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P Barone

Publications and source records attributed to P Barone.

At least 55 records · Page 3Linked to original sources
PubMed1999

Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes.

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, show a limited amino acid sequence divergence. Their embryonic expression patterns overlap in spatial and temporal profiles with two major exceptions: until 8 days post coitum (d.p.c. ) only Otx2 is expressed in gastrulating embryos, and from 11 d.p.c. onwards only Otx1 is transcribed within the dorsal telencephalon. Otx1 null mice exhibit spontaneous epileptic seizures and multiple abnormalities affecting primarily the dorsal telencephalic cortex and components of the acoustic and visual sense organs. Otx2 null mice show heavy gastrulation abnormalities and lack the rostral neuroectoderm corresponding to the forebrain, midbrain and rostral hindbrain. In order to define whether these contrasting phenotypes reflect differences in expression pattern or coding sequence of Otx1 and Otx2 genes, we replaced Otx1 with a human Otx2 (hOtx2) full-coding cDNA. Interestingly, homozygous mutant mice (hOtx2(1)/hOtx2(1)) fully rescued epilepsy and corticogenesis abnormalities and showed a significant improvement of mesencephalon, cerebellum, eye and lachrymal gland defects. In contrast, the lateral semicircular canal of the inner ear was never recovered, strongly supporting an Otx1-specific requirement for the specification of this structure. These data indicate an extended functional homology between OTX1 and OTX2 proteins and provide evidence that, with the exception of the inner ear, in Otx1 and Otx2 null mice contrasting phenotypes stem from differences in expression patterns rather than in amino acid sequences.

Animals↗
PubMed1998

Area-specific laminar distribution of cortical feedback neurons projecting to cat area 17: quantitative analysis in the adult and during ontogeny.

Corticocortical pathways can be classified as feedback and feedforward, in part according to the laminar distribution of the parent cell bodies. Here, we have developed exhaustive sampling procedures to determine unambiguously this laminar distribution. This shows that individual extrastriate areas in the adult cat have highly stereotyped proportions of supragranular layer neurons with respect to the total population of neurons back-projecting to area 17. During development, these adult laminar patterns emerge from an initially uniform radial distribution through a process of selective reorganization, which is highly specific to each area. Injections of fluorescent retrograde tracers were made in area 17. In areas 19, 20, posteromedial lateral suprasylvian area, and anteromedial lateral suprasylvian area, we defined a projection zone as the region containing retrogradely labeled neurons. In the neonate, counts of labeled neurons throughout the projection zones show constant percentages of 40% in the supragranular layers. During development, there is an area-specific reduction in the percentage of supragranular labeled neurons generating the laminar distributions characteristic of each area. Numbers of labeled neurons were estimated at different eccentricities of the projection zone. This finding indicates that during development there is a relative decrease in the numbers of labeled neurons of the periphery of the projection zone in the supragranular layers but not in the infragranular layers. This decrease is accompanied by a relative decrease in the dimensions of the supragranular projection zone with respect to the infragranular projection zone. These findings suggest that each extrastriate area precisely adjusts the proportions of supragranular layer neurons back-projecting to striate cortex in part by developmental changes in the divergence-convergence values of individual neurons. This shaping of corticocortical connectivity occurs relatively late in postnatal development and could, therefore, be under epigenetic control.

Animals↗
PubMed1998

Murine Otx1 and Drosophila otd genes share conserved genetic functions required in invertebrate and vertebrate brain development.

