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Biomedical subjects

F Parker

Publications and source records attributed to F Parker.

At least 55 records · Page 3Linked to original sources
PubMed1996

Tremor and voluntary repetitive movement in Parkinson's disease: comparison before and after L-dopa with positron emission tomography.

Brain regions involved in tremor and voluntary movement were compared in seven subjects with hemiparkinsonian tremor using positron emission tomography and the [15O] water bolus activation method. Repeated measurements of the regional cerebral blood flow were performed both before and after tremor arrest induced by administration of L-dopa as well as during voluntary repetitive movements of the hand contralateral to tremor side. The normalized regional cerebral blood flow (NrCBF) was measured in regions of interest with anatomical boundaries that were defined for each subject by means of a three-dimensional reconstruction of magnetic resonance imaging data. Taking the rest after L-dopa as a control condition, NrCBF increased during tremor in a network of regions including the precentral (mean +/- SD 5.36 +/- 4.6%, P = 0.006) and paracentral (6.11 +/- 6%, P = 0.01) gyri contralateral to tremor side, the supplementary motor area (SMA; 4.03 +/- 4%, P = 0.02, n = 8 pairs), and the cerebellar vermis (8.64 +/- 9.9%, P = 0.01, n = 12). During voluntary repetitive movement of the hand contralateral to tremor compared with rest after L-dopa, the same patients activated the precentral (8.25 +/- 2.6%, P = 0.0006) and postcentral regions contralateral to movement (8.43 +/- 3.7%, P = 0.002), and the cerebellar cortex (3.49 +/- 2.1%, P = 0.03), precentral (3.58 +/- 3.1%, P = 0.04), and paracentral (4.03 +/- 3.6%, P = 0.04) regions ipsilateral to movement. The cerebellar vermis was activated (8.15 +/- 5.6%, P = 0.02, n = 8) as well as the SMA, but not significantly at the 0.05 level (5.16 +/- 5%, P = 0.08, n = 5). These results confirm the similarities of brain structures involved in parkinsonian tremor and voluntary movement and provide an anatomofunctional substrate for their clinical interactions.

Aged↗
PubMed1996

The effects of bolus administration of opioids on cerebrospinal fluid pressure in patients with supratentorial lesions.

In many studies reporting an increase in cerebrospinal fluid pressure (CSFP) after opioid administration, concomitant decreases in mean arterial pressure (MAP) have been observed. Autoregulatory cerebral vasodilation may therefore have been a factor in the CSFP increases. We tested the hypothesis that increases in CSFP after bolus injection of opioids could be minimized by modifying concomitant decreases in MAP with phenylephrine. Thirty-three patients with supratentorial mass lesions were studied in a randomized, prospective, double-blind, saline-controlled comparative trial. The principal outcome measures were lumbar CSFP, MAP, and heart rate (HR). Study drugs, sufentanil 0.8 micrograms/kg (n = 12), fentanyl 4.5 micrograms/kg (n = 11), or normal saline (n = 10), were injected intravenously (IV) during stable general anesthesia with 0.3-0.7 minimum alveolar anesthetic concentration (MAC) of isoflurane in oxygen and controlled ventilation (end-tidal carbon dioxide 32-35 mm Hg). Phenylephrine 50-100 micrograms was injected IV when MAP decreased by more than 15% of initial values, and atropine 0.5 mg IV when HR decreased to less than 45 bpm. Opioid administration was associated with significant decreases in MAP, 21 +/- 9 mm Hg (mean +/- SD) in the sufentanil group and 16 +/- 7 mm Hg in the fentanyl group; P < 0.001. These decreases in MAP were of short duration (i.e., corrected with 1-2 min). Patients in the sufentanil group needed more phenylephrine than patients in the fentanyl group (170 +/- 89 micrograms vs 100 +/- 47 micrograms; P < 0.05). No significant change in the CSFP was seen in either the sufentanil (1 +/- 6 mm Hg) or fentanyl-treated patients (O +/- 2 mm Hg). No significant changes in MAP or CSFP were observed in the saline-treated patients. HR decreased after injection of either study drug (P < 0.01) but remained unchanged in the saline group. In summary, during stable anesthesia with isoflurane in oxygen, bolus injections of fentanyl or sufentanil, despite producing rapidly corrected mean decreases in MAP of 18% and 25%, respectively, were not associated with any change in CSFP.

