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Biomedical subjects

M Garcia

Publications and source records attributed to M Garcia.

At least 127 records · Page 7Linked to original sources
PubMed1997

Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo.

The voltage activated K+ channel (Kv1.3) has recently been identified as the molecule that sets the resting membrane potential of peripheral human T lymphoid cells. In vitro studies indicate that blockage of Kv1.3 inhibits T cell activation, suggesting that Kv1.3 may be a target for immunosuppression. However, despite the in vitro evidence, there has been no in vivo demonstration that blockade of Kv1.3 will attenuate an immune response. The difficulty is due to species differences, as the channel does not set the membrane potential in rodent peripheral T cells. In this study, we show that the channel is present on peripheral T cells of miniswine. Using the peptidyl Kv1.3 inhibitor, margatoxin, we demonstrate that Kv1.3 also regulates the resting membrane potential, and that blockade of Kv1.3 inhibits, in vivo, both a delayed-type hypersensitivity reaction and an Ab response to an allogeneic challenge. In addition, prolonged Kv1.3 blockade causes reduced thymic cellularity and inhibits the thymic development of T cell subsets. These results provide in vivo evidence that Kv1.3 is a novel target for immunomodulation.

Animals↗
PubMed1997

Increased cathepsin D level in the serum of patients with metastatic breast carcinoma detected with a specific pro-cathepsin D immunoassay.

BACKGROUND: An increased cathepsin D (cath-D) level in breast carcinoma cytosol has been proposed as a prognostic parameter. However, no increase had been previously detected in serum when assaying total cath-D concentration. METHODS: The authors compared 2 radioimmunoassays of total cath-D and pro-cath-D in the serum of 3 groups of patients: those with metastatic breast carcinomas (n = 30), those with nonmetastatic breast carcinomas (n = 24), and healthy women (n = 21). RESULTS: There was a significant increase of total cath-D and pro-cath-D in the serum of 18 of the 30 patients with metastatic breast carcinoma. No increase was observed in any of the patients with nonmetastatic disease compared with healthy women. Moreover, the level of pro-cath-D was often superior to that of total cath-D in the same patients, suggesting that the total cath-D assay in serum underestimates the actual concentration of pro-cath-D. This is not believed to be due to the masking of cath-D with the circulating mannose-6-phosphate/insulin-like growth factor II receptor because the purified receptor did not interfere in the binding of the monoclonal antibodies used in the assay to cath-D. CONCLUSIONS: An increased level of cath-D in the serum of breast carcinoma patients is a late event observed only in patients with metastatic disease. This increased circulating level is more likely due to increased secretion of the proenzyme rather than to tumor cell lysis.

Adult↗
PubMed1997

A truncated RAR alpha co-operates with the v-erbB oncogene to transform early haematopoietic progenitors in vitro and in vivo.

We have shown recently that a retrovirus vector expressing a natural mutant form of the PML-RAR alpha protein characteristic of human acute promyelocytic leukaemia can transform early chicken hematopoietic progenitors (Altabef et al., 1996). Neither truncated PML nor truncated RAR alpha alone could induce transformation which suggest that the two domains should cooperate for the oncogenicity of the fusion product. To further investigate the mechanisms of this co-operation, we have tested whether a truncated RAR alpha could cooperate with the v-erbB oncogene. This oncogene has previously been shown to co-operate with the rearranged thyroid hormone receptor, v-erbA, to transform erythrocytic progenitors. We show that v-erbB and a truncated RAR alpha co-operate when expressed simultaneously as independent products to transform very early chicken haematopoietic cells close to pluripotent stage. In addition, we show that v-erbB alters transcriptional abilities of RAR alpha by both enhancing its effects on RARE and reducing those on AP-1. Therefore, RAR alpha is able to co-operate with different kinds of proteins to induce transformation of early haematopoietic cells. This strongly suggests that RAR alpha are involved in the differentiation commitment of early haematopoietic progenitors during the normal process of haematopoietic differentiation. These data bring new insights in the mechanisms of oncogenic transformation by rearranged RAR alpha.

Animals↗
PubMed1997

Radiation and speciation of spider monkeys, genus Ateles, from the cytogenetic viewpoint.

