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Biomedical subjects

M Martinez

Publications and source records attributed to M Martinez.

At least 91 records · Page 5Linked to original sources
PubMed2000

Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge.

The efficacy of cidofovir for treatment of cowpox virus infection in BALB/c mice was investigated in an effort to evaluate new therapies for virulent orthopoxvirus infections of the respiratory tract in a small animal model. Exposure to 2(-5)x10(6) pfu of cowpox virus by aerosol or intranasally (inl) was lethal in 3- to 7-week-old animals. One inoculation of 100 mg/kg cidofovir on day 0, 2, or 4, with respect to aerosol infection, resulted in 90%-100% survival. Treatment on day 0 reduced peak pulmonary virus titers 10- to 100-fold, reduced the severity of viral pneumonitis, and prevented pulmonary hemorrhage. The same dose on day -6 to 2 protected 80%-100% of inl infected mice, whereas 1 inoculation on day -16 to -8 or day 3 to 6 was partially protective. Cidofovir delayed but did not prevent the death of inl infected mice with severe combined immunodeficiency. Treatment at the time of tail scarification with vaccinia virus did not block vaccination efficacy.

Administration, Intranasal↗
PubMed2000

DNA damage-inducible and RAD52-independent repair of DNA double-strand breaks in Saccharomyces cerevisiae.

Chromosomal repair was studied in stationary-phase Saccharomyces cerevisiae, including rad52/rad52 mutant strains deficient in repairing double-strand breaks (DSBs) by homologous recombination. Mutant strains suffered more chromosomal fragmentation than RAD52/RAD52 strains after treatments with cobalt-60 gamma irradiation or radiomimetic bleomycin, except after high bleomycin doses when chromosomes from rad52/rad52 strains contained fewer DSBs than chromosomes from RAD52/RAD52 strains. DNAs from both genotypes exhibited quick rejoining following gamma irradiation and sedimentation in isokinetic alkaline sucrose gradients, but only chromosomes from RAD52/RAD52 strains exhibited slower rejoining (10 min to 4 hr in growth medium). Chromosomal DSBs introduced by gamma irradiation and bleomycin were analyzed after pulsed-field gel electrophoresis. After equitoxic damage by both DNA-damaging agents, chromosomes in rad52/rad52 cells were reconstructed under nongrowth conditions [liquid holding (LH)]. Up to 100% of DSBs were eliminated and survival increased in RAD52/RAD52 and rad52/rad52 strains. After low doses, chromosomes were sometimes degraded and reconstructed during LH. Chromosomal reconstruction in rad52/rad52 strains was dose dependent after gamma irradiation, but greater after high, rather than low, bleomycin doses with or without LH. These results suggest that a threshold of DSBs is the requisite signal for DNA-damage-inducible repair, and that nonhomologous end-joining repair or another repair function is a dominant mechanism in S. cerevisiae when homologous recombination is impaired.

Bleomycin↗
PubMed2000

Vitamin B-6 deficiency in rats reduces hepatic serine hydroxymethyltransferase and cystathionine beta-synthase activities and rates of in vivo protein turnover, homocysteine remethylation and transsulfuration.

Vitamin B-6 deficiency causes mild elevation in plasma homocysteine, but the mechanism has not been clearly established. Serine is a substrate in one-carbon metabolism and in the transsulfuration pathway of homocysteine catabolism, and pyridoxal phosphate (PLP) plays a key role as coenzyme for serine hydroxymethyltransferase (SHMT) and enzymes of transsulfuration. In this study we used [(2)H(3)]serine as a primary tracer to examine the remethylation pathway in adequately nourished and vitamin B-6-deficient rats [7 and 0.1 mg pyridoxine (PN)/kg diet]. [(2)H(3)]Leucine and [1-(13)C]methionine were also used to examine turnover of protein and methionine pools, respectively. All tracers were injected intraperitoneally as a bolus dose, and then rats were killed (n = 4/time point) after 30, 60 and 120 min. Rats fed the low-PN diet had significantly lower growth and plasma and liver PLP concentrations, reduced liver SHMT activity, greater plasma and liver total homocysteine concentration, and reduced liver S-adenosylmethionine concentration. Hepatic and whole body protein turnover were reduced in vitamin B-6-deficient rats as evidenced by greater isotopic enrichment of [(2)H(3)]leucine. Hepatic [(2)H(2)]methionine production from [(2)H(3)]serine via cytosolic SHMT and the remethylation pathway was reduced by 80.6% in vitamin B-6 deficiency. The deficiency did not significantly reduce hepatic cystathionine-beta-synthase activity, and in vivo hepatic transsulfuration flux shown by production of [(2)H(3)]cysteine from the [(2)H(3)]serine increased over twofold. In contrast, plasma appearance of [(2)H(3)]cysteine was decreased by 89% in vitamin B-6 deficiency. The rate of hepatic homocysteine production shown by the ratio of [1-(13)C]homocysteine/[1-(13)C]methionine areas under enrichment vs. time curves was not affected by vitamin B-6 deficiency. Overall, these results indicate that vitamin B-6 deficiency substantially affects one-carbon metabolism by impairing both methyl group production for homocysteine remethylation and flux through whole-body transsulfuration.

