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Biomedical subjects

T Costa

Publications and source records attributed to T Costa.

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

X linked spondyloepiphyseal dysplasia: a clinical, radiological, and molecular study of a large kindred.

X linked spondyloepiphyseal dysplasia (SEDT) is a rare disorder characterised by disproportionate short stature and degenerative changes in the spine and hips. We report a large kindred with 11 affected males and 17 obligate carrier females. We examined clinically and radiographically the seven living affected males and obtained detailed historical information on the four dead. The natural history was characterised by normal growth until late childhood. Decreased growth velocity was the earliest detectable abnormality. In adulthood, four subjects required hip replacements but disability was minimal. Clinical examinations showed a characteristic habitus with short stature (> 2 SD below the mean) and a decreased upper segment to lower segment ratio (> 1 SD below the mean) in all affected subjects. Also noted were scoliosis (6/7), and decreased range of hip rotation (6/7), and decreased range of movement of the lumbar spine (4/7). Radiographic evaluations were available on nine subjects. Radiographic changes were evident in two patients in childhood; findings in adulthood included narrow disc spaces (8/9), platyspondyly (7/9), the characteristic central and posterior hump of the vertebral bodies (6/9), bony spurs (7/ 8), and pelvic abnormalities (7/9). We also systematically evaluated eight obligate carrier females. They could not be distinguished from the general population on clinical and radiographic findings. Linkage analysis showed significant linkage with markers on Xp22, as previously reported. A recombinant event between DXS43 and DXS207 places the locus distal to DXS43.

Adolescent↗
PubMed1995

Interferon-gamma and lipopolysaccharide reduce cAMP responses in cultured glial cells: reversal by a type IV phosphodiesterase inhibitor.

The aim of the present study was to determine whether two classical macrophage activators, bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) could affect the accumulation of the second messenger cAMP in cultured rat microglia and astrocytes. Purified microglia and astrocyte secondary cultures obtained from the neonatal rat were grown for 3 days in basal medium Eagle (BME) + 10% fetal calf serum (FCS). Exposure of microglia to LPS resulted into a dose- and time-dependent decrease in the accumulation of cAMP induced by receptor-mediated (isoproterenol or prostaglandin E2) or direct (forskolin) activation of adenylate cyclase. The inhibitory effect of LPS was rapid (a 10 min preincubation was sufficient to approach a maximal effect), occurred at low doses (IC50 = 1.2 ng/ml), and was not abrogated by pertussis toxin. A selective inhibitor of type IV phosphodiesterase (rolipram, 100 nM) prevented the effect of LPS on cAMP accumulation, while inhibitors of other forms of phosphodiesterase were unable to do so. IFN-gamma (100 u/ml) also caused a depression of the evoked cAMP accumulation in microglia after a 10 min preincubation, and its effect was prevented by rolipram, as in the case of LPS. Astrocytes differed from microglia in that LPS (1-100 ng/ml) did not inhibit the accumulation of cAMP induced by either isoproterenol or forskolin; on the other hand, IFN-gamma did have an inhibitory effect (though less pronounced than in microglia) that could be prevented by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Molecular analysis redefines three human chromosome 14 deletions.

We have used a panel of 13 DNA markers in the distal region of chromosome 14q to characterize deletions in three patients determined cytogenetically to have a ring or terminally deleted chromosome 14. We have characterized one patient with a ring chromosome 14 [r (14) (p13q32.33)] and two with terminal deletions [del (14) (pter-->q32.3:)]. The two patients with cytogenetically identical terminal deletions of chromosome 14 were found to differ markedly when characterized with molecular markers. In one patient, none of the markers tested were deleted, indicating that the apparent terminal deletion is actually due to either an undetected interstitial deletion or a cryptic translocation event. In the other patient, the deletion was consistent with the cytogenetic observations. The deleted chromosome was shown to be of paternal origin. The long-arm breakpoint of the ring chromosome was mapped to within a 350-kb region of the immunoglobulin heavy chain gene cluster (IGH). This breakpoint was used to localize markers D14S20 and D14S23, previously thought to lie distal to IGH, to a more proximal location. The ring chromosome represents the smallest region of distal monosomy 14q yet reported.

Abnormalities, Multiple↗
PubMed1995

A common FGFR3 gene mutation in hypochondroplasia.