The chromosomes of 22 animals of four subspecies of the genes Ateles (A. paniscus paniscus, A. p. chamek, A. belzebuth hybridus, and A. b. marginatus) were compared using G/C banding and NOR (nucleolar organizer region) staining methods. The cytogenetic data of Ateles in the literature were also used to clarify the phylogenetic relationships of the species and subspecies and to infer the routes of radiation and speciation of these taxa. Chromosomes 6 and 7 that showed more informative geographic variation and the apomorphic form 4/12, exclusively in A. p. paniscus, are the keys for understanding the evolution, radiation, and specification of the Ateles taxa. The ancestral populations of the genus originated in the southwestern Amazon Basin (the occurrence area of A. paniscus chamek) and spread in the Amazon Basin and westward, crossing the Andes and colonizing Central America and northwesternmost regions of South America. The evolutionary history of the northern South American taxa is interpreted using the model of biogeographical evolution postulated by Haffer [Science 185:131-137, 1969]. Ateles paniscus paniscus is the genetically most differentiated form and probably derives from A. belzebuth hybridus. Based on the karyotype differences, the populations of Ateles can be divided into four different groups. These findings indicate the necessity of a more coherent taxonomic arrangement for the taxa of Ateles.

Animals↗
PubMed1997

Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata.

The release of [3H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K+ from 6 to 15 mM in the presence of 10 microM sulpiride was inhibited by 73 +/- 3% by 1 microM SCH 23390, consistent with a large component of release dependent upon D1 receptor activation. The histamine H3 receptor-selective agonist immepip (1 microM) and the non-selective agonist histamine (100 microM) inhibited [3H]GABA release by 78 +/- 2 and 80 +/- 2%, respectively. The inhibition by both agonists was reversed by the H3 receptor antagonist thioperamide (1 microM). However, in the presence of 1 microM SCH 23390 depolarization-induced release of [3H]GABA was not significantly decreased by 1 microM immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [3H]GABA, but in the presence of 1 microM SKF 38393, which produced a 7 +/- 1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 microM) also inhibited the depolarization-induced release of [3H]dopamine from substantia nigra pars reticulata slices, by 38 +/- 3%. The evidence is consistent with the proposition that activation of histamine H3 receptors leads to the selective inhibition of the component of depolarization-induced [3H]GABA release in substantia nigra pars reticulata slices which is dependent upon D1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [3H]dopamine release.

Animals↗
PubMed1997

Anomalous branch of the internal carotid artery maintains patency distal to a complete occlusion diagnosed by duplex scan.

A 67-year-old man had symptoms of peripheral vascular disease and was noted to have a carotid bruit. Duplex ultrasound examination of the neck demonstrated a short segmental occlusion of the proximal internal carotid artery (ICA) with antegrade flow distal to the occlusion maintained by an anomalous branch of the ICA. Angiography confirmed the findings and suggested that the branch was from the distribution of the occipital artery. The ICA findings were surgically proved, and endarterectomy was successfully performed without complication. This case reinforces the usefulness of duplex ultrasonography of the carotid arteries and is a rare situation in which a completely occluded ICA can be repaired with a good clinical outcome.

Aged↗
PubMed1997

Both estradiol and tamoxifen decrease proliferation and invasiveness of cancer cells transfected with a mutated estrogen receptor.

Previous studies have shown that, after wild-type estrogen receptor (ER) transfection in ER-negative breast cancer cells, estradiol but not tamoxifen prevents growth, invasiveness and metastasis of these cells in mice. Because an ER mutation at position 400 converts the triphenylethylene antiestrogen, OH-tamoxifen into a full estrogen agonist, we transfected this mutated form of human ER in an ER-negative rat cancer cell line. This was aimed at inducing an inhibitory, estrogen-like response of tamoxifen in these cells. In two stable ER-positive transfectants, OH-tamoxifen inhibited cell growth and invasiveness in vitro as efficiently as estradiol. The pure antiestrogen, ICI 164,384, was not agonistic alone and antagonized estrogen action. In contrast, the three compounds were ineffective in control mock-transfected cells. When injected into ovariectomized nude mice, ER-negative mock-transfected cells formed tumours which were significantly stimulated by estradiol and inhibited by tamoxifen treatment. This indicates that estradiol and tamoxifen altered the growth of ER-negative tumours via a general effect on the host response. Surprisingly, the hormone responsiveness of ER-positive tumours developed from ER-transfected cells did not significantly differ from that of ER-negative (mock-transfected) tumours. We conclude that transfection of a mutated human estrogen receptor inhibited, through an estrogenic activity of tamoxifen, the growth and invasiveness of these cancer cells in vitro. However, the low expression of ER did not allowed us to obtain the same effect of tamoxifen in vivo.

