Biomedical subjects
Publications and source records attributed to E Fabre.
An unexpected case of leiomyoma (LM) of the rectum in a 10-month-old female patient. The patient presented with a palpable mass and symptoms of intestinal obstruction, constipation and rectal discomfort. Rectal examination revealed a clearly visible mass. The treatment consisted of a surgical resection with wide margins. Pathology reported a leiomyoma. The patient was submitted to a careful clinical evaluation and a continuous follow up.
An intrastriatal injection with 18.8 nmoles of the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced in rats a progressive parkinsonism characterized by a major loss of striatum dopamine (DA) levels and an increased turnover of this neurotransmitter 96 h after the administration. In addition, the intrastriatal administration of MPTP produced an alteration in various behavioral markers of motor activity. Loss of DA was accompanied by a significant decrease of reduced glutathione (GSH) and an increase in GSH oxidation in the striatum. When deprenyl (10 mg/kg) was i.p. administered 2 h before the intrastriatal injection of MPTP, DA, GSH, glutathione redox status and the indexes of motor activity were not altered. These results show that MPTP increases striatum oxidative stress leading to cellular and in vivo degenerative changes which are prevented by pretreatment with deprenyl.
Mutant alleles with the 677C-->T and 1298A-->C polymorphisms of the MTHFR gene, and consequent lower methylentetrahydrofolate reductase enzyme activity, have been related to higher plasma homocysteine levels, which are associated with cardiovascular diseases. We assessed the genotype frequencies, degrees of fertility and homocysteine levels, and discuss a possible genetic selection for the gene polymorphisms studied. A total of 1777 subjects (897 women and 880 men), divided into four age groups, were genotyped by PCR and restriction fragment length polymorphism. The total homocysteine concentration in plasma was determined by fluorescence polarization immunoassay. Based on random pairs and linkage disequilibrium of the two polymorphisms, we estimated the rate of fetal non-viability according to the combinations of these two polymorphisms to be 4.63% for the group >24 years old and 6.31% for the group <24 years old. We detected an increased frequency of mutant alleles in the youngest age group, coincident with a generally increased folate intake by pregnant women in Spain. The genetic selection detected leads to an increase in mutated individuals, the number of whom could increase four-fold over the next 75 years. Although generally reduced in the younger age groups, the homocysteine plasma levels were shown to increase in individuals according to the number of mutations, especially those of the 677T allele.
BACKGROUND: Increases in total plasmatic homocysteine (tHcy) represents a risk factor for neural tube defects. We studied the effects of levofolinic acid (l,5-formyl-tetrahydrofolic) on the plasmatic tHcylevels in women of child-bearing age. MATERIALS AND METHOD: Healthy women aged 18-35 years (n = 30) received levofolinic acid, 5 mg/day,orally for 30 days. Both tHcy and intraerythrocytic folate levels were measured before treatment (day 0), on days 2, 5, 10 and 30 within the treatment period and on days 30 (day 60) and 60 (day 90) after the treatment was finished. Plasmatic tHcy was measured by fluorescence polarisation immunoassay and intraerythrocyticfolates by chemiluminescent immunoassay. RESULTS: Plasmatic tHcy decreased from the second day of treatment onwards (day 0 vs. 2: mean of difference: -1.24 micromol/l; CI 95% = -0.84 to -1.63; p < 0.001). The maximum decline (32.3%) was observed after 30 days (mean of difference = -2.72 micromol/l; CI 95% = -2.20 to -3.24; p < 0.001).After finishing the treatment, the hypohomocysteinic effect persisted up to days 60 (mean of difference = -2.67 micromol/l; CI 95% = -2.07 to -3.26; p < 0.001)and 90 (mean of difference = -1.49 micromol/l; CI 95% = -0.94 to -2.03; p < 0.001). The response was greater when the plasmatic tHcy concentration was >= 9 micromol/l. CONCLUSIONS: Levofolinic acid leads to a earlier, intense and persistent drop of the plasmatictHcy levels.
We report the case of a woman, with a 15-year history of high-dosage oral contraceptive use, who came to our center for a gynecological screening. Elevated liver enzymes were detected in blood samples and an abdominal ultrasound showed a hypoechogenic nodular image of 8 cm in the right hepatic lobe of the liver. Routine examinations, including hepatitis B surface antigen, hepatitis C viral antibody and alpha-fetoprotein, were all negative. Imaging studies, including computerized tomography scan, magnetic resonance imaging, sulfur colloid gammagraphy and hepatic angiography, were performed and confirmed the presence of the lesion, detecting the characteristic central scar structure of focal nodular hyperplasia. Discontinuation of oral contraceptives and follow-up showed no change in lesion size so that a surgical approach was adopted in order to remove the hepatocellular carcinoma. Pathological findings confirmed focal nodular hyperplasia.
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Nup145p is a component of the nuclear pore complex of Saccharomyces cerevisiae and is essential for mRNA export. Nup145p and its apparent vertebrate homologue are the only known nucleoporins to be composed of two functionally independent peptide moieties resulting from the post-translational cleavage of a large precursor molecule. In this study, the proteolytic cleavage site of Nup145p has been mapped upstream of an evolutionary conserved serine residue. Cleavage occurs at the same site when a precursor is artificially expressed in Escherichia coli. A hydroxyl-containing residue is critical for the reaction, although a thiol-containing residue offers an acceptable replacement. In vitro kinetics experiments using a purified precursor molecule demonstrate that the cleavage is self-catalyzed and that the catalytic domain lies within the N-terminal moiety. Taken altogether, our data are consistent with a proteolytic mechanism involving an N>O acyl rearrangement and a subsequent ester intermediate uncovered in other self-processing proteins.