Animals↗
PubMed2000

Nitric oxide may contribute to nocturnal hemodynamic changes in cirrhotic patients.

OBJECTIVE: Patients with liver cirrhosis have a nocturnal worsening of hemodynamic parameters that has been associated with an increased risk of variceal bleeding at nighttime. The aim of this study was to investigate whether nitric oxide and cytokines are implicated in these hemodynamic changes. METHODS: Ten cirrhotic patients and eight controls were studied. Mean blood pressure, heart rate, plasma norepinephrine, tumor necrosis factor alpha and interleukin-6 levels, and serum nitrite + nitrate levels were determined at 0800, 1600, and 2400 h. All determinations were performed in supine rest and at least 4 h after meals. In a second study, nitrite + nitrate levels were assessed in 10 cirrhotic patients before and after eating a standard meal. RESULTS: Mean arterial pressure levels that were always lower in the patient group showed a nocturnal decrease in both groups of subjects. Heart rate values that were always higher in cirrhotic patients showed a nocturnal fall in controls, whereas cirrhotics maintained elevated values at nighttime. Norepinephrine levels were higher in cirrhotics and maintained similar values during the study, whereas controls had a significant nocturnal decrease. Nitrite + nitrate levels that were higher in cirrhotic patients showed a significant mean increase of 40% from morning (0800 h) to night (2400 h) in the patient group, whereas in controls no change was observed (p < 0.05). Tumor necrosis factor alpha and interleukin-6 levels did not change either in patients or controls during the entire period. Cirrhotic patients with or without ascites maintained a pattern of hemodynamic and biochemical changes similar to the pattern observed in the entire group of patients. Finally, no changes in serum nitrite + nitrate levels were observed in patients before and after eating the standard meal. CONCLUSION: An increased nocturnal nitric oxide production might contribute to the hemodynamic changes observed in cirrhotic patients during nighttime.

Aged↗
PubMed2000

Outcome in patients with adrenal incidentaloma selected for surgery: an analysis of 88 cases investigated in a single clinical center.

OBJECTIVE: The study was designed to evaluate the clinical, endocrinological and radiological parameters used to investigate adrenal incidentalomas and select patients for surgery. DESIGN AND METHODS: An analysis of 88 consecutive patients with adrenal incidentaloma selected for surgery and investigated in a single clinical center was performed. RESULTS: Mean (+/-s.d.) age of the patients was 53+/-14 years. Fourteen (16%) of the adrenal incidentalomas were malignant tumors (2 adrenocortical carcinomas, 3 metastases, 4 adenocarcinomas, 4 sarcomas and 1 mesenchymoma), 10 (11%) were pheochromocytomas, 32 (36%) were non-secretory benign adrenal adenomas and the remaining were benign adrenal (n = 8; 9%) or extra-adrenal (n = 24; 27%) masses. Endocrinological investigations revealed 1 Conn adenoma, 4 tumors responsible for Cushing's syndrome or silent hypercortisolism and 1 androgen secreting tumor. Abnormalities of endocrine evaluations were observed in the 2 malignant adrenocortical carcinomas. Elevated 24-h urinary metanephrine levels were observed in the 9 pheochromocytomas tested. Complications of surgery occurred in 14% of the cases. Regardless of the endocrine status, parameters associated with malignant tumors were: older age (mean age of patients harboring malignant tumors vs patients with benign incidentalomas: 62+/-17 years vs 52+/-13 years, P = 0.005), weight loss (39% vs 7%, P = 0. 005), and mass diameter greater than 60mm (69% vs 15%, P < 0.001). By multiple logistic regression analysis malignant tumors were associated with increased age, diameter greater than 60mm and bilateral masses. CONCLUSION: This study points to a high rate of pheochromocytomas and malignant tumors in patients selected for surgery. This high rate differs from some previous reports and might be explained by the criteria used to select patients for surgery. Among these two groups of tumors, careful systematic endocrinological investigations allow the detection of altered secretion in the vast majority - if not all - malignant tumors of adrenal origin and pheochromocytomas. Only 5% of the incidentalomas below 30 mm selected for surgery in this study were malignant, in keeping with the use of this criteria as an important parameter to select patients with normal hormonal investigations for careful follow-up.

