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M Martinez

Publications and source records attributed to M Martinez.

At least 145 records · Page 8Linked to original sources

De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group.

The presenilin 1 (PS1) gene, located on chromosome 14, is the major gene involved in the autosomal dominant forms of early onset Alzheimer's disease (AD). In order to estimate the frequency of de novo PS1 mutations, we have sequenced the PS1 open reading frame in 13 clinically diagnosed patients with no affected relatives, who had developed AD before the age of 50. In one case with onset at 37 years, we identified a missense mutation resulting in a methionine to lysine substitution at codon 139 of the PS1 gene. This substitution is the fourth identified at the same codon. This study, in agreement with previous reports, suggests that de novo PS1 mutations can occur but at a low frequency.

Adult↗

MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders.

OBJECTIVE: We have found that docosahexaenoic acid (DHA; 22:6n-3), an important constituent of the CNS and retina, is dramatically decreased in patients with generalized peroxisomal disorders. Such a DHA deficiency could be pathogenic. Our aim was to test the possible beneficial effects of normalizing the DHA levels in these patients. The current report focuses on MRI changes during the treatment and reports follow-up evidence of myelin improvement in five peroxisomal disorder patients treated with DHA. METHODS: DHA ethyl ester (DHA-EE), about 90% pure, was used at daily oral doses of 100 to 600 mg. The treatment was monitored both clinically and biochemically, with periodic neurophysiologic and MRI examinations and repeated controls of liver tests and blood fatty acids by capillary column gas chromatography. RESULTS: DHA-EE normalized the blood levels of DHA in a few weeks. The levels of very-long-chain fatty acids decreased in plasma and those of plasmalogens increased in erythrocytes. Visual and liver function improved. On MRI, a virtual normalization of the brain myelin images was found in the three youngest patients. A clear improvement was noticed in the other two. CONCLUSIONS: The beneficial effects obtained indicate that DHA deficiency plays an important role in the pathogenesis of peroxisomal disease, probably in relation to myelinogenesis. Early initiation of DHA therapy is thus strongly recommended in patients with generalized peroxisomal disorders.

Brain Diseases↗

Defective peroxisome biogenesis with a neuromuscular disorder resembling Werdnig-Hoffmann disease.

OBJECTIVE: Characterization of the defect in a patient presenting a peripheral neuropathy with atypical features of distal motor involvement mimicking Werdnig-Hoffmann disease. PATIENT: Clinical signs included generalized hypotonia and floppiness, absence of stretch reflexes, muscle wasting, lack of head control and lingual fasciculations associated with unaffected facial muscles, and normal intellectual development. RESULTS: Normal muscle histology ruled out Werdnig-Hoffmann disease. Elevated plasma concentrations of very long-chain fatty acids and bile acid intermediates combined with normal plasmalogen levels in erythrocytes suggested defective peroxisomal beta-oxidation directly demonstrated by deficient pristanic acid and partially deficient C26:0 was present oxidation in cultured fibroblasts. Severely impaired pipecolic acid oxidation in liver and phytanic acid oxidation in fibroblasts was present. On light and electron microscopy of the liver tissue, rare peroxisomal membrane ghosts and trilamellar inclusions but absence of peroxisomes was noted. Immunoblot analysis revealed absence of peroxisomal beta-oxidation enzymes in liver tissue but normal results in fibroblasts. Remarkably, expression of the peroxisomal defect in fibroblasts was indicated by the finding of mainly cytoplasmatic catalase, as in liver. Preliminary studies excluded classification of this patient within the large PEX1 complementation group. CONCLUSIONS: The results suggest a novel peroxisome biogenesis disorder involving peroxisomal beta-oxidation as well as phytanic and pipecolic acid oxidation rather than an isolated defect of peroxisomal beta-oxidation. The association of a clinical picture mimicking Werdnig-Hoffmann disease with a novel peroxisomal disorder raises the question of whether investigation for peroxisomal function should be considered in every patient with an enigmatic spinal muscular atrophy-like syndrome.

