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S Suarez

Publications and source records attributed to S Suarez.

At least 19 recordsLinked to original sources
PubMed2001

Signalling properties of an HIV-encoded angiogenic peptide mimicking vascular endothelial growth factor activity.

HIV-1 expresses a multifunctional protein called TAT (trans-acting transcriptional activator), the function of which in vivo is tightly correlated with the incidence of Kaposi's sarcoma in AIDS patients. TAT is angiogenic and apparently binds to receptors specific for vascular endothelial growth factor (VEGF). Amino acids 46-60 of HIV-TAT, known as the basic peptide, have been shown to be responsible for its functional interaction with VEGF receptors. To characterize further the binding properties of this peptide, its coding sequence was fused to the reading frame of bacterial thioredoxin, allowing the production of large amounts of chimaeric polypeptides in bacteria in a biologically active form. Binding of chimaeric proteins to VEGF receptors was studied in vitro in endothelial cell cultures expressing either of the two receptors. Chimaeric thioredoxin proteins carrying the basic domain of TAT bound to both VEGF receptors with affinities similar to those of HIV-TAT or VEGF. Interestingly, these polypeptides competed only partially with VEGF for receptor binding, implying different binding sites for the TAT peptide and VEGF. This suggests that TAT binds VEGF receptors at new sites that might be useful targets for pharmacological intervention during pathological angiogenesis. The thioredoxin/basic-peptide chimaeras are functional agonists that mediate VEGF receptor signalling: (1) they stimulate the growth of endothelial cells; (2) together with basic fibroblast growth factor they cause tube formation of endothelial cells in collagen gels; (3) they induce blood vessel formation on the chicken chorioallantoic membrane; and (4) they activate VEGF receptor kinase and mitogen-activated protein kinase activity.

Animals↗
PubMed2001

Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy.

OBJECTIVE: To examine the impact of highly active antiretroviral therapy (HAART) on the outcome of HIV-1-related cognitive impairments using a neuropsychological (NP) battery to assess separately the psychomotor, executive function and memory fields. DESIGN: A longitudinal study of HIV-1-infected patients based on serial NP tests in a Paris University Hospital. METHODS: A group of 91 HIV-1-infected patients, of whom 47 were already taking HAART at their first NP examination, were initially categorized as cognitively impaired (n = 53) or non-impaired (n = 38) and underwent one to six serial NP batteries (mean follow-up 12.3+/-8.3 months). Generalized estimating equations (GEE) were used to evaluate performance in a given NP test according to the number of days on HAART. RESULTS: Despite a 25% mortality rate among patients who had cognitive impairment at their first NP examination, GEE showed a positive relationship between the duration of HAART and cognitive performance. Performance in psychomotor tests (e.g. Purdue Pegboard dominant hand) improved continuously during the study period, while memory test performance (e.g. Grober and Buschke free recall) tended to reach a plateau. CONCLUSIONS: HAART improves subcortical cognitive functions during the first year of treatment. Distinct neuropathological mechanisms appear to underlie psychomotor and memory dysfunctions in AIDS.

Adult↗
PubMed2001

Clinical and spectroscopic improvement in HIV-associated cognitive impairment.

To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.

AIDS Dementia Complex↗
PubMed2001

Pharmacokinetics and pharmacodynamics of dexamethasone sodium-m-sulfobenzoate (DS) after intravenous and intramuscular administration: a comparison with dexamethasone phosphate (DP).

The pharmacokinetics (PK) and pharmacodynamics (effects on blood lymphocytes) of dexamethasone (D) after intravenous (i.v.) administration of dexamethasone phosphate (DP, 10 mg, equivalent to 8.3 mg of dexamethasone) and after intravenous and intramuscular (i.m.) administration of dexamethasone sulfobenzoate sodium (DS, 9.15 mg, equivalent to 6 mg of dexamethasone) were assessed. Only 25% of DS was converted into dexamethasone with a half-life for DS of 5.4 hours and 7.4 hours after i.v. and i.m. administration, respectively. Consequently, the mean residence time of D after both i.m. and i.v. administration of DS (10.4-11.6 h) was longer than that after DP administration (6.1 h). The smaller lymphocyte suppression induced by DS (50% of that after DP administration) was shown to be related to differences in the pharmacokinetics. This study revealed significant differences in the pharmacokinetics of D after administration of DS and DP and stresses the importance of the prodrug for the pharmacological response. Because of the slow and incomplete conversion of DS into dexamethasone, its use in emergency medicine situations should be critically evaluated.