Despite the obvious differences in anatomy between invertebrate and vertebrate brains, several genes involved in the development of both brain types belong to the same family and share similarities in expression patterns. Drosophila orthodenticle (otd) and murine Otx genes exemplify this, both in terms of expression patterns and mutant phenotypes. In contrast, sequence comparison of OTD and OTX gene products indicates that homology is restricted to the homeodomain suggesting that protein divergence outside the homeodomain might account for functional differences acquired during brain evolution. In order to gain insight into this possibility, we replaced the murine Otx1 gene with a Drosophila otd cDNA. Strikingly, epilepsy and corticogenesis defects due to the absence of Otx1 were fully rescued in homozygous otd mice. A partial rescue was also observed for the impairments of mesencephalon, eye and lachrymal gland. In contrast, defects of the inner ear were not improved suggesting a vertebrate Otx1-specific function involved in morphogenesis of this structure. Furthermore, otd, like Otx1, was able to cooperate genetically with Otx2 in brain patterning, although with reduced efficiency. These data favour an extended functional conservation between Drosophila otd and murine Otx1 genes and support the idea that conserved genetic functions required in mammalian brain development evolved in a primitive ancestor of both flies and mice.

Animals↗
PubMed1997

Behavioural sensitization in 6-hydroxydopamine-lesioned rats is related to compositional changes of the AP-1 transcription factor: evidence for induction of FosB- and JunD-related proteins.

Rats with unilateral dopamine denervation exhibit turning behaviour in response to the selective D1 agonist SKF 38393 only after a previous exposure to dopamine agonists. We demonstrate here that this 'priming' phenomenon is related to both an increased expression of the pre-existing AP-1 complex and the occurrence of novel AP-1 complexes which are formed by FosB- and JunD-related proteins. While the former protein is expressed as a consequence of the dopamine denervation, the latter is related to the first exposure to a dopamine agonist. Pre-treatment with MK-801, an antagonist for glutamatergic receptors, prevents both the priming development and the AP-1 compositional changes. Rotational behaviour induced by SKF 38393 closely correlates with the presence of the priming AP-1 complexes, regardless of the capability of the D1 agonist to induce the immediate-early gene cFos.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Nitric oxide-haemoglobin interaction: a new biochemical hypothesis for signal changes in fMRI.

A new hypothesis on the origin of activation-induced signal changes in functional magnetic resonance imaging (fMRI) is presented, involving transient formation of paramagnetic species, i.e. methaemoglobin (Hb+) and nitrosylhaemoglobin (Hb-NO), by reaction of nitric oxide (NO) with oxy-(Hb-O2) and deoxyhaemoglobin (Hb). Hb+ and Hb-NO, generated in erythrocytes, were found to produce marked concentration-dependent signal intensity changes when examined by T1-, T2- and T2*-weighted MRI. Intravenous administration of ascorbic acid (3 g) to healthy volunteers, to specifically reduce any Hb+ formed during brain activation, markedly decreased fMRI signal changes during standard tasks, suggesting a blood flow-independent effect produced by the reductant. These results open a new perspective on the fMRI evaluation of physiological processes associated with task-specific activation of brain structures.

Brain↗
PubMed1997

Conversion of recent onset atrial fibrillation to sinus rhythm using a single oral loading dose of propafenone: comparison of two regimens.

A population of 105 patients with recent onset (< 72 h) atrial fibrillation was randomly treated with propafenone as a single oral loading dose of 450 mg (Regimen A) or 600 mg (Regimen B) or with placebo. A 24-h Holter was performed. Criteria of efficacy were conversion to sinus rhythm at 2, 4 and 8 h compared to placebo and also significant reduction of mean ventricular rate in persistent atrial fibrillation. After 2 h, regimen B was more effective than either regimen A (43% vs. 8%; p = 0.001) or placebo (11%; p = 0.004). At 4 h, both the active treatments were more effective than placebo (17% vs. 46% regimen A and 57% vs. regimen B; p < 0.04 and p < 0.001, respectively). Sinus rhythm resumed within 24 h in 71%, 80% and 69% of the patients with regimen A, B and placebo, respectively (p = not significant). The mean ventricular rate reduction after 1 h was 8%, 11% and 4% for regimen A, B and placebo, respectively (p < 0.005 vs. regimen B), and 17%, 25% and 6% respectively (p < 0.001 placebo vs. regimen A and B, p < 0.05 regimen B vs. A) at 2 h. No major adverse effect occurred. Atrial flutter with 1:1 atrioventricular conduction only in one case who received placebo. Propafenone acute oral administration is more effective than placebo in rapidly converting recent-onset atrial fibrillation to sinus rhythm and may be the treatment of choice in this setting limiting hospitalization and contributing to improved quality of life.

