nigra pars compacta by the subthalamic neurons has been implicated in the pathophysiology of Parkinson's disease. The objectives of the present study were to determine the subcellular and subsynaptic localization of subunits of the N-methyl-D-aspartate and AMPA receptors in the substantia nigra, and also to determine whether co-localization of N-methyl-D-aspartate and AMPA receptor subunits occur at individual synapses. To achieve this, pre-embedding and post-embedding immunocytochemistry was applied to sections of substantia nigra using antibodies that recognize the NR1 and NR2A/B subunits of the N-methyl-D-aspartate receptor, and GluR2/3 subunits of the AMPA receptor. In both regions of the substantia nigra, immunolabelling for each of the subunits was observed in numerous perikarya and proximal dendrites. At the subcellular level, silver-intensified immunogold particles localizing N-methyl-D-aspartate and AMPA receptor subunits were most commonly present within dendrites where they were associated with a variety of intracellular organelles and with the internal surface of the plasma membrane. Post-embedding immunogold labelling revealed immunoparticles labelling for NR1, NR2A/B and GluR2/3 to be enriched at asymmetric synaptic specializations, although a large proportion of asymmetric synapses were immunonegative. Double immunolabelling revealed, in addition to single-labelled synapses, the co-localization of subunits of the N-methyl-D-aspartate receptor and subunits of the AMPA receptor at individual asymmetric synapses. Similarly, double immunolabelling also revealed the co-localization of the NRl and NR2A/B subunits of the N-methyl-D-aspartate receptor at individual asymmetric synapses. Labelling for NR1 and GluR2/3 was, on average, relatively evenly distributed across the width of the synapse with a gradual reduction towards the periphery when analysed in single sections. In summary, the present results demonstrate that AMPA and N-methyl-D-aspartate receptors are selectively localized at a subpopulation of asymmetric synapses in the substantia nigra pars compacta and reticulata and that the two receptor types, at least partially co-localize at individual synapses. It is concluded that glutamatergic transmission in the substantia nigra pars compacta and pars reticulata occurs primarily at asymmetric synapses and, at least in part, is mediated by both N-methyl-D-aspartate and AMPA receptors.
Animals↗
Telomerase allows the immortalization of T antigen-positive DMD myoblasts: a new source of cells for gene transfer application.
The limited proliferative capacity of DMD myoblasts severely limits their ability to be genetically modified and used for myoblast transplantation. Transformation by SV40 large T antigen (Tag) delays senescence of mouse and human myoblasts but fails to immortalize these cells. The cells ceased to proliferate and entered into crisis. Reconstitution of telomerase activity has been shown sufficient to enable different types of transformed cells to escape crisis. DMD myoblasts, previously transformed by Tag, were therefore infected with a telomerase retrovirus. The expression of telomerase was sufficient to allow DMD-Tag myoblasts to escape crisis. The telomerase-positive transformed myoblasts continued to divide for more than 55 doublings while Tag myoblasts stopped proliferating after 35 doublings. These cells are able to fuse and to differentiate normally. The average telomere length of these telomerase-positive DMD-Tag myoblasts seems to continue to elongate. Thus, transiently genetically modified myoblasts could constitute an important pool of DMD myoblasts for autologous transplantation in DMD patients.
Animals↗
Regulation of the subcellular distribution of m4 muscarinic acetylcholine receptors in striatal neurons in vivo by the cholinergic environment: evidence for regulation of cell surface receptors by endogenous and exogenous stimulation.
Our aim was to determine how the cholinergic environment influences, in vivo, the membrane abundance and the intracellular trafficking of the muscarinic receptor m4 (m4R). Immunohistochemistry at light and electron microscopic level was used to detect the subcellular localization of m4R in several populations of striatal cholinoceptive neurons, including cholinergic neurons and medium spiny neurons. (1) In control rats, in cholinergic neurons, m4R is mostly restricted to intracytoplasmic sites involved in its synthesis, especially endoplasmic reticulum. In contrast, m4R is preferentially located at the plasma membrane in cell bodies and dendritic shafts and spines of medium spiny neurons. The density of m4R was greater at the membrane of perikarya in patches (striatal areas with low acetylcholine activity) than in matrix (striatal areas with high acetylcholine activity). (2) Stimulation of muscarinic receptor with oxotremorine provokes translocation of m4R from the membrane to endosomes in perikarya and dendrites of medium spiny neurons but has no influence on the localization of m4R in the cytoplasm of cholinergic cell bodies. Our results suggest that the intraneuronal trafficking and the abundance of membrane-bound m4R in vivo is under regulation of the cholinergic environment. The m4R subcellular compartmentalization depends on the phenotype of the cholinoceptive neuron and on its neurochemical environment. Such regulation, by modulating availability of receptor for endogenous and exogenous ligands, may play key roles in the response of target neurons.