Hypochondroplasia is a genetic disorder of disproportionate short stature. Linkage analysis provisionally placed hypochondroplasia in the chromosome 4p 16.3 region, a location to which the FGFR3 gene has been mapped. The genotyping of a three-generation family showed no recombinants between the hypochondroplasia phenotype and three highly polymorphic markers flanking the FGFR3 gene. Mutation analysis was performed by RT-PCR and direct sequencing. Primers covering most of the coding sequence of the FGFR3 gene were used for RT-PCR of FGFR3 mRNA and PCR amplification of genomic DNA. A C-->A transversion was detected in nucleotide 1659 predicting an N540K substitution in exon 11 which encodes part of the TK1 domain. The same mutation was found in an individual suspected to be an achondroplasia/hypochondroplasia compound phenotype and affected individuals from three other unrelated families. A second mutation, a C-->G transversion, also in nucleotide 1659 was detected in all affected individuals of another family. The latter also predicts an N540K substitution. These findings establish that a common mutation in the FGFR3 gene underlies hypochondroplasia.

Amino Acid Sequence↗
PubMed1995

Human thrombin receptors are insensitive to thrombin-like snake venom enzymes.

Thrombin-like snake venoms enzymes, flavoxobin, and okinaxobin I isolated from Trimeresurus flavoviridis and Trimeresurus okinavensis, respectively, were examined in SH-EP cells and evaluated whether or not they can activate human thrombin receptors. Flavoxobin was almost completely inactive in both assays for phosphoinositide turnover and DNA synthesis. In contrast, okinaxobin I stimulated phosphoinositide turnover in a dose dependent manner, but considerably weakly. The EC50 value was about 100 nM, which was 4,000 times larger than that of alpha-thrombin. This stimulation was not inhibited by hirudin, an effective inhibitor of alpha-thrombin. Okinaxobin I also induced a very weak stimulation of DNA synthesis. These results suggest that thrombin-like snake venom enzymes interact with human thrombin receptors in inefficient ways. Weak interactions of the enzymes with thrombin receptor and inhibitor were ascribed to the incomplete formation of a lysine-cation cluster necessary for electrostatic molecular recognition.

Amino Acid Sequence↗
PubMed1994

Differential roles of two consecutive phenylalanine residues in thrombin receptor-tethered ligand peptides (SFFLRNP) in thrombin receptor activation.

A synthetic heptapeptide H-Ser-Phe-Phe-Leu-Arg-Asn-Pro-NH2, which corresponds to the ligand peptide latent in rodent thrombin receptors, was able to activate the thrombin receptor with no thrombin. In order to evaluate the structural requisites of two consecutive phenylalanines, three sets of analogs with substitutions at position either 2 or 3 were synthesized and examined for their stimulatory activity in phosphoinositide turnover in SH-EP epithelial-like cells. The replacement of Phe-2 by Ala completely eliminated the activity, while that of Phe-3 retained about 50% activity with a full stimulation. The Phe/Leu substitution resulted in a large increase (37-fold) in EC50 value for Phe-2, but in insignificant change for Phe-3. Substitution of para-fluorophenylalanine ((p-F)Phe) for Phe-2 enhanced strongly (4-fold) the activity, in contrast to a reduction by the Phe-3/(p-F)Phe substitution. Elimination of either Phe-2 or Phe-3 resulted in a complete loss of activity. These results indicated that Phe-2 and Phe-3 play different roles in the receptor activation. A highly specific aromatic phi-phi interaction was suggested between Phe-2-phenyl and thrombin receptor binding site, while Phe-3 appeared to be important for retaining a bioactive conformation.

Amino Acid Sequence↗
PubMed1994

Esophageal motility disorders in patients with Sjögren's syndrome.

Esophageal motility was studied in 21 patients with Sjögren's syndrome, and in 25 normal volunteers, in order to record the prevalence and type of esophageal motor abnormalities. Esophageal motor abnormalities were detected in seven of the 21 patients (33.3%). These esophageal abnormalities did not correlate with the presence of dysphagia, the extraglandular involvement, or the presence of autoantibodies.

Deglutition Disorders↗
PubMed1994

Stereokinetic effects with sharp and fuzzy illusory contours.