Bile Acids and Salts↗

Ultrastructural study of the lateral lobe of the prostate of Wistar rats submitted to experimental chronic alcohol ingestion.

Alcoholism is considered today one of the most serious social and medical problems. Different investigators have demonstrated that chronic exposure to alcohol causes morphological and physiological changes in the testes and in the accessory sex glands, in the prostate in particular. In the present study, experimental rats were divided into groups receiving sugar cane brandy diluted to 30 degrees G.L. (30%, v/v) and Purina ration ad libitum for 60, 120, 180, 240 and 300 days, respectively. At the end of each period the animals were sacrificed and the lateral lobe of the prostate was collected for histological examination. The results showed atrophied epithelium, accumulation of lipidic droplets and rupture of the microvilli that line the cell surface facing the lumen of cells of the secretory epithelium of the lateral lobe of the prostate.

Alcoholism↗

Morphological changes on the hard palatine mucosa of rats (Rattus norvegicus albinus) after chronic alcohol consumption.

In order to examine the effects of alcohol on the hard palatine mucosa of rats, sixty adult female rats (Rattus norvegicus albinus) were divided into two experimental groups. The control group received solid diet (Purina rat chow) and tap water ad libitum. The alcoholic group received the same solid diet and was allowed to drink only sugar cane brandy dissolved in 30% Gay Lussac (v/v). At the end of periods of 90, 180 and 270 days of treatment, the animals at estro were sacrificed and the hard palatine mucosa were prepared for TEM and SEM methods. The basal cells of the alcoholic groups (90, 180 and 270 days of treatment) demonstrated some alterations: the intercellular spaces between these cells were higher, presented cytoplasmatic lipid droplets and autolysis. Also, the connective tissue showed intense lipid droplets accumulation in the alcoholic groups. These modifications suggested that chronic alcohol ingestion was able to modify the integrity of the cells in the rat hard palatine mucosa.

Alcoholism↗

[Genetics of Alzheimer's disease].

This review reports epidemiological data and biological mechanisms about the Apolipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease (AD). The second part describes the three genes, amyloid precusor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes, which when mutated cause early-onset autosomal dominant AD. Mutations on each of these genes have as a common consequence elevated levels of A beta (42,3).

Alzheimer Disease↗

Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees.

We have investigated whether there is a locus on chromosome 6 that confers an increased susceptibility to schizophrenia using a two-stage approach and nonparametric linkage analysis. Allele sharing identical by descent (IBD) and multipoint maximum likelihood score (MLS) statistics were employed. Results from two tested data sets, a first data set, or genome scanning data set, and a second replication data set, show excess allele sharing for multiple markers in 6q, a chromosomal region not previously reported as linked to schizophrenia. In our genome scanning data set, excess allele sharing was found for markers on 6q13-q26. The greatest allele sharing was at interval 6q21-q22.3 at marker D6S416 (IBD percentage 69; P = 0.00024). The multipoint MLS values were greater than 2.4 in the 11.4-cM interval delimited by D6S301 and D6S303, with a maximum value of 3.06 close to D6S278 and of 3.05 at D6S454/D6S423. We did not confirm, however, the previously described linkage in 6p, when tested in the systematic genome scanning data set. The replication data set also showed excess allele sharing in chromosomal area 6q13-q26, which overlapped with the aforementioned positive linkage area of the genome scanning data set. The highest sharing of the second data set was at D6S424 (IBD percentage 64; P = 0.0004), D6S283 (IBD percentage 62; P = 0.0009), and D6S423 (IBD percentage 63; P = 0.0009). Multipoint MLS analysis yielded MLS values greater than 1 in an area of about 35 cM, which overlaps with the MLS multipoint area of linkage from the genome scanning data set. The multipoint MLS at the D6S454/D6S423 locus was 2.05. In the second data set, the maximum multipoint MLS was located about 10 cM centromeric from the maximum of the genome scanning data set, at the interval D6S424-D6S275 (2.35). Our results provide very suggestive evidence for a susceptibility locus for schizophrenia in chromosome 6q from two independent data sets.