The amebic liver abscess in newborns is an uncommon disease. There are few cases reported in the literature. This is a case of a 20 day-old female newborn who presented an abdominal mass, yellowish diarrheic depositions and jaundice. An abdominal CT scan showed a cystic mass located in the right hepatic lobe. The laboratory exams confirmed the amebic etiology. The clinical treatment failed and the surgery was decided. The pathologic results confirmed the diagnosis of an amebic liver abscess. Eight days after the resection the patient died because of a necrotizing enterocolitis.
An experimental rat model of Parkinson's disease was established by injecting rats directly in the striatum with the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study the action mechanism of this neurotoxic agent, MPTP and its main metabolite 1-methyl-4-phenylpyridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemented nonsynaptic brain mitochondria, and the rates of hydrogen peroxide and ATP production were measured. Intrastriatal administration of MPTP produced a pronounced decrease in striatal dopamine levels (p < 0.005) and a strong increase in 3,4-hydroxiphenylacetic acid/dopamine ratio (an indicator of dopamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydrogen peroxide production by 90%, from 1.37+/-0.35 to 2.59+/-0.48 nanomoles of H2O2/minute . mg of protein (p < 0.01). The metabolite MPP+ produced a marked decrease on the rate of ATP production of brain mitochondria (p < 0.005). These findings support the mitochondria-oxidative stress-energy failure hypothesis of MPTP-induced brain neurotoxicity.
AIMS: No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score > or =4 (six-point scale) 30 to 60 min after dosing was rated as a success. METHODS: A double-blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg(-1) dose range. RESULTS: Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg(-1) dose was 81% (95% CI: 78.5 to 84%). The time to reach a score > or =4 was longer than expected and the median duration-time at score > or =4 was shorter (15 min) than expected. CONCLUSIONS: Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg(-1) administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.
The authors present a study of 83 cases of sclerodermiform basal cell carcinoma. This series constitutes 2.3% of all skin cancers treated in the authors' unit from 1981 to 1996. The predominant site of these carcinomas is the centrofacial region with 46% of tumours involving the nose. In the majority of cases, treatment consisted of cover by a flap (52.6% of cases). Full-thickness skin grafts were used in 29% of cases and excision-suture was performed in 18.4% of cases. The authors emphasize the need to perform large resection with safety margins determined by the macroscopically visible tumour diameter. As frozen section pathological examination is not contributive, they prefer to defer reconstruction until the final pathology results are obtained. The only exception is the need to cover a vital region, such as the eye. These carcinomas must be followed in the long-term, as 20% of recurrences were detected in this series, comprising many orbitopalpebral sites, associated with difficult staging, and which always have a reserved prognosis. The authors therefore propose the use of epitheses in so-called high-risk sites. The three main guidelines in this disease, one of the most worrying forms of skin cancer, are surgical aggressiveness, modesty in terms of the cosmetic result and alertness in the follow-up.
Nup145p is an essential yeast nucleoporin involved in nuclear export of polyadenylated RNAs. We demonstrate here that Nup145p is cleaved in vivo to yield two functionally distinct domains: a carboxy-terminal domain (C-Nup145p) which is located at the nuclear pore complex (NPC) and assembles into the Nup84p complex, and a GLFG-containing amino-terminal domain (N-Nup145p) which is not part of this complex. Whereas the essential C-Nup145p accomplishes the functions required for efficient mRNA export and normal NPC distribution, N-Nup145p, which is homologous to the GLFG-containing nucleoporins Nup100p and Nup116p, is not necessary for cell growth. However, the N-Nup145p becomes essential in a nup188 mutant background. Strikingly, generation of a free N-domain is a prerequisite for complementation of this peculiar synthetic lethal mutant. These data suggest that N- and C-domains of Nup145p perform independent functions, and that the in vivo cleavage observed is of functional importance.
Eukaryotic cells evolved when their genetic information was packed into the cell nucleus. DNA replication and RNA biogenesis occur inside the nucleus while protein synthesis takes place in the cytoplasm. Bi-directional trafficking between these two compartments is mediated by a single supramolecular assembly, the nuclear pore complex. Nucleocytoplasmic transport is signal mediated, energy dependent, and requires, besides nuclear pore proteins (nucleoporins), a number of soluble transport factors. We review here our current knowledge on the role of nucleoporins, and on the mechanism of nucleocytoplasmic transport, with emphasis on the yeast Saccharomyces cerevisiae.
We have cloned a novel and essential gene, NBP35, from Saccharomyces cerevisiae that encodes a putative Nucleotide Binding Protein of 35 kDa. Sequence analysis revealed structural homology of Nbp35p with a family of bacterial ATPases involved in cell division processes and chromosome partitioning. A search in databases identified closely related sequences from yeast and higher eukaryotes, suggesting a conserved function for this family of proteins. By indirect immunofluorescence, a tagged version of Nbp35p carrying two immunoglobulin G-binding domains derived from Staphylococcus aureus Protein A was localised to the nucleus. A single amino-acid substitution in the conserved nucleotide-binding motif of Nbp35p renders the protein non-functional. Furthermore, a conserved cluster of four cysteines in the N-terminal end of the protein is also required for an essential role of Nbp35p.