A black, 8-shaped pattern, whose centre of gravity is in the centre of a rotating disc, appears to split into two black discs rotating with phenomenal independent motion, orientation stability, and sliding of one on the other. The type of observed movement, the order of overlapping, and the extent of the stereokinetic depth in relation to the contour type and different dimensions of the pattern were investigated. The experimental data show that a fuzzy contour facilitates the stereokinetic effect. Furthermore, the extent of the stereokinetic depth has been found to be greater in case of fuzzy contour and vertical orientation of the pattern. These results are in contrast with the models in which this effect is considered as a problem of minimisation of distances or velocities. A vector model of the observed movement and an interpretation of the overlapping based on an energy approach are proposed. A tentative explanation of the stereokinetic depth for our patterns is put forward.

Adult↗
PubMed1994

Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor.

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

Amino Acid Sequence↗
PubMed1994

Modifications of the Poggendorff effect as a function of random dot textures between the verticals.

In the present research, we investigated the modification of the strength of the Poggendorff illusion as a function of different densities of random dot textures filling the space between the verticals. The results of Experiment 1 show that the illusory effect is a nonlinear function of the texture parameter r, the ratio of black pixels to white and black pixels, with a minimum for r = 0.5, approximately, and a maximum for r = 0 and r = 1. The results may be interpreted by an analytical model of perceptual space dynamics, in which the effect depends on the amount of interaction between points of different light intensity. A computer simulation performed by applying the analytical model to different values of r shows a good agreement between the predictions and the experimental data. To test the hypothesis underlying the model, a second experiment was carried out to measure the magnitude of the expansion of the space between the verticals as a function of the parameter r. The results are consistent with the hypothesis of the model. The overall data are discussed in terms of their implications on various theories proposed for the Poggendorff illusion.

Adult↗
PubMed1994

Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.

The beta 2-adrenergic receptor undergoes isomerization between an inactive conformation (R) and an active conformation (R*). The formation of the active conformation of the receptor molecule can be promoted by adrenergic agonists or by mutations in the third cytoplasmic domain that constitutively activate the receptor. Here we show that, of several beta-adrenergic receptor-blocking drugs tested, only two, ICI 118551 and betaxolol, inhibit the basal signaling activity of the beta 2-adrenergic receptor, thus acting as negative antagonists. We document the molecular properties of the more efficacious ICI 118551; (i) it shows higher affinity for the inactive form of the receptor and (ii) it inhibits the spontaneous formation of a beta-adrenergic receptor kinase substrate by the receptor. These properties are opposite those of adrenergic agonists, indicating that, in a fashion reciprocal to that of agonists, negative antagonists promote the formation of an inactive conformation of the receptor.

Adrenergic beta-Antagonists↗
PubMed1993

Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.

Immunoglobulin (Ig) antigen receptors are composed of a noncovalently-associated complex of Ig and two other proteins, Ig alpha and Ig beta. The cytoplasmic domain of both of these Ig associated proteins contains a consensus sequence that is shared with the signaling proteins of the T cell and Fc receptor. To test the idea that Ig alpha-Ig beta heterodimers are the signaling components of the Ig receptor, we have studied Ig mutations that interfere with signal transduction. We find that specific mutations in the transmembrane domain of Ig that inactivate Ca2+ and phosphorylation responses also uncouple IgM from Ig alpha-Ig beta. These results define amino acid residues that are essential for the assembly of the Ig receptor. Further, receptor activity can be fully reconstituted in Ca2+ flux and phosphorylation assays by fusing the cytoplasmic domain of Ig alpha with the mutant Igs. In contrast, fusion of the cytoplasmic domain of Ig beta to the inactive Ig reconstitutes only Ca2+ responses. Thus, Ig alpha and Ig beta are both necessary and sufficient to mediate signal transduction by the Ig receptor in B cells. In addition, our results suggest that Ig alpha and Ig beta can activate different signaling pathways.

Amino Acid Sequence↗
PubMed1993

Hydrops-ectopic calcification-moth-eaten skeletal dysplasia (Greenberg dysplasia): prenatal diagnosis and further delineation of a rare genetic disorder.

An offspring of consanguineous parents of East-Indian origin was found prenatally to have hydrops fetalis, short limb dwarfism, polydactyly and chondro-osseous changes consistent with Greenberg hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM) dysplasia. The radiological changes include platyspondyly with multiple extra ossification centers, extraneous calcification in the ribs, sternum, pelvis, and epiphysis, and moth-eaten long bones. The histopathological changes included chondrocytes with dilated rough endoplasmic reticulum and inclusion bodies with homogeneous material of intermediate electron density. These findings further delineate the spectrum of this rare autosomal recessive skeletal dysplasia.

Abnormalities, Multiple↗