Adenoma↗
PubMed2000

Gene-covariate interaction between dysplastic nevi and the CDKN2A gene in American melanoma-prone families.

The CDKN2A gene has been implicated in cutaneous malignant melanoma pathogenesis. Although CDKN2A mutations confer substantial risk for melanoma, clinicoepidemiological covariates including dysplastic nevi (DN), total nevi, and solar injury also enhance melanoma risk. To examine the relationship between CDKN2A and these three risk factors, we conducted combined segregation/linkage analysis using the class D regressive logistic model, as implemented in the computer program REGRESS. Genetic and covariate data were collected on 20 American melanoma-prone families, 13 of which had cosegregating CDKN2A mutations. Two types of analyses were conducted. The missing-indicator method used a missing-value indicator, set to 1 for unknown and 0 for known covariate status, and a second variable set to 1 for exposed and 0 for unexposed or unknown. The second method, complete-cases method, coded subjects with missing covariates as unknown for the affection status. The results for both analyses were very similar. Overall, there was a significant improvement in the likelihood when DN, total nevi or both covariates were added to the base model, which included dominant transmission of the CDKN2A gene and a linear increase of risk with the logarithm of age on the logit scale. In contrast, inclusion of solar injury did not significantly improve the likelihood for the base model. Significant evidence for a gene-covariate interaction was detected between DN and CDKN2A when DN was the only covariate in the model (missing-indicator method or complete-cases method) or when both DN and total nevi were in the model (complete-cases method only). Interestingly, in both methods, the odds ratio (OR) for DN was greater in subjects without mutations (OR, 20.1; 95% confidence interval, 4.8-92.8) versus those with CDKN2A mutations (OR, 3.3; 95% confidence interval, 1.1-10.0; complete-cases method). The CDKN2A-DN interaction illustrates the complex etiology of melanoma and needs to be confirmed in a larger sample of families.

Adolescent↗
PubMed2000

Morphology of testis and epididymis in an ethanol-drinking rat strain (UChA and UChB).

The objective of the present study was to analyze the prospective alterations of the testis and epididymis in a defined strain of alcoholic rats in order to contribute to our understanding of the effects of chronic alcoholism on reproduction. The testis and epididymis of the animals were submitted to morphological analysis by macroscopy, light microscopy and electron microscopy and to morphometric analysis. The UCh rats showed atrophy of the epithelium and reduction of testis and epididymis weight, liver hypertrophy and fat infiltration and alterations of the hypothalamus-pituitary axis. Ethanol induces changes in the weight and in the epithelium of the testis and epididymis and in the hypothalamus-pituitary axis of the UCh rats.

Alcoholism↗
PubMed1999

Linkage disequilibrium on the COMT gene in French schizophrenics and controls.

Catechol-O-methyltransferase (COMT) catalyzes the degradation of catecholamines and could therefore play a role in the etiology of schizophrenia. Moreover, microdeletions including the COMT locus have been found in schizophrenics presenting typical features of the velo-cardio-facial syndrome. In the present work, five single-strand conformation polymorphisms were detected in exons of the COMT gene. The linkage disequilibria between the polymorphisms were estimated, and the genotypic frequencies were calculated on a sample of 126 to 137 schizophrenics and 136 to 140 controls, depending on the marker. Patients and controls were matched for ethnicity and geographical origin. A trend toward association was found between schizophrenia and (i) genotype 11 of the Pml I polymorphism (p = 0.034; OR = 1.82); (ii) haplotype 1-2 for the Pml I and Bcl I polymorphisms (p = 0.022; OR = 1.75). The Pml I polymorphism is in complete linkage disequilibrium with the common Met-->Val(158) substitution, which affects the activity of the enzyme. This finding suggests a possible minor effect of COMT in a multifactorial threshold model of vulnerability to schizophrenia.