Acetylcholine↗
Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease.
Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.
Aged↗
In vivo regulation of intraneuronal trafficking of G protein-coupled receptors for neurotransmitters.
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Animals↗
Subcellular redistribution of m2 muscarinic acetylcholine receptors in striatal interneurons in vivo after acute cholinergic stimulation.
The purpose of our work was to investigate how the cholinergic environment influences the targeting and the intracellular trafficking of the muscarinic receptor m2 (m2R) in vivo. To address this question, we have used immunohistochemical approaches at light and electron microscopic levels to detect the m2R in control rats and rats treated with muscarinic receptor agonists. In control animals, m2Rs were located mostly at postsynaptic sites at the plasma membrane of perikarya and dendrites of cholinergic and NPY-somatostatin interneurons as autoreceptors and heteroreceptors, respectively. Presynaptic receptors were also detected in boutons. The m2Rs were usually detected at extrasynaptic sites, but they could be found rarely in association with symmetrical synapses, suggesting that the cholinergic transmission mediated by m2R occurs via synaptic and nonsynaptic mechanisms. The stimulation of muscarinic receptors with oxotremorine provoked a dramatic alteration of m2R compartmentalization, including endocytosis with a decrease of the density of m2R at the membrane (-63%) and an increase of those associated with endosomes (+86%) in perikarya. The very strong increase of m2R associated with multivesicular bodies (+732%) suggests that oxotremorine activated degradation. The slight increase in the Golgi apparatus (+26%) suggests that the m2R stimulation had an effect on the maturation of m2R. The substance P receptor located at the membrane of the same neurons was unaffected by oxotremorine. Our data demonstrate that cholinergic stimulation dramatically influences the subcellular distribution of m2R in striatal interneurons in vivo. These events may have key roles in controlling abundance and availability of muscarinic receptors via regulation of receptor endocytosis, degradation, and/or neosynthesis. Further, the control of muscarinic receptor trafficking may influence the activity of striatal interneurons, including neurotransmitter release and/or electric activity.
Animals↗
Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: co-localization at synapses with the GluR2/3 subunit of the AMPA receptor.
Glutamatergic neurotransmission in the neostriatum and the globus pallidus is mediated through NMDA-type as well as other glutamate receptors and is critical in the expression of basal ganglia function. In order to characterize the cellular, subcellular and subsynaptic localization of NMDA receptors in the neostriatum and globus pallidus, multiple immunocytochemical techniques were applied using antibodies that recognize the NR1 subunit of the NMDA receptor. In order to determine the spatial relationship between NMDA receptors and AMPA receptors, double labelling was performed with the NR1 antibodies and an antibody that recognizes the GluR2 and 3 subunits of the AMPA receptor. In the neostriatum all neurons with characteristics of spiny projection neurons, some interneurons and many dendrites and spines were immunoreactive for NR1. In the globus pallidus most perikarya and many dendritic processes were immunopositive. Immunogold methods revealed that most NR1 labelling is associated with asymmetrical synapses and, like the labelling for GluR2/3, is evenly spread across the synapse. Double immunolabelling revealed that in neostriatum, over 80% of NR1-positive axospinous synapses are also positive for GluR2/3. In the globus pallidus most NR1-positive synapses are positive for GluR2/3. In both regions many synapses labelled only for GluR2/3 were also detected. These results, together with previous data, suggest that NMDA and AMPA receptor subunits are expressed by the same neurons in the neostriatum and globus pallidus and that NMDA and AMPA receptors are, at least in part, colocalized at individual asymmetrical synapses. The synaptic responses to glutamate in these regions are thus likely be mediated by both AMPA and NMDA receptors at the level of individual synapses.
Animals↗
Histone H4 mRNA from the nematode Ascaris lumbricoides is cis-spliced and polyadenylated.
A histone H4 gene from Ascaris lumbricoides contains an intron of approx. 2040 bp. Transcripts of the gene are spliced and polyadenylated. This is the first intron-containing H4 gene described for a metazoan. Notably, H4 mRNA from another nematode, Caenorhabditis elegans, is intron-less and lacks poly A (Roberts, S.B., Emmons, S.W. and Childs, G. (1989) J. Mol. Biol. 206, 567-577).