Administration, Oral↗
PubMed1997

Hormonally induced modulation in the phosphate metabolites of breast cancer: analysis of in vivo 31P MRS signals with a modified prony method.

A modified Prony method (MPM) was applied to analyze the main signals present in spatially resolved 31P NMR spectra of MCF7 breast tumors implanted in nude mice. First, the method was tested on synthetic data to establish its limits of reliability. Its performance with respect to peak identification and quantification of signal intensities was then exploited on data from three implanted tumors during hormonal manipulation with estrogen and the antiestrogenic drug tamoxifen. The phosphomonoester peak was resolved into phosphocholine (PC) and phosphoethanolamine (PE). Treatment with tamoxifen led to a significant reduction in the PE to PE+PC peak amplitude ratio in the tumors under consideration. MPM analysis also revealed the presence of two different inorganic phosphate pools: a larger acidic pool and a smaller alkaline pool during estrogen-induced growth and the reverse during tumor regression.

Animals↗
PubMed1996

Role of directed growth and target selection in the formation of cortical pathways: prenatal development of the projection of area V2 to area V4 in the monkey.

In experiments combining retrograde tracers and histochemistry, we have looked at the prenatal development of the cortical pathway linking areas V2 and V4. Transient expression of acetylcholinesterase in fetal area V2 reveals the separate compartments that project to V4 (temporal directed pathway) and V5 (parietal directed pathway). During early stages of pathway formation, V2 neurons projecting to area V4 are clustered in the appropriate compartments. During the phase of rapid axonal growth, there is a selective increase of connections originating from the appropriate compartments leading to a strongly clustered organization at the peak of connectivity. During this phase, injections involving the white matter also showed clustering, but this was somewhat reduced in comparison to that of gray matter injections. The growth phase is followed by an elimination phase during which there is a tendency for a preferential loss of intercluster connections, which may sharpen the early formed pattern. These results demonstrate the primary role of axonal guidance and target recognition mechanisms followed by a limited extent of selective elimination during the formation of functional cortical pathways in the primate isocortex. Compared to previous findings, these results suggest that the developmental restriction of callosal connections is not a universal model of cortical development. In the present report, the directed growth and early specification of feed-forward connections contrast with the prolonged remodelling of monkey feedback projections, suggesting two distinct developmental strategies of pathway formation in the monkey.

Acetylcholinesterase↗
PubMed1996

Epilepsy and brain abnormalities in mice lacking the Otx1 gene.

The morphogenesis of the brain and the differentiation of the neural structures are highly complex processes. A series of temporally and spatially regulated morphogenetic events gives rise to smaller areas that are phylogenetically, functionally and often morphogenetically different. Candidate genes for positional information and differentiation during morphogenesis have been isolated. Both in vivo inactivation in mice and impairment in human diseases revealed, that they are required in regional specification and/or correct cell-type induction. We have previously cloned and characterized the murine Otx1 gene, which is related to orthodenticle (otd), a homeobox-containing gene required for Drosophila head development. Expression data during murine embryogenesis and postnatal brain development support the idea that Otx1 could be required for correct brain and sense organs development. To decipher its role in vivo we produced null mice by replacing Otx1 with the lacZ gene. Otx1-/- mice showed spontaneous epileptic behaviour and multiple abnormalities affecting mainly the telencephalic temporal and perirhinal areas, the hippocampus, the mesencephalon and the cerebellum, as well as the acoustic and visual sense organs. Our findings indicate that the Otx1 gene product is required for proper brain functions.

Animals↗
PubMed1996

Conversion of recent onset atrial fibrillation with single loading oral dose of propafenone: is in-hospital admission absolutely necessary?