3' Untranslated Regions↗
PubMed1999

Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.

Chromosomes, Human, Pair 6↗
PubMed1999

The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease.

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinson's disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.

Aged↗
PubMed1999

Detection of quantitative trait loci associated with alcohol-dependence: use of model-free sib-pair method and combined segregation-linkage analysis based on regressive models.

Two linkage methods were used to detect loci underlying neurophysiological measures associated with alcohol dependence 1) the Haseman-Elston (H-E) sib pair method for genome-wide search, and 2) the combined segregation-linkage (CSL), based on regressive models, to confirm positive linkages found by the genome screening. Among 14 linkage results that were significant at the 0.5% level using H-E, the CSL method leads to similar p-values in only three cases but to higher p-values in all others. Investigation of these discrepancies shows that assumptions (normality and homoscedasticity of the error term) of H-E least-squares regression method are not verified. A robust estimator of slope parameters without assuming any distribution function for the linear model error terms increases the p-values and reduces the difference between H-E and CSL results. Alternatively, the CSL approach may lack power when multiple genes with small effects are involved.

Alcoholism↗
PubMed1999

Sib-pair linkage analysis of alcohol dependence taking into account covariates and age-of-onset variability: evaluation of the residual approach.

The construction of residuals allowed us to consider a phenotype related to alcohol dependence (ALDX1) adjusted for age, gender and current smoking status. Using the Haseman and Elston regression test, we compared genome scan results for detection of loci for the unadjusted and adjusted ALDX1 phenotypes in the Collaborative Study on the Genetics of Alcoholism (COGA) data. More markers were significant at the 1% level for the binary than for the residual analyses. Overall, our residual analyses do not show substantial improvement in their ability to detect linkage for alcohol dependence in the COGA data. This may be due to the relatively small sample size of discordant sib pairs.

Age of Onset↗
PubMed1999

Improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome.

OBJECTIVE: Inhaled nitric oxide (NO) and prone position improve arterial oxygenation in patients with the acute respiratory distress syndrome. This study was undertaken to assess the combined effects of NO and prone position in these patients. DESIGN: Prospective clinical study. SETTING: General intensive care service in a community teaching hospital. PATIENTS: 14 mechanically ventilated adult patients with the acute respiratory distress syndrome (mean lung injury score 3.23+/-0.27). MEASUREMENTS AND RESULTS: We measured hemodynamic and oxygenation parameters in the supine position and 2 h later in the prone position, before and during inhalation of 10 ppm NO. A positive response in oxygenation was defined as a > or =20% increment in the arterial oxygen tension/fractional inspired oxygen ratio (PaO2/FIO2). In the prone position PaO2/FIO2 increased significantly (from 110+/-55 to 161+/-89 mm Hg, p<0.01) and venous admixture decreased (from 38+/-12 to 30+/-7%, p<0.01) compared to the supine position. Ten of the 14 patients were responders in the prone position. In the supine position, inhalation of NO improved oxygenation to a lesser extent, increasing PaO2/FIO2 to 134+/-64 mm Hg (p<0.01) and decreasing venous admixture to 35+/-12%, (p<0.01). Five of the 14 patients responded to NO inhalation supine and 8 of 14 responded prone (p = 0.22). The combination of NO therapy and prone positioning was additive in increasing PaO2/FIO2 (197+/-92 mm Hg) and decreasing venous admixture (27+/-8%) (p<0.01). This combination also showed a positive oxygenation response on compared to the supine value without NO in 13 of the 14 patients (93 %). NO-induced changes in PaO2/FIO2 were correlated to changes in pulmonary vascular resistance only in the prone position. CONCLUSIONS: In patients with the acute respiratory distress syndrome, the combination of NO and prone position is a valuable adjunct to mechanical ventilation.

Administration, Inhalation↗
PubMed1999

Fatty acid composition of brain glycerophospholipids in peroxisomal disorders.