Alleles↗

6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

Bipolar Disorder↗

Light microscopic quantification of morphological changes during aging in neurons and glia of the rat parietal cortex.

BACKGROUND: Different changes in neuronal and glial population of the aging brain have been described; however, the degree and extent of these changes are controversial. This study evaluates the quantitative and cytomorphometric effects of aging on neuronal and glial populations in the parietal cortex of the rat. METHODS: The study was performed in two groups of rats aged 4-6 and 30-32 months. Cortical volume, neuronal density, glial density, and neuronal area, and shapes of the soma and nucleus were analyzed in cortical layers I, II-IV, V, and VI using serial sections stained with cresyl-fast-violet, and quantitative morphometric techniques. RESULTS: No changes with age were found in volume of the cortex or neuronal density. Glial density increased significantly (mean for all layers 17%) in older rats. Layers II-IV, V, and VI showed an age-related decrease in the area of the neuronal soma. Neuronal shape, as revealed by the major/minor diameter ratio, also showed a decrease in old rats but only in layer II-IV. Nuclear area decreased with age only in layer VI. CONCLUSIONS: The stability of neuronal density together with the increased number of glial cells and the changes in neuronal soma size suggest that aged-related cognitive impairment could be a consequence of neuronal dysfunction rather than actual neuronal losses.

Aging↗

Empirical affected-sib-pair statistics: two simulation strategies.

We compare two simulation procedures used to determine empirical distributions of three affected sib-pair test-statistics in family samples with missing parental marker information. P1 and P2 procedures differ according to whether affected sibs' genotypes are ignored (P1) or accounted for (P2) to generate the unknown parental genotypes. Overall, our results show that P2 procedure performs better than P1, particularly when marker heterozygosity is high (H = 75%) or when marker data from unaffected siblings are available with low marker heterozygosity (H = 50%). These results are similar for all affected sib-pair tests.

Computer Simulation↗

Affected sib-pair tests for linkage: type I errors with dependent sib-pairs.

We compared the robustness of affected-sib-pair (ASP) tests for multiple-affected sibships. Forming all possible pairs increases the type I errors only slightly whereas the most used weighting procedures decrease the efficiency of the tests. Another weighting procedure accounting for the reduction of variance of the weighted identical by descent (IBD) information appears robust. Missing parental marker data leads to a decrease of type I errors in all cases.

Age of Onset↗

Association of rheumatoid arthritis with an amino acid allelic variation of the T cell receptor.

OBJECTIVE: To investigate allelic variations of T cell receptor residues for a contribution to rheumatoid arthritis (RA) susceptibility. METHODS: We conducted an RA case-control study involving 1,579 northwest Europeans: 766 patients with erosive and rheumatoid factor-positive disease and 813 control subjects. Productive changes of segments TCRAV6S1, TCRAV7S1, TCRAV8S1, TCRAV10S2, and TCRBV6S1, TCRBV6S7 were investigated by single-strand conformation polymorphisms. The TCRAV8S1 association was confirmed by restriction fragment length polymorphism. RESULTS: In the systematic study (77 patients and 119 controls), an increase in 1 TCRAV8S1 genotype was found in the RA patients (P = 0.0004). This finding was replicated in 2 further populations, one from France (212 patients and 254 controls) and the other from Britain (477 patients and 440 controls), with a similar odds ratio (OR), which allowed pooling of the data and confirmation of the association (OR 1.3 [95% confidence interval 1.1-1.7], P = 0.008). CONCLUSION: These findings show evidence that TCRA is an RA susceptibility locus.

Alleles↗

Haemonchus contortus: cloning and functional expression of a cDNA encoding ornithine decarboxylase and development of a screen for inhibitors.

