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Biomedical subjects

C Fernandes

Publications and source records attributed to C Fernandes.

At least 19 recordsLinked to original sources
PubMed2006

Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task.

RATIONALE: Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. OBJECTIVES: The aim was to examine the role of alpha7 receptors in attentional performance of mice and in effects of nicotine. MATERIALS AND METHODS: Mice with targeted deletion of the gene coding for the alpha7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. RESULTS: Initially the alpha7(-/-) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in alpha7(-/-) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in alpha7(-/-) and wild-type mice. CONCLUSIONS: alpha7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal.

Animals↗
PubMed2006

Bioaccumulation of heavy metals in Liza saliens from the Esmoriz-Paramos coastal lagoon, Portugal.

Heavy metal (Cu and Zn) concentrations in liver, gills, and muscle of leaping grey mullet, Liza saliens, from the Portuguese Esmoriz-Paramos coastal lagoon were measured to evaluate their bioaccumulation as a function of sediment contamination. The highest metal concentrations were observed in the liver (254 mg Cu kg(-1)) and gills (114 mg Zn kg(-1)). Bioaccumulation factors (BAFs) were found to follow the order: Cu-liver>Cu-gills>Cu-muscle and Zn-gills>Zn-liver>Zn-muscle. The highest BAFs were observed in the organs mainly implicated in metal metabolism and a significant positive relationship was found between BAFs and fish age. These results suggest the loss of homeostatic capacity of L. saliens under chronic metal exposure leading to bioaccumulation. Furthermore, Cu-liver and Zn-gills accumulation can be good environmental indicators of metal stress in L. saliens.

Animals↗
PubMed2006

Performance deficit of alpha7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory.

Patients with schizophrenia exhibit deficits in a range of cognitive functions, particularly working and episodic memory, which are thought to be core features of the disorder. Memory dysfunction in schizophrenia is familial and thus a promising endophenotype for genetic studies. Both human and animal studies suggest a role for the neural nicotinic acid receptor family in cognition and specifically the alpha7-receptor subunit in schizophrenia and its endophenotypes. Consequently, we tested mice lacking the alpha7 subunit of the neural nicotinic receptor (B6.129S7-Chrna7(tm1Bay)/J) in the delayed matching-to-place (DMP) task of the Morris water maze, a measure of working/episodic memory akin to human episodic memory. We report that a minor impairment in alpha7 knockout mice was observed in the DMP task, with knockout mice taking longer to find the hidden platform than their wildtype controls. This suggests a role for the alpha7 subunit in working/episodic memory and a potential role for the alpha7 neural nicotinic receptor gene (CHRNA7) in schizophrenia and its endophenotypes.

Acetylcholine↗
PubMed2005

Tolerance to nicotine in mice lacking alpha7 nicotinic receptors.

RATIONALE: Previous studies have suggested that a knockout of the gene coding for alpha7 nicotinic receptor subunits influences the behaviour of undrugged mice but not the acute effect of nicotine on locomotor activity. OBJECTIVES: The present studies extend these observations to nicotine tolerance assessed by means of schedule-controlled behaviour. METHODS: Groups of alpha7-/- and alpha7+/+ mice were trained to press levers under an FR20 schedule of food reinforcement. The acute response rate-depressant effects of nicotine were determined in both genotypes and the mice were then subdivided into groups treated daily with nicotine (1.2 mg/kg/day) or saline. After 39 days of exposure to this regimen, the dose-response curves were re-determined. RESULTS: Knockout of the alpha7 gene had no consistent effect on the lever-pressing behaviour of undrugged mice and did not influence the acute, dose-related, response rate-depressant effect of nicotine (0.2-1.2 mg/kg). When dose-response curves for nicotine (0.4-2.0 mg/kg) were re-determined after daily dosing with the drug, both wild-type and knockout mice developed similar tolerance to nicotine, as shown by approximately 2.5-fold shifts to the right of the dose-response curves. CONCLUSIONS: Nicotinic receptors containing the alpha7 subunit do not play a significant role in the regulation of the lever-pressing behaviour studied or in the acute behavioural depressant effect of nicotine and the development of tolerance to that effect. Such results contrast with previous reports suggesting profound impairments in sensitivity to nicotine in nicotinic receptor beta2-/- mice.

Animals↗
PubMed2004

The role of nicotinic receptor alpha 7 subunits in nicotine discrimination.

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. The experiments described here use mice lacking the alpha7 subunit of nicotinic receptors to investigate the role of alpha7-containing receptors in nicotine discrimination. Wild-type and alpha7-knockout mice were trained in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement. Mutant mice exhibited baseline rates of lever-pressing as low as 52.2% of rates in wild-type controls (n=21-24). Mutant and wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) at a similar rate (n=10-12) and reached similar final levels of accuracy (71.9 +/- 4.4% and 90.8 +/- 3.1% after 60 training sessions for 0.4 and 0.8 mg/kg training doses, respectively, in mutant mice, as compared with 75.0 +/- 6.5% and 87.6 +/- 4.8% for wild types). The genotypes exhibited similar steep dose-response curves for nicotine discrimination. In both genotypes, dose-response curves for mice trained with 0.8 mg/kg of nicotine were displaced three- to four-fold to the right as compared with those for the mice trained with the smaller dose. The predominant effect of nicotine on the overall rate of responding was a reduction at the largest doses tested and there was no difference between the genotypes. The results suggest that nicotinic receptors containing the alpha7 subunit do not contribute to the discriminative stimulus or response-rate-depressant effects of nicotine, although they may regulate baseline rates of operant responding.