Adult↗
PubMed2001

VEGF transiently disrupts gap junctional communication in endothelial cells.

Vascular endothelial growth factor, VEGF, stimulates angiogenesis by directly acting on endothelial cells. The effects of VEGF are mediated by two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR) that are highly related to receptors of the platelet derived growth factor (PDGF) receptor family. We are interested in early signalling events downstream from VEGF receptors that affect blood vessel homeostasis. Endothelial cells form multiple types of cell-cell junctions that are required for cellular organization into complex networks. These junctions also regulate communication among adjacent cells. Stimulation by various growth factors such as epidermal growth factor (EGF) or PDGF has been shown to disrupt cell-cell junctions, consequently affecting cell-to-cell communication. We investigated gap junctional communication (GJC) by monitoring the transfer of a low molecular mass fluorescent tracer molecule between adjacent cells using immunofluorescence microscopy. VEGF maximally blocked GJC 15 minutes after growth factor administration. The cells resumed communication via gap junctions within 1-2 hours after treatment. This early effect of VEGF on communication correlated with changes in the phosphorylation state of one of the proteins involved in gap junction formation, connexin 43 (Cx43). The signalling mechanisms involved in this phenomenon depend on activation of VEGFR-2, impinge on a tyrosine kinase of the Src family and activate the Erk family of MAP kinases. The function of VEGF-mediated disruption of GJC might be to restrict an increase in endothelium permeability to the environment affected by local injury to blood vessels.

CSK Tyrosine-Protein Kinase↗
PubMed2000

Drug properties affecting aerosol behavior.

The widespread use of aerosol therapy in the treatment of pulmonary diseases is based on optimizing drug properties and aerodynamic behavior of airborne particulates. In order to understand drug properties and aerodynamic behavior, it is important to recognize that each category of inhaler delivers a product with different physicochemical characteristics, and that these properties determine the site of deposition and the mechanism of clearance from the lungs. The complex interplay of these properties and the physiology and anatomy of the lungs must be considered to fully understand the implications for drug delivery. The aerodynamic behavior of aerosols under various inspiratory flow conditions influences the site of deposition. Once the particle comes to rest in the lungs, mechanisms of clearance are invoked, including dissolution and absorption, or, for more insoluble materials, mucociliary transport or cell-mediated transport. Finally the pharmacokinetics of drug disposition dictate the pharmacodynamic effects of the drugs responsible for efficacy.

Absorption↗
PubMed1999

Selective GRB2 SH2 inhibitors as anti-Ras therapy.

Given the key role of Ras in the mitogenic signaling by receptor tyrosine kinases, several targets upstream of Ras may prove to be excellent targets for drugs in the treatment of cancer caused by oncogenic tyrosine kinases. CGP78850 is a potent competitor of Grb2 SH2-phosphopeptide interactions. This inhibitor has been obtained by rational drug design and is specific toward the Grb2 SH2 vs. other SH2 domains and the PTB domain of SHC in vitro. Accordingly, CGP78850 blocks epidermal growth factor receptor (EGFR)-Grb2 and Shc-Grb2 interactions in living cells. It also inhibits the growth of cells transformed by receptor tyrosine kinases, which transmit a proliferative signal through Grb2 to Ras, but not cells transformed by oncogenic Raf or cells that contain activating Ras mutations. Moreover, our results demonstrate that, in cells overexpressing receptor tyrosine kinases, such as the EGFR, Grb2 SH2 inhibitors induce expression of the cell cycle inhibitors p21(Waf1/Cip1/CAP1) and p27(Kip1) and reverse transformation.