A population of 283 patients with recent onset (< 72 hours) AF, without heart failure, who received a single 450- or 600-mg oral dose of propafenone, or digoxin 1 mg, or placebo for conversion to sinus rhythm (SR), was studied to determine whether a routine admission to the hospital for drug administration is justified. Previous bradyarrhythmias or sick sinus syndrome (SSS), and concomitant use of antiarrhythmic drugs were exclusion criteria. None of the 283 patients studied experienced VT or VF and none of them needed implantation of a temporary pacemaker. Periods of atrial tachyarrhythmias with regularization of atrial waves and 1:1 AV conduction were observed in only two cases, both receiving placebo. No predictor of proarrhythmia was found among the clinical variables considered (age, etiology, arrhythmia duration, atrial dimension, and blood potassium). No serious hemodynamic adverse effects were noted in either group. The rates of conversion to SR after 4 hours were: 80 (57%) of 141 patients who received propafenone and 35 (25%) of 142 patients who received digoxin or placebo (P < 0.001). Acute oral treatment with propafenone is simple and effective for the conversion of recent onset AF to SR in patients without clinical signs of heart failure. The routine admission of these patients to the hospital is not necessary. Home-based administration of oral propafenone to a selected group of patients could significantly increase the cost effectiveness of this treatment.

Administration, Oral↗
PubMed1996

Cortical synthesis of azimuth-sensitive single-unit responses with nonmonotonic level tuning: a thalamocortical comparison in the cat.

1. Azimuth and sound pressure level (SPL) tuning to noise stimulation was characterized in single-unit samples obtained from primary auditory cortex (AI) and in areas of the medial geniculate body (MGB) that project to AI. The primary aim of the study was to test the hypothesis that AI is an important site of synthesis of single-unit responses that exhibit both azimuth sensitivity (tendency for directionally restricted responsiveness) and nonmonotonic (NM) level tuning (tendency for decreased responsiveness with increasing SPL). This was accomplished by comparing the proportions of such responses in AI and MGB. 2. Samples consisted of high-best-frequency (BF) single units located in MGB (n = 217) and AI (n = 216) of barbiturate-anesthetized cats. The MGB sample was obtained mainly from recording sites located in two nuclei that project to AI, the ventral nucleus (VN, n = 118) and the lateral part of the posterior group of thalamic nuclei (Po, n = 84). In addition, a few MGB units were obtained from the medial division (n = 8) or uncertain locations (n = 7). Each unit's responses were studied using noise bursts presented from azimuthal sound directions distributed throughout 180 degrees of the frontal hemifield at 0 degrees elevation. SPL was varied over an 80-dB range in steps of < or = 20 dB at each location. Similarities and differences in azimuth and level tuning were evaluated statistically by comparing the AI sample with the entire MGB sample. If they were found to differ, the AI, VN, and Po samples were compared. 3. Azimuth function modulation was used as a measure of azimuth sensitivity, and its mean was greater in AI than in MGB. NM strength was defined as the percentage reduction in level function value at 75 dB SPL and its mean was greater in AI (showing a greater tendency for decreased responsiveness) than in MGB. Azimuth-sensitive (AS) NM units were identified by jointly categorizing each sample according to both azimuth sensitivity (sensitive and insensitive categories) and NM strength (NM and monotonic categories). AS NM units were much more common in the AI sample than in any of the MGB samples, suggesting that some such responses are synthesized in AI. 4. A vast majority of AI NM units have been reported to be AS, showing a preferential association (linkage) between these two response properties. This finding was confirmed in AI, but was not found to be the case in MGB. This suggests that a linkage between these response properties emerges in the cortex, presumably as a result of synthesis of NM AS responses. Although the functional significance of the linkage is unknown, NM responses may reflect excitatory/inhibitory antagonism that provides AS AI neurons with sensitivity to stimulus features beyond that which is present in MGB. 5. Breadth of azimuth tuning of AS cells was measured as the portion of the frontal hemifield over which azimuth function values were > 75% of maximum (preferred azimuth range, PAR). PARs were broadly distributed in each structure, and mean PAR was narrower in AI than in MGB. A preferred level range (PLR) was defined for NM level functions as the range over which values were > 75% of maximum, and mean PLRs were similar in each sample. There was a weak, but significant, positive correlation between PARs and PLRs in AI but not in MGB. This further suggests a linkage between azimuth and level tuning in AI that does not exist in MGB. 6. Best azimuth (midpoint of the PAR) was used to classify cells as contralateral preferring, ipsilateral preferring, midline preferring, or multipeaked. Samples from AI and MGB exhibited similar distributions of these categories. Contralateral-preferring cells represented a majority of each sample, whereass midline-preferring, ipsilateral-preferring, and multipeaked cells each represented smaller proportions. This suggests that the azimuth preference distribution in AI largely reflects that in MGB. 7. A best SPL was defined as the midpoint of the PLR. This wa