Polyamines (PA) are essential for viability and replication of all cells; organisms either synthesize PA or acquire them from the environment. How nematodes that parasitize the gut satisfy their PA requirement has not been resolved. The primary regulatory enzyme in PA biosynthesis in most animals is ornithine decarboxylase (ODC). This enzyme has recently been characterized in free-living nematodes and in the parasitic species. Haemonchus contortus. Nematode and mammalian ODC are reported to differ in subcellular localization, kinetics, and sensitivity to inhibitors. We cloned an H. contortus cDNA that encodes a full-length ODC (sequence data from this article have been deposited with the GenBank Data Library under Accession Nos. AF016538 and AF016891). This cDNA was functionally expressed in strains of Escherichia coli and Saccharomyces cerevisiae that lack ODC and are dependent upon exogenous PA for survival. Expression of nematode ODC reversed the PA-dependence phenotype of both microorganisms. The complemented yeast strain was used to develop a nutrient-dependent viability screen for selective inhibitors of nematode ODC. The antiprotozoal drug stilbamidine isethionate was identified as active in this screen, but biochemical characterization revealed that this compound did not inhibit ODC. Instead, like other cationic diamidines, stilbamidine probably inhibits yeast S-adenosylmethionine decarboxylase. Nonetheless, the activity in the screen of the known ODC inhibitor difluoromethylornithine (DFMO) validates the concept that specific recombinant microorganisms can serve as the basis for extremely selective and facile screens.

Amino Acid Sequence↗

Hemodynamic and gas exchange responses to inhalation of nitric oxide in patients with the acute respiratory distress syndrome and in hypoxemic patients with chronic obstructive pulmonary disease.

OBJECTIVE: Inhalation of nitric oxide (NO) can improve oxygenation and decrease mean pulmonary artery pressure (MPAP) in patients with the acute respiratory distress syndrome (ARDS). It is not known whether inhaled NO exerts a similar effect in hypoxemic patients with chronic obstructive pulmonary disease (COPD). DESIGN: Prospective clinical study. SETTING: General intensive care unit in Sabadell, Spain. PATIENTS: Nine mechanically ventilated COPD patients (mean age 72 +/- 2 years; forced expiratory volume in 1 s 0.91 +/- 0.11 l) and nine ARDS patients (mean age 57 +/- 6 years; mean lung injury score 2.8 +/- 0.1). MEASUREMENTS AND RESULTS: We measured hemodynamic and gas exchange parameters before NO inhalation (basal 1), during inhalation of 10 ppm NO (NO-10), and 20 min after NO was discontinued (in basal 2) in the ARDS group. In the COPD group, these parameters were measured before NO inhalation (basal 1), during different doses of inhaled NO (10, 20, and 30 ppm), and 20 min after NO was discontinued (basal 2). A positive response to NO was defined as a 20% increment in basal arterial partial pressure of oxygen (PaO2). MPAP and pulmonary vascular resistance (PVR) decreased significantly, while other hemodynamic parameters remained unchanged after NO-10 in both groups. Basal oxygenation was higher in the COPD group (PaO2/FIO2 (fractional inspired oxygen) 190 +/- 18 mmHg) than in the ARDS group (PaO2/FIO2 98 +/- 12 mmHg), (p < 0.01). After NO-10, PaO2/FIO2 increased (to 141 +/- 17 mmHg, p < 0.01) and Qva/Qt decreased (39 +/- 3 to 34 +/- 3%, p < 0.01) in the ARDS group. There were no changes in PaO2/FIO2 and Qva/Qt when the NO concentration was increased to 30 ppm in the COPD group. In both groups, a correlation was found between basal MPAP and basal PVR, and between the NO-induced decrease in MPAP and in PVR. The NO-induced increase in PaO2/FIO2 was not correlated with basal PaO2/FIO2. In the ARDS group, six of the nine patients (66%) responded to NO and in the COPD group, two of nine (22%) (p = 0.05). CONCLUSIONS: NO inhalation had similar effects on hemodynamics but not on gas exchange in ARDS and COPD patients, and this response probably depends on the underlying disease.