3T3 Cells↗
PubMed1999

Effect of potent and selective inhibitors of the Grb2 SH2 domain on cell motility.

Cell motility has been correlated both with oncogenic invasiveness and metastatic potential. The development of selective inhibitors of motility has thus great potential importance. Grb2 is a SH2/SH3 domain-containing adaptor protein that links growth factor receptor tyrosine kinases to the Ras signaling pathway. We have developed specific small molecule inhibitors of the Grb2 SH2 domain as potential leads for drug discovery. Synthesis of the inhibitors and their effects on growth factor-induced growth in cells have been reported previously. In the current study, we establish that these inhibitors inhibit hepatocyte growth factor/scatter factor-induced A431 and Madin-Darby canine kidney cell motility and various cell motility-related events, including epidermal growth factor-induced ruffling of A431 cells and epidermal growth factor-induced translocation of the small GTPase Rac in these cells. We demonstrate for the first time a direct role for Grb2 in cell motility and indicate a new avenue for cancer therapeutics.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Plasma and cerebrospinal fluid human immunodeficiency virus type-1 (HIV-1) RNA levels in HIV-related cognitive impairment.

Cerebrospinal fluid (CSF) and plasma HIV-1 RNA levels were prospectively measured by the Roche Amplicor Monitor polymerase chain reaction assay in 30 HIV-1 infected patients without central nervous system opportunistic infections. All participants completed a global neuropsychological battery consisting of Mattis Dementia Rating Scale. Additional tests were used to better characterize the type of cognitive changes with a specific reference to frontal lobe function. The neuropsychological evaluation confirmed the subcortical pattern of cognitive dysfunction. CSF and plasma HIV-1 RNA levels were significantly correlated. No correlation was detected with either blood or CSF RNA levels and the global cognitive status, but when stratified in three cognitive subgroups, higher CSF HIV-1 RNA levels were observed in the more cognitively impaired subjects. Our results provide further evidence that plasma and CSF HIV-1 RNA level cannot be used as a reliable diagnostic marker for HIV-1 associated cognitive disorders. Only longitudinal studies will determine whether a high CSF HIV-1 level could be a risk factor for HIV-1 dementia.

AIDS Dementia Complex↗
PubMed1999

Vascular endothelial growth factor (VEGF) and its receptors in tumor-bearing dogs.

The molecular biology of the angiogenic growth factor, vascular endothelial growth factor (VEGF), has been studied in the dog. All major isoforms of VEGF are present in the dog. The amino acid sequences are identical between human and dog in the loop regions that are responsible for receptor binding. Accordingly, the VEGF receptors of dogs and humans are very similar and permit functional exchange of the growth factor. Here we show that canine VEGF activates human endothelial cells to the same extent as human VEGF. Similarly, the two proteins display identical cell binding properties. The VEGF receptor 1 (Flt-1) shows the same alternative splicing in humans and dogs and is overexpressed in the majority of tumors in both species. VEGF occurs also in canine tumors in similar relative quantities as in human malignancies. Based on the literature and our study we suggest that the molecular biology and the function of the VEGF signaling system are virtually identical in humans and canines and in healthy as well as in disease conditions.

Alternative Splicing↗
PubMed1999

[Fronto-temporal degenerative dementia. A modern neuropathologic approach].

The classification of degenerative dementias with fronto-temporal atrophy has been debated since the description of Pick's disease. The study of a clinico-pathological series of 10 cases using immunohistochemistry lead to the following conclusions: reserving the name of Pick's disease to those cases with argyrophilic inclusions, the most recognisable and characteristic marker at neuropathological examination, allows an easy and reliable diagnosis; keeping on with the splitting of these disorders into various clinico-pathologic entities seems today more useful than grouping them into a single syndrome until new data, based for example on genetic analysis, show that different phenotypes correspond to the same disease.

Adult↗
PubMed1998

Binding characteristics of purified Escherichia coli K88ab fimbriae to guinea pig erythrocyte membrane.