Adult↗
PubMed1996

A Ras-GTPase-activating protein SH3-domain-binding protein.

We report the purification of a Ras-GTPase-activating protein (GAP)-binding protein, G3BP, a ubiquitously expressed cytosolic 68-kDa protein that coimmunoprecipitates with GAP. G3BP physically associates with the SH3 domain of GAP, which previously had been shown to be essential for Ras signaling. The G3BP cDNA revealed that G3BP is a novel 466-amino-acid protein that shares several features with heterogeneous nuclear RNA-binding proteins, including ribonucleoprotein (RNP) motifs RNP1 and RNP2, an RG-rich domain, and acidic sequences. Recombinant G3BP binds effectively to the GAP SH3 domain G3BP coimmunoprecipitates with GAP only when cells are in a proliferating state, suggesting a recruitment of a GAP-G3BP complex when Ras is in its activated conformation.

3T3 Cells↗
PubMed1996

Synthesis and biological evaluation of a new series of phenylhydroquinone derivatives as inhibitors of EGF-R-associated PTK activity.

In order to design new potent inhibitors of the epidermal growth factor receptor (EGF-R) associated protein tyrosine kinase (PTK) activity as antitumor agents, several families of phenylhydroquinone derivatives were synthesized. Some of these compounds were shown to block PTK activity in vitro, but also efficiently to inhibit EGF-stimulated DNA synthesis in ER 22 cells (CCL 39 hamster fibroblasts transfected with EGF-R) with IC50 values in the range 1-10 microM. In some cases, a correlation between the two sets of data was observed, allowing structure-activity relationships to be established. However, inhibitors which had in vitro specificity with regard to other kinases were not specific in the cellular test. Similar effects on DNA synthesis were observed after stimulation by various activating agents, suggesting that our compounds may also act against other cellular targets involved in the EGF-dependent pathways leading to cell proliferation.

Amino Acid Sequence↗
PubMed1996

Synthesis and biological evaluation of a series of hydroxybenzylphenylamine derivatives as inhibitors of EGF receptor-associated tyrosine kinase activity.

In order to obtain non-degradable and more potent protein-tyrosine kinase inhibitors, derived from the 5-(2,5-dihydroxybenzyl)-aminosalicylates already described, we have developed a new series of 5-(2,5-dihydroxybenzyl)phenylamines. The compounds, diversely substituted on the phenyl ring by alcohol, nitrile, ether, ketone, amide and thioamide groups, were tested for their ability to inhibit epidermal growth factor (EGF) receptor-associated tyrosine kinase activity in vitro. They inhibit the phosphorylation of the peptide substrate RR-Src by the EGF receptor purified from ER 22 cells, with IC50 values in the range 0.02-0.45 microns. Several of these compounds inhibit EGF-dependent DNA synthesis in ER 22 cells with IC50 values of around 1 micron and furthermore their inhibition has been found to be specific for various protein kinases.

Aniline Compounds↗
PubMed1995

Inhibition of the EGF-stimulated cellular proliferation of ER 22 cells by hydroxybiphenyl derivatives.

Several series of hydroxybiphenyl compounds substituted by a hydrophobic group (tert-butyl or phenyl) and bearing a free or protected carboxylic moiety were synthesized. The compounds were tested for their ability to inhibit the intrinsic tyrosine protein kinase activity of the EGF-receptor in vitro and the EGF-stimulated DNA-synthesis by ER 22 cells. Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 microM), most of them inhibited the EGF-dependent cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.1 microM for compound 14). Structure-activity studies based on the cellular results showed that the most interesting series was the linear terphenyl series B of 2'-hydroxy-1,1':4',1"-terphenyl-4-carboxylates. The availability of the hydroxyl group, either protected or unprotected, the linear arrangement of the hydrophobic moiety, the biphenyl skeleton, and the carboxylic group seem to be essential for the activity of the compounds.