Administration, Inhalation↗

Short-term effects of prone position in critically ill patients with acute respiratory distress syndrome.

OBJECTIVE: Changing the position from supine to prone is an emerging strategy to improve gas exchange in patients with the acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the acute effects on gas exchange, hemodynamics, and respiratory system mechanics of turning critically ill patients with ARDS from supine to prone. DESIGN: Open, prospective study. SETTING: General intensive care units. PATIENTS: 23 patients [mean age 56 +/- 17 (SD) years] who met ARDS criteria and had a Lung Injury Score > 2.5 (mean 3.25 +/- 0.3). INTERVENTIONS: The decision to turn a patient was made using a protocol based on impaired oxygenation despite the use of positive end-expiratory pressure and a fractional inspired oxygen (FIO2) of 1. MEASUREMENTS AND RESULTS: We measured gas exchange and hemodynamic variables in all patients and in 16 patients calculated respiratory system compliance when they were supine and 60 to 90 min after turning them to a prone position. This latter position was remarkably well tolerated and no clinically relevant complications or events were detected either during turning or while prone. The partial pressure of oxygen in arterial blood (PaO2)/FIO2 ratio improved from 78 +/- 37 mm Hg supine to 115 +/- 31 mm Hg prone (p < 0.001), and intrapulmonary shunt decreased from 43 +/- 11 to 34 +/- 8% (p < 0.001). Cardiac output and other hemodynamic parameters were not affected. Respiratory system compliance slightly improved from 24.7 +/- 10.2 ml/cmH20 supine to 27.8 +/- 13.2 ml/cmH20 prone (p < 0.05). An improvement in PaO2/FIO2 of more than 15% from changing from supine to prone was found in 16 patients (responders). Responders had more hypoxemia (PaO2/FIO2 70 +/- 23 vs 99 +/- 53 mm Hg in non-responders, p < 0.01), more hypercapnia (partial pressure of carbon dioxide in arterial blood (70 +/- 27 vs 64 +/- 9 mm Hg, p < 0.01) and a shorter elapsed time to the onset of ARDS and turning to the prone position (11.8 +/- 16 vs 32.8 +/- 42 days, p < 0.01). CONCLUSIONS: Turning critically ill, severely hypoxemic patients from the supine to the prone position is a safe and useful therapeutic intervention. Our data suggest that prone positioning should be carried out early in the course of ARDS.

Adult↗

High-resolution ultrasound associated with aspiration biopsy in the follow-up of patients with differentiated thyroid cancer.

OBJECTIVE: To assess the value of ultrasound in the follow-up of patients undergoing surgery for differentiated thyroid carcinoma. SUBJECTS: The study included 89 patients (70 women and 19 men) with differentiated thyroid carcinoma (76 papillary and 13 follicular cancer). METHODS: High-frequency ultrasound (US) was used in the evaluation of 89 subjects who underwent surgery for thyroid carcinoma. Fine-needle aspiration was performed in cases with positive US. In addition, determinations of thyroglobulin (Tgb) in serum, scintigraphy with (131)I, and cervical palpation were evaluated. We determined sensitivity, specificity, and overall accuracy for each of these diagnostic methods. RESULTS: Ultrasonography was positive in 22 subjects, 16 in the nodal area and 6 in the thyroid bed. Twenty-two subjects received fine-needle aspiration with US control; 13 (59%) of 22 were positive for cancer. The results of the US for detecting neoplastic disease showed a sensitivity of 65%, specificity of 86%, and overall accuracy of 82%. The overall accuracy for scintigraphy was 88% and for Tgb, 91%. CONCLUSION: We concluded that US can be included in the follow-up protocol for patients undergoing surgery for differentiated cancer of thyroid, as a valuable tool to localize the recurrence. This technique is particularly useful in the evaluation of patients who are found to have elevated Tgb levels.

Adenocarcinoma, Follicular↗