The characteristics of the binding of biotinylated E. coli K88ab fimbriae to guinea pig erythrocyte membranes, as a possible model of the target host cell were studied. Binding showed sigmoidal dependence, with an apparent saturation at about 0.8 ng of fimbriae. Hill coefficient values (h) were about 2-2.4, which indicated that the receptor population showed positive cooperativity with at least three binding sites. Apparent binding constants to the first and third binding sites (1K3 and 3K3) were determined. Three K88ab binding proteins, of 67, 63 and 48 kDa, were identified on solubilized erythrocyte membranes and were recovered mainly in a detergent phase, suggesting a possible integral localization of the receptors.

Adhesins, Bacterial↗
PubMed1998

Pediatric antifungal therapy.

The most common superficial dermatophyte infections in children involve the scalp, skin, and nails. Griseofulvin has traditionally served as the standard of care for scalp and nail infections, but an increasing proportion of tinea capitis infections are proving refractory or very slowly responsive to treatment. This article will review new antifungal therapies available and their future role in the treatment of pediatric dermatophyte infections. As these new agents are not yet FDA approved for use in the pediatric dermatophyte infections, the practitioner must be aware of possible risks and benefits of such drugs, and counsel families appropriately regarding "off-label" use.

Antifungal Agents↗
PubMed1998

Effect of dose and release rate on pulmonary targeting of liposomal triamcinolone acetonide phosphate.

PURPOSE: To demonstrate the importance of dose and drug release rate for pulmonary targeting of inhaled glucocorticoids using an animal model of intrapulmonary drug deposition. METHODS: Liposomes composed of 1,2-distearoyl phosphatidylcholine (DSPC), 1,2-distearoyl phosphatidylglycerol (DSPG) and triamcinolone acetonide phosphate (TAP) or liposomes containing triamcinolone acetonide (TA) were prepared by a mechanical dispersion method followed by extrusion through polycarbonate membranes. Encapsulation efficiency was assessed after size exclusion gel chromatography by reverse phase HPLC. The effect of liposome size (200 nm and 800 nm) on the release kinetics of water-soluble encapsulated material was determined in vitro at 37 degrees C using 6-carboxyfluorescein as a marker and Triton X-100 (0.03%) as a leakage inducer. To investigate the relationship between drug release and pulmonary targeting, 100 micrograms/kg of TAP in 800 nm liposomes was delivered to male rats by intratracheal instillation (IT) and the results compared to data for 100 micrograms/kg TA liposomes (recently shown to exhibit a rapid drug release under sink conditions) and to previous studies reported for an equal dose of TAP in solution and TAP in 200 nm (1). Pulmonary targeting was assessed by simultaneously monitoring glucocorticoid receptor occupancy over time in lung and liver using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. To assess the effect of dose on pulmonary targeting experiments were performed using 2.5, 7.5, 25, 100, and 450 micrograms/kg of TAP in 800 nm liposomes. RESULTS: The in vitro efflux of 6-carboxyfluorescein from (DSPC:DSPG) liposomes after exposure to Triton-X was biexponential. The terminal half-lives of 3.7 h and 9.0 h for the 200 nm and 800 nm liposomes, respectively, demonstrated that larger liposomes promote slower release of encapsulated water-soluble solute while previous results already indicated that encapsulation of lipophilic TA does not result in sustained release. Pulmonary targeting, defined as the difference between cumulative lin and liver receptor occupancies was most pronounced for the 800 nm liposomes (370%xh), followed by the 200 nm preparation (150%xh). No targeting was observed for TAP in solution (30%xh) or the rapid releasing TA liposome preparation. Correspondingly, the mean pulmonary effect time (MET) increased from 2.4-3.0 hr for TA liposomes or TAO in solution to 5.7 h and > 6.2 h for TAP in 200 nm and in 800 nm liposomes, respectively. Escalating doses of TAP encapsulated in 800 nm liposomes revealed a distinct bell shaped relationship between the TAP dose and pulmonary targeting with a maximum occurring at 100 micrograms/kg (370%xh). CONCLUSIONS: The in vivo data presented here confirm that pulmonary residence time and dose affect the extent of lung targeting of glucocorticoids delivered via the lung.