Animals↗
PubMed1997

Impaired intestinal sugar transport in cirrhotic rats: correction by low doses of insulin-like growth factor I.

BACKGROUND & AIMS: Malnutrition is a complication of liver cirrhosis accompanied by reduced insulin-like growth factor I (IGF-I) availability. The aim of this study was to analyze the effect of IGF-I on intestinal D-galactose absorption in cirrhotic rats. METHODS: IGF-I (2 micrograms.100 g body wt-1.day-1) or saline were given for 14 days to rats in whom cirrhosis was induced with CCl4. Galactose transport and sodium-glucose/galactose-ligand transporter 1 (SGLT-1) expression were assessed in jejunal rings and in brush border membrane vesicles (BBMVs). RESULTS: Compared with that in controls, galactose transport in everted jejunal rings was significantly reduced in cirrhotic rats but showed normal values after IGF-I treatment. The kinetic study of D-galactose uptake by BBMVs showed decreased maximal velocity (Vmax) and diminished transporter affinity in cirrhotic rats. These kinetic parameters reverted to normal after IGF-I treatment. Microvilli were significantly elongated in cirrhotic rats but of normal size in the IGF-I-treated group. The expression of SGLT-1 on BBMVs (Western blot) and on the luminal membrane of enterocytes (immunohistochemistry) was not reduced in cirrhotic animals compared with controls or IGF-treated cirrhotic rats. CONCLUSIONS: Intestinal sugar transport is disturbed in experimental cirrhosis, and this alteration is corrected by IGF-I.

Alanine Transaminase↗
PubMed1997

Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis.

BACKGROUND & AIMS: Bioavailability of insulin-like growth factor (IGF-I) is reduced in liver cirrhosis. The aim of this study was to analyze the effect of IGF-I on liver histopathology and function in experimental cirrhosis. METHODS: Rats received CCl4 inhalations for 11 or 30 weeks (protocols 1 and 2, respectively) and were treated with 2 microg x 100 g body wt(-1) x day(-1) IGF-I (group CI + IGF) or saline (group CI) on weeks 13 and 14 (protocol 1) or on weeks 28-30 (protocol 2). Normal rats were studied in parallel. RESULTS: Serum albumin and total protein levels were reduced in CI but not in CI + IGF rats compared with normal rats. Clotting factors II, VII, and X were significantly greater in CI + IGF than in CI rats. Liver lipid peroxidation products were significantly increased in CI but not in CI + IGF rats, and liver fibrosis was less pronounced in CI + IGF than in CI animals. The activities of antioxidant enzymes and mitochondrial transmembrane potential were reduced compared with normal animals in CI but not in CI + IGF rats. CONCLUSIONS: IGF-I improves liver function and reduces oxidative liver damage and fibrosis in rats with compensated or advanced liver cirrhosis. Improved mitochondrial function could play a role in the hepatoprotective effect of this hormone.

Animals↗
PubMed1997

An epidural abscess due to resistant Staphylococcus aureus following epidural catheterisation.

We report a case of abscess formation after epidural analgesia, a rare complication that developed in our patient 13 days after placement of a thoracic epidural catheter for patient controlled analgesia. Culture of the pus grew methicillin-resistant Staphylococcus aureus. Although early diagnosis and rapid management have been reported to yield a satisfactory outcome, the case we describe ended in severe sequelae.

Abscess↗
PubMed1997

NodV and NodW, a second flavonoid recognition system regulating nod gene expression in Bradyrhizobium japonicum.

In Bradyrhizobium japonicum, members of two global regulatory families, a LysR-type regulator, NodD1, and a two-component regulatory system, NodVW, positively regulate nod gene expression in response to plant-produced isoflavone signals. By analogy to other two-component systems, NodV and NodW are thought to activate transcription via a series of phosphorylation steps. These include the phosphorylation of NodV in response to the plant signal and the subsequent activation of NodW via the transfer of the phosphoryl group to an aspartate residue in the receiver domain of NodW. In this study, we demonstrated that NodW can be phosphorylated in vitro by both acetyl phosphate and its cognate kinase, NodV. In addition, in vivo experiments indicate that phosphorylation is induced by genistein, a known isoflavone nod gene inducer in B. japonicum. By using site-directed mutagenesis, a NodWD70N mutant in which the aspartate residue at the proposed phosphorylation site was converted to an asparagine residue was generated. This mutant was not phosphorylated in either in vitro or in vivo assays. Comparisons of the biological activity of both the wild-type and mutant proteins indicate that phosphorylation of NodW is essential for the ability of NodW to activate nod gene expression.