Amino Acid Sequence↗
PubMed1995

A role for Grb2 in apoptosis?

Src homology type 2 (SH2) and type 3 (SH3) domains appear to have an important role in signal transduction pathways initiated by tyrosine kinases. SH2 domains allow proteins with signalling functions to interact with tyrosine kinases and tyrosine-phosphorylated proteins at the plasma membrane, whereas SH3 domains allow a distinct type of interaction through binding to proline-rich sequences. The adaptor protein Grb2 consists of one SH2 domain and two SH3 domains and connects tyrosine kinase receptors to activation of the Ras pathway. Its closely related counterpart, Grb3-3, thought to arise by alternative splicing of Grb2 transcripts, lacks a functional SH2 domain but retains functional SH3 domains. We recently presented evidence that Grb3-3 might deliver specific signals causing cells to undergo apoptosis. This review will document the mechanism of Grb3-3 function and discuss its putative involvement in several pathologies. It also further strengthens the notion that cells may use alternative splicing as a means to drive either a proliferative or a suicidal program.

Journal Article↗
PubMed1995

[Role of radiotherapy in the treatment of meningioma].

Between 1962 and 1986, 32 patients with intracranial meningiomas were referred to the Institut Gustave-Roussy for external radiotherapy either after incomplete surgery, or unfavorable histology (meningiosarcoma/anaplastic meningioma), or after recurrences. In the latter case, the mean time interval between the first surgery and the recurrence was 2 years (range: 1-6 years). Radiotherapy was performed using photons, electrons or mixed photons-electrons. The mean total dose was 48 Gy (range: 9-65 Gy) delivered in a mean time of 35 days with a 19 mean number of fractions. Radiotherapy was interrupted in three cases at 9 Gy-17 Gy-20 Gy because of neurological worsening. The actuarial 5-year survival was 64%. Among the 32 patients, 11 died, eight of tumoral progression or recurrence and three of other causes (one ovarian carcinoma, two unknown). Among the 21 alive patients, eight presented a recurrence; five of them could be reoperated on with two complete resections. None of the following factors were found to be of prognostic value on the survival nor on the recurrence occurrence: age, tumor location, first surgical resection type, and, in the group of patients treated at the time of recurrence, the quality of the surgery at the time of recurrence and the time interval between the first surgery and the recurrence. Only one factor was evidenced as of significant value on the recurrence as well as the 10-year survival: the total dose of irradiation with a 10-year survival rate of 74% for total doses higher than or equal to 47 Gy versus 14% when the total dose was lower than 47 Gy.

Adult↗
PubMed1994

Structure-activity relationships in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylate inhibitors of EGF-receptor-associated tyrosine kinase: importance of additional hydrophobic aromatic interactions.

Potent inhibitors of EGF-dependent protein tyrosine kinase (PTK) activity were synthesized in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylates. Several of these compounds inhibited EGF-dependent DNA synthesis in ER 22 cells with IC50 < 1 microM. In this series of PTK inhibitors, the role of the salicylate moiety as a potential divalent ion chelator was tested and found to be nonessential in all cases. The length and ramification of the substituting carboxyl group were investigated to improve cellular bioavailability, and this analysis provided compounds with increased inhibitory effect on EGF-induced DNA synthesis. Salicylates esterified with long hydrophobic chains were shown to be noncompetitive inhibitors of ATP, in contrast to the free acid and methyl salicylate. Moreover, all the tested inhibitors were shown to be noncompetitive inhibitors of the peptide substrate. Structure-activity relationships allowed us to suspect a hydrophobic pocket in the tyrosine kinase domain, preferentially interacting with aromatic rings. Finally, the selectivity of the best inhibitors was tested against other kinases, and they were found to be selective for tyrosine kinase. They were also shown to be good inhibitors of EGF-receptor autophosphorylation.

Animals↗
PubMed1994

NMR structure of the N-terminal SH3 domain of GRB2 and its complex with a proline-rich peptide from Sos.