Animals↗
PubMed1998

[Diseases transmitted by non-conventional agents ("prions"): nosology and diagnosis].

Transmissible non conventional agents are currently called "Prions". This is not a neutral terminology: the attractive Prion hypothesis (the infectious agent being a protein able to replicate in the absence of DNA or RNA) due to Stanley Prusiner is the prevalent one, and has shown to be heuristic, but has not been formally proven and does not easily explain all the data, unless modified and expanded. No simple account has been given for the very unusual physical, chemical, and biological properties of non conventional agents. These infectious agents are associated with degenerative diseases of the nervous system that are either the consequence of a genetic mutation or develop spontaneously in apparently normal individuals, and then can be transmitted to various susceptible hosts, including man. Thus, non conventional agents cannot be considered only as fascinating biological enigmas. They constitute a challenge for public health. The changing characteristics of prion-associated diseases has led to a renewing of their clinical and neuropathological diagnostic criteria. A brief survey of the nosology and neuropathology of prions diseases, with emphasis on new data and on difficulties, is provided. A simple classification based on the familial, sporadic or infectious variety of the disease is suggested. Familial diseases can be named according to the genetic disorder. Sporadic and infectious diseases can be classified following the main clinical symptoms and signs, and the presence or absence of amyloid plaques in the brain, until new tools (analysis of the glycosylation pattern of PrP, strain recognition) allow a more precise nomenclature. The new epidemiology of Prion disorders allowed by these new approaches relies on a full study of Prion diseases affected patients, which necessarily involves their genetic study, and the analysis of brain tissue. This, for practical and ethical reasons, is better achieved by autopsy.

Diagnosis, Differential↗
PubMed1998

[Memory: clinico-pathologic data].

Synaptic modifications are probably the basis of the memory processes that take place in the central nervous system. They have been studied in Aplysia or in hippocampal slices. How these minute alterations of the synaptic strength are integrated in larger neural systems is still poorly understood. In man, hippocampal lesions, when bilateral, cause a deficit in anterograde episodic memory. The loss of previously acquired memories (retrograde amnesia) is limited. Procedural memory is spared. Young patients with hippocampal lesions remain able to learn how to read or to write (abilities that belong to semantic memories). Recordings obtained with intracerebral electrodes have shown that some neurons of the hippocampus act as "place cells". They fire when the animal is in a specific place of the experimental maze, an observation that suggests that the hippocampus acts as a map that may also be viewed as a context indicator (a "cognitive map"). Computer models have been devised to test the hypothesis that the hippocampus recorded the map of the activated synapses at a particular moment in time. This pattern of activity could secondarily be transferred to the isocortex during a process known as consolidation. The frontal lobe plays a role in attention, which greatly influences the memory process. It also plays a role in the various strategies that are used to recall a memory and in the analysis of the quality of the recall (metamemory). An asymmetry has been shown by the PET-scan: the left frontal lobe is activated during acquisition, and the right one during recall. The ability to integrate one's own memories in one's own history and consciousness (self-awareness or "autonoesis") also depends on the activity of the prefrontal region. The loss of acquired memories (retrograde amnesia) is most often observed in cases of large lesions of the anterior part of the temporal lobe. Partial amnesias are difficult to separate from possibly localized deficits of a cognitive function (some types of aphasia may be considered as an amnesia of words). Subcortical amnesias are caused by diencephalic lesions; the topography of the critical structures is still discussed: mamillary bodies and mamillo-thalamic tract or dorsomedial nucleus of the thalamus. The amygdaloid nucleus, the frontal lobe and the dorsomedial nucleus of the thalamus belong to a network of connections that could be involved in emotions. It could be responsible for the emotional flavor of a memory. Basal ganglia could play a role in procedural memory, but experimental or clinicopathological confirmations are still scarce. Finally, the involvement of the cholinergic innervation in the memory processes has been discussed: it could be direct, or according to more recent data, related to its role in attention.

Amnesia↗