Animals↗
PubMed2004

Synthesis and biological evaluation of silylated mixed-ligand 99mTc complexes with the [PNS/S] donor atom set.

New oxotechnetium complexes of general formula [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) were synthesized by direct reduction of [99mTcO4]- with stannous chloride, in the presence of the tridentate heterofunctionalized phosphine H2PNS and of the monodentate silylated thiols [HS(CH2)nOSiR3] (n = 2, R = Ph (1); n = 3, R = Ph (2); n = 3, R = Et (3)). The mixed-ligand rhenium and technetium complexes of general formula [M(O)(PNS)(S(CH2)nOH)] (n = 2: M = 99mTc, (7), M = Re, (7a); n = 3: M = 99mTc, (8), M = Re, (8a)) were also prepared. All the 99mTc complexes were obtained with high radiochemical purity (> 95%), after purification by HPLC, and were characterized by comparison of their HPLC profiles with the ones obtained for the corresponding Re compounds. The silylated compounds 4-6 are stable in phosphate saline buffer (PBS) pH 7.4, rat plasma, human serum and whole blood, and do not bind to plasmatic proteins, and also do not challenge with glutathione. The biological behavior of [99mTc(O)(PNS)(S(CH2)nOH)] (7, 8) and [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) was studied. The effect of the pH on the cleavage of the O-Si bond in complexes 4-6 was also evaluated.

Animals↗
PubMed2001

Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.

The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.

Alkyl and Aryl Transferases↗
PubMed2001

N,N'-Bis[tris(hydroxymethyl)methyl]-ethanediamide: six O-H...O hydrogen bonds generate only a two-dimensional structure.

Molecules of the title compound, C(10)H(20)N(2)O(8), adopt a conformation which is almost centrosymmetric. The molecules are disordered over two sets of sites with an occupancy ratio of 0.94:0.06. In the major form, there are two intramolecular O-H...O hydrogen bonds [O...O 2.756 (4) and 2.765 (4) A; O-H...O 144 and 146 degrees ], in which the two amidic O atoms act as acceptors. In addition, there are four intermolecular O-H...O hydrogen bonds [O...O 2.650 (3)-2.666 (3) A; O-H...O 158-171 degrees ]; these link each molecule to six others in a continuous sheet structure which contains five distinct ring motifs, two of the S(7) type, two of the R(3)(3)(10) type and one of the R(2)(2)(22) type.

Journal Article↗
PubMed2001

High-performance liquid chromatography/mass spectrometry characterization of Ki4B-Ras in PSN-1 cells treated with the prenyltransferase inhibitor L-778,123.

Cellular transformation by Ras oncoproteins requires the posttranslation modification of farnesylation in a reaction catalyzed by farnesyl protein transferase (FPTase). Thus, inhibitors of FPTase have been developed as potential anticancer agents. However, recent studies with selective inhibitors of FPTase have shown that Ki4B-Ras retains its ability to transform cells by undergoing alternative prenylation by the related geranylgeranyl protein transferase I (GGPTase-I) in human tumor cells. We have developed a high-performance liquid chromatography/mass spectrometry assay for the detection and quantitation of the different processing states of Ki4B-Ras isolated from PSN-1 cells (a human pancreatic cell line with an activating Gly12 to Arg mutation) treated with the prenyltransferase inhibitor, L-778,123. Recently tested in the clinic, L-778,123 is a potent inhibitor of FPTase (in vitro IC50 = 2 nM) with some activity against GGPTase-I (in vitro IC50 = 98 nM). We find primarily farnesylated-Ki4B-Ras in vehicle-treated PSN-1 cells, a mixture of farnesylated- and geranylgeranylated-Ki4B-Ras in cells treated with nanomolar concentrations of L-778,123, and a mixture of unprocessed, farnesylated, and geranylgeranylated-Ki4B-Ras in cells treated with micromolar concentrations of compound. Of importance, this technique does not require metabolic labeling and may be used as a pharmacodynamic assay for Ki4B-Ras processing in mouse models.

Alkyl and Aryl Transferases↗
PubMed2001

Influence of the preparation method on the physicochemical properties of tolbutamide/cyclodextrin binary systems.