GRB2 is a small adaptor protein of 217 amino acids comprising one SH2 domain surrounded by two SH3 domains. GRB2 couples receptor tyrosine kinase activation to Ras signalling by interacting, through its SH3 domains, to the carboxy-terminal proline-rich regions of the guanine nucleotide exchange factor Sos. Here we report the synthesis and solution structure of the amino-terminal SH3 domain of GRB2 and of its more stable Ser 32 mutant. 1H NMR analysis of the complex between the Ser-32-GRB2-N-SH3 domain and the proline-rich peptide VPPPVPPRRR, derived from h-Sos, shows that relative to the SH3 peptide complexes described for PI3K, Fyn and Abl, the proline-rich peptide in this complex binds in the opposite orientation.

Adaptor Proteins, Signal Transducing↗
PubMed1994

A technique of measuring the precision of an MR-guided stereotaxic installation using anatomic specimens.

PURPOSE: To develop a method for direct measurement, using anatomic specimens, of the precision of MR-guided stereotaxic location and to describe its application to a 1.5-T MR unit with a Leksell stereotaxic frame. METHODS: Small pieces of gelfoam (1 X 1 X 1 mm), soaked in gadopentetate dimeglumine, were stereotaxically introduced into formalin-fixed human heads using a Leksell D (three experiments) or G (nine experiments) stereotaxic frame. The head and the frame were then introduced into a 1.5-T MR unit. The target coordinates (as set on the stereotaxic frame by one investigator) were then compared with the MR-determined stereotaxic coordinates (calculated independently by another investigator). The imprecisions Ex, Ey, and Ez in each direction were defined as the differences between the calculated and the chosen coordinates. RESULTS: Regarding the three targets studied with the D frame, mean imprecision Ex was 1.08 +/- 0.50 mm (mean +/- SEM), Ey 0.83 +/- 0.58 mm, and Ez 0.75 +/- 0.25 mm. For the nine targets studied with the G frame, Ex was 0.48 +/- 0.17 mm, Ey 0.69 +/- 0.14 mm, and Ez 0.82 +/- 0.13 mm. Statistical analysis of the results showed no significant difference between Ex or Ey and half the size of a pixel, indicating that, in the axial plane, stereotaxic MR precision is limited only by pixel size. A statistically significant difference was observed in the coronal plane between Ez and half the size of a pixel, but it must be stressed that Ez remained smaller than 1 mm. CONCLUSION: MR-guided stereotaxic location can be used with confidence for most diagnostic, functional, and therapeutic procedures.

Calibration↗
PubMed1993

Synthesis and structure-activity studies of a series of [(hydroxybenzyl)amino]salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity.

The synthesis and structure-activity relationships of a series of [(hydroxybenzylidene)amino]salicylates and a series of [(hydroxybenzyl)amino]salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity are described. Their inhibitory potency was evaluated in vitro using ER 22 cell membranes (CCL 39 cells transfected with EGF receptor) as an enzyme source and the tridecapeptide RRSrc (RRLIEDAEYAARG) as substrate. Their cellular activity was measured by inhibition of the EGF-stimulated DNA synthesis of ER 22 cells. Chemical modifications were made to analyze the role of the different substituents. The amino series was found to be more active than the imino series. The hydroquinone moiety appears to be essential for tyrosine kinase inhibitory activity in the series of 5-[(2,5-dihydroxybenzyl)amino]salicylates. Comparison of the imino and amino series by molecular modeling techniques provides further evidence in support of the hypothesis that the important reduced linking chain, CH2NH, allows the correct positioning of the 2,5-dihydroxybenzyl ring, possibly in a cis-like conformational arrangement.

Aminosalicylic Acids↗
PubMed1993

Identification of the SH3 domain of GAP as an essential sequence for Ras-GAP-mediated signaling.

Guanosine triphosphatase activating protein (GAP) is an essential component of Ras signaling pathways. GAP functions in different cell types as a deactivator and a transmitter of cellular Ras signals. A domain (amino acids 275 to 351) encompassing the Src homology region 3 (SH3) of GAP was found to be essential for GAP signaling. A monoclonal antibody was used to block germinal vesicle breakdown (GVBD) induced by the oncogenic protein Ha-ras Lys12 in Xenopus oocytes. The monoclonal antibody, which was found to recognize the peptide containing amino acids 275 to 351 within the amino-terminal domain of GAP, did not modify the stimulation of the Ha-Ras-GTPase by GAP. Injection of peptides corresponding to amino acids 275 to 351 and 317 to 326 blocked GVBD induced by insulin or by Ha-Ras Lys12 but not that induced by progesterone. These findings confirm that GAP is an effector for Ras in Xenopus oocytes and that the SH3 domain is essential for signal transduction.