Bacterial Proteins↗
PubMed1997

Graves' disease triggered by autoinfarction of an autonomously functioning thyroid adenoma.

A patient whose nontoxic autonomously functioning thyroid adenoma had been stable for at least 3 yr developed enlargement of the nodule and hyperthyroidism. It was assumed the hyperthyroidism was caused by evolving toxicity in the autonomous adenoma, but imaging showed the nodule had undergone infarction and the hyperthyroidism was secondary to Graves' disease. This case demonstrates the necessity of thyroid imaging in patients with nontoxic autonomously functioning thyroid adenomas when there is a change in nodule size or thyroid function which requires treatment.

Adenoma↗
PubMed1996

Self-Association of Phenothiazine Drugs: Influence of the Counterion on the Mode of Association

The association characteristics of the phenothiazine drug trimeprazine tartrate in water and aqueous electrolyte solution have been examined using static and dynamic light scattering techniques and compared with those reported for the structurally related drug promethazine hydrochloride, to identify differences in association pattern arising from differences in the counterions of the two drugs. The association of trimeprazine tartrate was micellar in water and in the presence of added electrolyte. A progressive increase of aggregation number and micellar radius was observed with increase of sodium chloride concentration over the range 0.05 to 0.60 M NaCl. This behavior is in contrast to that of promethazine hydrochloride which exhibits continuous association above the critical concentration in electrolyte of concentrations >/=0.2 M NaCl. Moreover, static light scattering curves for trimeprazine tartrate showed a single discontinuity corresponding to the onset of micellization, whereas the association behavior of promethazine hydrochloride (and other phenothiazine drugs with chloride counterions), in water and dilute electrolyte (0.05-0.1 M NaCl), is complex, with discontinuities in solution properties at several critical concentrations. The results of this study highlight the influence of the counterion on the association characteristics of this class of amphiphile.

Journal Article↗
PubMed1996

Glycosylated human growth hormone (hGH): a novel 24 kDa hGH-N variant.

We have identified a human pituitary protein as a novel glycosylated variant of hGH. Isolation of the denatured protein included separation of human pituitary extract by Sephadex G-100 chromatography in ammonium bicarbonate, followed by Sephadex G-100 chromatography in 10% acetic acid, with subsequent DEAE Sephacryl chromatography in ammonium bicarbonate, and finally by preparative SDS PAGE. The pituitary protein has a molecular weight of 24 kDa as determined by SDS PAGE analysis and is thus larger than the normal 22 kDa hGH. N-Terminal amino acid sequence analysis of the first twenty-six residues reveals that this protein is not derived from the hGH-V gene but is rather a hGH-N gene product. Assays for the detection of glycoconjugates (periodate oxidation, sialidase treatment, trifluoromethanesulfonic acid treatment) indicate that the hGH variant has carbohydrate moieties. The discovery of new hGH raises questions about the role of glycosylation in the structure/function relationships of this hormone.

Amino Acid Sequence↗
PubMed1996

Effect of X-rays on germ cells in female fetuses of Rattus norvegicus irradiated at three different times of gestation.

We analyzed the effect of X-rays on the number of recoverable germ cells in female rat fetuses irradiated at three different times of gestation: 14 days (oogonia), 16 days (leptotene) and 18 days (zygotene). Our results show that irradiation significantly decreases the number of germ cells, and increases the incidence of synaptonemal complex fragmentation. The different sensitivity of the germ cells to irradiation could depend on the meiotic stage at the time of irradiation.

Animals↗
PubMed1996

A retrovirus carrying the promyelocyte-retinoic acid receptor PML-RARalpha fusion gene transforms haematopoietic progenitors in vitro and induces acute leukaemias.

The promyelocyte (PML)-retinoic acid receptor alpha (RARalpha) fusion gene results from a t(15;17) chromosome translocation in acute promyelocytic leukaemia. We have analysed the oncogenic potential of the human fusion PML-RARalpha product in chicken using retrovirus vectors. We show that PML-RARalpha transforms very early haematopoietic progenitor cells in vitro and induces acute leukaemias. Neither PML nor RARalpha domains alone achieve such a transformation. The PML-RARalpha viruses recovered from the transformed cells carry two point mutations in the PML domain, one of which alters both the pattern of intracellular localization of the fusion protein and its functional interference with AP-1, thus defining an essential domain in PML for oncogenic transformation.

Acute Disease↗