Animals↗
PubMed1995

Comparison of noise and tone azimuth tuning of neurons in cat primary auditory cortex and medical geniculate body.

1. A comparison of the azimuth tuning of single neurons to broadband noise and to best frequency (BF) tone bursts was made in primary auditory cortex (AI: n = 173) and the medial geniculate body (MGB: n = 52) of barbiturate-anesthetized cats. Observations were largely restricted to cells located within the tonotopically organized divisions of the MGB (i.e., the ventral nucleus and the lateral division of the posterior nuclear group) and the middle layers of AI. All cells studied had BFs > or = 4 kHz. 2. The responses of each cell to sounds presented from seven frontal azimuthal locations (-90 to +90 degrees in 30 degrees steps; 0 degree elevation) and at five sound pressure levels (SPLs: 0-80 dB or 5-85 dB in 20-dB steps) provided an azimuth-level data set. Responses were averaged over SPL to obtain an azimuth function, and a number of features of this function were used to describe azimuth tuning to noise and to tone stimulation. Azimuth function modulation was used to assess azimuth sensitivity, and cells were categorized as sensitive or insensitive depending on whether modulation was > or = 75% or < 75% of maximum, respectively. The majority (88%) of cells in the sample were azimuth sensitive to noise stimulation, and statistical analyses were restricted to these cells, which are presumably best suited to encode sound source azimuth. Azimuth selectivity was assessed by a preferred azimuth range (PAR) over which azimuth function values exceeded 75% (PAR75) or 50% of maximum response. Cells were categorized according to the location and extent of their noise PARs. Unbounded cells had laterally located PARs that extended to the lateral pole (+/- 90 degrees); bounded cells had PARs that were contained entirely within the frontal hemifield, and a subset of these had PARs centered on the midline (+/- 15 degrees). A final group of cells exhibited multipeaked azimuth functions to noise stimulation. 3. Azimuth functions to noise were generally more selective and/or more sensitive than those to tones. Statistical analyses showed that these differences were significant for cells in each azimuth function category, and for the thalamic and cortical samples. With the exception of multipeaked cells, responsiveness to noise was significantly lower than that to tones in all categories, and for the thalamic and cortical samples.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗
PubMed1995

Dopamine mediated responses in 6-hydroxydopamine lesioned rats involve changes of the signal transduction.

A single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning in unilaterally 6-hydroxydopamine lesioned rats only after a previous exposure of the animals to a dopamine agonist. This priming phenomenon is here investigated by studying the phosphorylation of DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 in striatal tissue was measured by a back-phosphorylation assay. While the levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged, a significant decrease of dephospho-DARPP-32 was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. This study shows that an alteration of the dopamine-dependent signal transduction is related to the behavioral response to dopamine agents, suggesting a possible mechanism involved in the effects of these drugs in parkinsonian patients.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Autoradiographic characterization of binding sites for [3H]milnacipran, a new antidepressant drug, and their relationship to the serotonin transporter in rat brain.