Amino Acid Sequence↗
PubMed1993

[Neural sarcoidosis in children. A case report].

A case of cerebral sarcoidosis of fortuitous discovery is reported in an adolescent. Neurosarcoidosis is exceedingly rare in the pediatric age groups. Clinical manifestations are widely variable and nonspecific, making diagnosis difficult in patients without extraneurologic involvement. The mainstay of management is early, prolonged corticosteroid therapy. Outcome varies with location of the lesions.

Adolescent↗
PubMed1992

Evidence for a common network of brain structures involved in parkinsonian tremor and voluntary repetitive movement.

Repeated measurements of regional cerebral blood flow (rCBF) were obtained in 7 patients who underwent a stereotactic thalamic electrode implantation in the nucleus ventralis intermedius (nVIM) of the thalamus for severe hemi-parkinsonian tremor. Using positron emission tomography and oxygen-15 labelled water, rCBF was studied in each patient in two conditions: in absence of tremor, e.g. under nVIM electrical stimulation, and in presence of tremor. X-ray tomograms permitted individual definition of anatomical regions of interest. In presence of tremor, normalized rCBF increases were observed in the following regions: postcentral (13.6 +/- 8.4%, P = 0.0003), precentral (7.7 +/- 8.8%, P = 0.016), paracentral (7.7 +/- 8.4%), supplementary motor (8.2 +/- 10.4%, P = 0.025), caudate nucleus (5.7 +/- 7.6%, P = 0.03), vermis (9.7 +/- 7.3%, P = 0.007), cerebellar grey nuclei (9 +/- 6%, P = 0.016) on the electrode side and on the contralateral vermis (17.8 +/- 7.5%, P = 0.0003) and cerebellar grey nuclei (22 +/- 6.3%, P = 0.0004). These results clearly indicate an activation of the sensory-motor cortex, as well as an involvement of the supplementary motor area and the cortico-cerebellar pathways in Parkinsonian resting tremor (PRT). They demonstrate that PRT shares common network of brain structures with repetitive voluntary movement.

Aged↗
PubMed1992

Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus.

The authors report on the long-term results of chronic stereotactic stimulation of the ventralis intermedius thalamic nucleus performed in 14 cases of disabling and intractable tremor. There were 10 patients with parkinsonian tremor and four with essential tremor. Three of the 10 parkinsonian patients had previously undergone contralateral thalamotomy. Tremor was assessed by clinical evaluation, surface electromyography, accelerometer, and videotape recordings before and after stimulation. The deep-brain electrode was implanted in the ventralis intermedius nucleus according to stereotactic procedure and connected to a subcutaneous pulse generator after a stimulation test period. Tremor suppression or reduction was obtained in all cases with high-frequency (130 Hz) stimulation. Marked functional improvement was maintained in 11 patients with a mean follow-up interval of 17 months. Levodopa-induced dyskinesias observed in five parkinsonian patients prior to surgery were improved or suppressed in four cases by thalamic stimulation. Stimulation was continued during the day and stopped at night in eight cases. Six patients were stimulated night and day to avoid a rebound effect which appeared as soon as the pulse generator was stopped. The only side effects were hand tonic posture in one case and persistent paresthesia in another case. The mechanism of action of this attractive treatment may be a functional alteration of the thalamic discharging area. The authors conclude that this technique is a good alternative to thalamotomy, especially when the risks of high-frequency coagulation are severe in frail and older patients.

Adult↗
PubMed1992

Claims payment issues: an HMO perspective.

One of the primary objectives of a complete healthcare delivery system is to provide appropriate and timely payment to providers. One major health maintenance organization (HMO) meets that objective by refining database management, fee uniformity, and electronic claims submission.

Health Maintenance Organizations↗