Tolbutamide (TBM) was found to form an inclusion complex with beta cyclodextrin (beta-CD) in solution and in solid state. Inclusion complex formation between tolbutamide and beta-cyclodextrin in aqueous solution was studied by phase solubility and spectral shift methods. The apparent stability constant Ks calculated by these techniques, in water, were estimated as 195.7 and 236.5 M(-1), respectively. The phase solubility studies revealed a B(S)-type diagram with an inclusion complex of 1:2 molar ratio. The solid inclusion complexes of TBM and beta-CD were prepared at a molar ratio of 1:2 by kneading, coprecipitation, freeze-drying, and spray-drying methods. In addition, the physical mixture was prepared. Characterization of TBM: beta-CD inclusion was performed using differential scanning calorimetry (DSC), Raman spectroscopy, and X-ray diffractometry and by application of a so-called ether wash method. All the inclusion systems investigated led to a significant improvement in the dissolution over free TBM, and the dissolution rate of the active material was observed to be independent of the preparation method.

Calorimetry, Differential Scanning↗
PubMed2001

Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred's syndrome.

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendred's syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendred's syndrome.

Adult↗
PubMed2001

Are lorazepam-induced deficits in attention similar to those resulting from aging?

The purpose of this experiment was to compare, in three tasks of attention, the impairment caused by lorazepam (1 and 2.5 mg) administered to young volunteers with the impairment that results from aging. Performance on digit cancellation (DC), digit-symbol substitution (DSS), and Paced Auditory Serial Addition Task (PASAT) was significantly impaired by lorazepam (2.5 mg) and was significantly worse in the middle-aged group (mean +/- SEM, aged 58.9+/-0.8 years) compared with the younger, IQ-matched group (20.7+/-0.2 years). However, there were interesting differences in the extent of impairments among the three tests. In the DC test, lorazepam (2.5 mg) produced a significantly greater impairment than was seen in either the middle-aged men or middle-aged women. However, in the DSS test, the middle-aged women were significantly more impaired than either the middle-aged men or the young volunteers tested after lorazepam (2.5 mg). In the PASAT, both the lorazepam (2.5 mg) group and the middle-aged women were more impaired than the middle-aged men. These results raise the important possibility of gender differences in age-related decline of attentional processes.

Adult↗
PubMed2001

Evaluation of regional bond strength of resin cement to endodontic surfaces.

The purpose of this study was to test the feasibility of adapting a new microtensile testing technique to measure resin cement bond strengths to the cervical, middle, and apical thirds of root canals. Post spaces were created in extracted human teeth, and the roots were ground flat on one side to expose the canal and permit ideal placement of one of two resin cements (Panavia 21 or C&B Metabond). After 48 h of storage, serial 1-mm-thick cross-sections were cut to create 6-10 specimens per root. The first three specimens were from the cervical third, the next three were from the middle third, and the last three were from the apical third of the root. Each 1 x 1 x 8 mm specimen was pulled to failure in a miniature testing machine. The results indicated that both resin cements produced high bond strengths (12-23 MPa), and that bond strengths to the apical third were significantly higher (p < 0.05) than to the cervical or middle third with either cement. This new method shows promise for evaluating resin bond strengths within root canals.

Adhesiveness↗
PubMed2001

Characterisation of the somatic evolution of Portuguese children with Trisomy 21--preliminary results.

We present preliminary results of a cross-sectional study which had the following objectives: 1--to develop percentile curves of weight, height and head circumference of Portuguese children with Trisomy 21 from 0 to 48 months of age; 2--a comparison of the growth of children with Trisomy 21 with a control population of their siblings, and 3--a comparison between the growth of Portuguese and American children with Trisomy 21 (based on the data of Cronk et al). We conclude that: 1--there is growth delay (weight, height, head circumference) in the Portuguese children with Trisomy 21, in all of the parameters evaluated and in all age groups; 2--Portuguese children with Trisomy 21 present values similar to those obtained by Cronk et al until 24 months of age; 3--from the age of 30 months onward Portuguese children with Trisomy 21 were heavier and taller than American children with Trisomy 21. This supports the usefulness of percentile curves specifically for Portuguese children with Trisomy 21.

Anthropometry↗
PubMed2000

Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes.

The purpose of the present study was to evaluate the enhancement of tolbutamide (TBM) oral bioavailability and hypoglycaemic activity through complexation with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). TBM and its freeze-dried inclusion complexes were administered to rabbits (New zealand breed; n=6), in a dose of 20 mg/kg. TMB plasma levels were measured by HPLC and glucose levels were analysed according to Trinder (Trinder, P., 1969. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem. 6, 24-28). The pure drug attained a maximum of plasma concentration (C(max)) of 18.58+/-3.27 microg/ml at 8.5 h (T(max)), whereas with inclusion complexes, C(max) increased about two times and appeared at ca. 4 h. AUC(0-24) of complexes was about 1.6 times as much as that of the pure drug. Thus, the extent of oral absorption of TBM from inclusion complexes was significantly greater and faster when compared with drug alone. In addition, without cyclodextrins the maximum hypoglycaemic effect (CVG(max)) of TBM (34. 1%) was observed at 5.6 h (Tg(max)). CVG(max) of TBM/beta-CD and TBM/HP-beta-CD inclusion complexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC(0-24) of inclusion complexes was 1.4 times larger than that of pure drug. Hence, the oral administration of complexed TBM not only improved the drug absorption, but also the TBM hypoglycaemic activity.

2-Hydroxypropyl-beta-cyclodextrin↗