Animals↗
Cellular, subcellular, and subsynaptic distribution of AMPA-type glutamate receptor subunits in the neostriatum of the rat.
Glutamate released in the basal ganglia is involved in the expression of clinical symptoms of neurodegenerative diseases like Parkinson's or Huntington's. Neostriatal neurons are the targets of glutamatergic inputs derived from the cortex and the thalamus acting via AMPA-type as well as other glutamate receptors. To determine the location of subunits of the AMPA subclass of glutamate receptors (GluR) in the rat neostriatum, we applied multiple immunocytochemical techniques using anti-peptide antibodies against the GluR1, GluR2/3, and GluR4 subunits at both the light and electron microscopic levels. All medium spiny efferent neurons, some of which were identified as striatonigral neurons, displayed immunoreactivity for GluR1 and GluR2/3 subunits. Double immunofluorescence revealed that at least 70-90% of parvalbumin-immunopositive GABAergic interneurons were immunoreactive for each of GluR1, GluR2/3, or GluR4 subunits and that at least 40% of choline acetyltransferase-immunopositive cholinergic interneurons were immunopositive for GluR1 or GluR4 subunits. The majority of nitric oxide synthase-immunopositive neurons had no detectable immunoreactivity for any of the AMPA receptor subunits. Electron microscopic analysis confirmed the presence of immunoreactivity for GluR1 and GluR2/3 in the perikarya of spiny neurons and interneurons and GluR4 in perikarya of interneurons only. GluR1 and GluR2/3 subunits were detected in dendrites and spines. A significant population of extrasynaptic receptors was revealed by pre-embedding immunogold labeling along the plasma membranes of perikarya, dendrites, and spines. Receptors were concentrated in the postsynaptic membrane specialization of asymmetrical synapses, as revealed by the postembedding immunogold method. Quantitative analysis demonstrated that immunoreactivity for the GluR1 and GluR2/3 subunits is higher at the periphery than at the middle of the postsynaptic membrane specialization. Our results demonstrate that AMPA receptor subunits are distributed widely and heterogeneously among striatal neurons and are concentrated on the postsynaptic membrane of asymmetrical synaptic specializations, although extrasynaptic receptors are also present.
Animals↗
Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in Parkinson's disease and rat with 6-OHDA lesion.
The overactivity of subthalamopallidal and corticostriatal glutamatergic neurons observed in Parkinson's disease (PD) suggests that antagonists of glutamate receptor could be used to alleviate the motor symptoms of the disease. In this study, we analysed two features of the striatopallidal complex: (1) the distribution of alpha-amino-3 hydroxy-5-methyl-4-isoxasol-propionate (AMPA) and kainate receptors and their corresponding mRNA by immunohistochemistry and in situ hybridisation and (2) the effect of dopaminergic denervation on AMPA receptor gene expression in PD patients and rats with 6-hydroxydopamine (6-OHDA)-induced degeneration of the nigrostriatal dopaminergic system. All AMPA receptor mRNAs and proteins (GluR1-4) were detected in the internal segment of the globus pallidus (GPi). Among kainate receptors, only KA1 and KA2 were detectable and only at a low level. Only GluR4 protein was detected in the neuropil of the GPi. In the striatum, GluR1, GluR2, and GluR3 were detected in about 70% of medium-sized and large neurons. By contrast, GluR4 mRNA was detected in only a small number of large and medium-sized neurons. Among kainate receptors, GluR6, GluR7, and KA2 were detected in about 50-60% of medium-sized neurons, whereas GluR5 and KA1 were restricted to 1-2% and 20-30% of these neurons, respectively. These results suggest that antagonists of AMPA and kainate receptors could be effective in alleviating motor symptoms in Parkinson's disease by blocking the overstimulation of pallidal and striatal neurons by glutamate. A significant decrease in GluR1 gene expression (-33%) was observed in the neurons of the GPi in PD patients and in rat entopeduncular nucleus ipsilateral to the 6-OHDA lesion (-20%). GluR2, GluR3, and GluR4 mRNA levels in the GPi and GluR1-4 levels in the striatum were unchanged in PD patients and 6-OHDA-lesioned rats compared with their respective controls. These data suggest that dopamine positively regulates only GluR1 gene expression in the GPi.
Animals↗