Milnacipran is a new antidepressant drug and an equipotent inhibitor of the uptake of serotonin and noradrenaline. Quantitative autoradiography and radioligand binding studies were used to characterize recognition sites of [3H]milnacipran in rat brain. [3H]Milnacipran demonstrated saturable, reversible and nanomolar affinity binding. The binding was Na(+)-dependent, potently displaced by serotonin uptake inhibitors in all structures and moderately or weakly displaced by catecholamine uptake inhibitors (order of potency: paroxetine > fluoxetine > mazindol > desipramine > nomifensine > maprotiline). High density of recognition sites were found in structures dense in serotonergic innervation (raphe, basal ganglia, colliculi, cortex). The autoradiographic pattern of [3H]milnacipran recognition sites resembled that of [3H]paroxetine, but their distribution did not correlate well in some structures. Selective lesioning of serotonergic neurons by intracerebral injection of 5,7-dihydroxytryptamine caused a large decrease of [3H]milnacipran binding in various regions (septum, caudate, hippocampus, thalamus, ventral and dorsal hypothalamus), but in other structures, the [3H]milnacipran binding was partially affected (putamen) or even unchanged (amygdala, lateral hypothalamus). In contrast, lesion of noradrenergic neurons by intraperitoneal administration of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] did not affect the binding of [3H]milnacipran in any region. These results show that [3H]milnacipran mainly binds to the serotonin transporter and does not recognize the catecholamine transporters under the conditions used. In addition, [3H]milnacipran might also bind to other sites, serotonin transporter localized on non-serotonergic neurons or serotonergic neurons insensitive to 5,7-DHT neurotoxicity.

5,7-Dihydroxytryptamine↗
PubMed1994

Quantitative autoradiography of 5-HT1D and 5-HT1E binding sites labelled by [3H]5-HT, in frontal cortex and the hippocampal region of the human brain.

In human cortex and hippocampus area, [3H]5-HT (5 nM) labels 5-HT1A, 5-HT1D and 5-HT1E sites. After masking 5-HT1A receptors by 0.1 microM 8-OH-DPAT, the binding displaced by 0.1 microM 5-CT presumably represented 5-HT1D sites and the remaining binding 5-HT1E sites. In frontal cortex, 5-HT1A receptors represented the main binding in layers II and VI and a lower fraction in other layers. 5-HT1D and 5-HT1E sites, were more homogeneously distributed in layers II to VI (21-34% of specific [3H]5-HT binding). 5-HT1E sites were of similar affinities (KD close to 6-8 nM) in the cortical layers II to VI. In CA1 field of hippocampus, (pyramidal layer, stratum radiatum, molecular layer), CA2 and dentate gyrus, 5-HT1A receptors represented the major fraction, 5-HT1D sites a significant fraction and 5-HT1E a minor fraction of the specific [3H]5-HT binding. In CA3-CA4 fields, 5-HT1A receptors were less densely present, 5-HT1D sites were predominant and 5-HT1E sites represented a significant fraction (27%). The highest densities of 5-HT1E sites have been measured in subiculum, where 5-HT1A, 5-HT1D and 5-HT1E binding sites were equally represented and in entorhinal cortex where 5-HT1E sites represented the major binding in layer III. They were also present in layers II and IV (29 and 24%) and, to a lesser extent, in layers V and VI. 5-HT1A sites were predominant in layer VI, II and V and were less abundant in other layers. 5-HT1D were homogeneously present in layers II, III, IV and were present in low amounts in other layers. No 5-HT1E were detected in choroid plexus, where [3H]5-HT was dramatically reduced by mesulergine (5-HT2C receptors). No significant displacement of [3H]5-HT by mesulergine was measured in other structures.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Developmental changes in the distribution of acetylcholinesterase in the extrastriate visual cortex of the monkey.

In the fetal and neonatal monkey, periodically organized regions of high activity of acetylcholinesterase were found in the visual cortical area V2 (Area 18). The acetylcholinesterase bands, like the thin and thick stripes of cytochrome oxidase, were found to run orthogonal to the area 17/18 border. During neonatal development these bands progressively narrow and finally disappear shortly after four months of age.

Acetylcholinesterase↗