This paper shows for the first time the differential fatty acid composition of ethanolamine plasmalogens (EP) and phosphatidylethanolamine (PE) in the brains of 12 patients with disorders of peroxisomal biogenesis and compares the results to normal values for the age. Other important glycerophospholipids (GPL), such as phosphatidylserine (PS) and phosphatidylcholine (PC), are also included in this study. GPL were separated by two-dimensional thin-layer chromatography, and their fatty acid composition was determined by capillary column gas-liquid chromatography. Total brain GPL were slightly decreased in peroxisomal disorders (27.98+/-2.95 micromol/g in the patients against 34.5+/-6.21 micromol/g in age-matched controls, P = 0.005), and the distribution of the different GPL classes was much altered. In confirmation of known data, EP were very much decreased (2.18+/-1.3 micromol/g in the patients against 6.9+/-2.3 micromol/g in controls) at the expense of PE, which was increased (8.58+/-2.17 micromol/g in the patients against 5.97+/-0.58 micromol/g in controls, P<0.005). PS and PC were both significantly decreased (P = 0.0001 and P = 0.037, respectively). The polyunsaturated fatty acid (PUFA) composition of all the GPL fractions was markedly abnormal. In absolute terms, docosahexaenoic acid (22:6n-3) was drastically decreased in all GPL classes (always at the P<0.0001 level) while arachidonic acid (20:4n-6) was increased in PE and PS (P<0.001 in both cases). In the alkenyl acyl form, EP, 22:6n-3, and 20:4n-6 were both very significantly decreased (P<0.0001), although the former was always the most affected. The myelin PUFA adrenic acid (22:4n-6) was decreased in EP (P<0.0001) and slightly increased in PS (P<0.05). The changes found confirm that 22:6n-3 deficiency is a predominant defect in the brain in peroxisomal disorders.

Brain↗
PubMed1999

Effect of predatory stress on sucrose intake and behavior on the plus-maze in male mice.

In this study, the effect of the exposure of male mice to sensory stimuli from rats was assessed on both sucrose intake and the elevated plus-maze tests. CDl male mice were trained in the sucrose intake task (the prestress phase) and, subsequently, distributed into two groups. The stressed group was accommodated in the same room as rats and the control group with mice (the stress phase). After being transferred, animals were tested on sucrose intake and the plus-maze (acute tests) and retested three times a week for sucrose intake and once on plus-maze on the last day (chronic tests). After acute exposure to the predator, the only difference between stressed and control animals was a higher number of fecal boli left on the plus-maze by the former. During the chronic phase, stressed animals showed a lower level of sucrose intake and higher level of anxiety than controls. In conclusion, this study shows that chronic exposure of male mice to stimuli from rats reduces the sensitivity to the rewarding properties of sucrose and prevents the habituation to the plus-maze observed in controls. Thus, this study suggests that exposure of mice to sensory stimuli from rats may provide an animal model of stress, and that these species should not be routinely housed together.

Analysis of Variance↗
PubMed1999

Tolerance to trichlorophenols in microorganisms from a polluted and a pristine site of a river

The effect of 2,4,5- and 2,4,6-trichlorophenol on the microbiota from a polluted and a pristine site of a river was studied. Bacterial metabolic activity measurements by epifluorescence microscopy showed that the polluted site contained more metabolically active cells than the pristine site. Total culturable bacterial counts and tolerant bacterial counts from both sites were not affected by incubation (for up to 5 days) with 200 ppm of chlorophenols. However, the incubation with 500 ppm of 2,4,5-trichlorophenol prevented detection of total and tolerant bacterial counts in the pristine site, and inhibited tolerants in the polluted site. None of 250 bacterial colonies directly isolated from these samples was able to grow on chlorophenols. However, bacteria able to grow on 2,4,6-trichlorophenol, were obtained by enrichment of water and sediments samples.

Journal Article↗
PubMed1999

Central serotonin depletion modulates the behavioural, endocrine and physiological responses to repeated social stress and subsequent c-fos expression in the brains of male rats.

Intraspecific confrontation has been used to study effect of depleting central serotonin on the adaptation of male rats to repeated social stress (social defeat). Four groups of adult male rats were used (serotonin depletion/sham: stressed; serotonin depletion/sham: non-stressed). Central serotonin was reduced (by 59-97%) by a single infusion of the neurotoxin 5,7-dihydroxtryptamine (150 microg) into the cerebral ventricles; levels of dopamine and noradrenaline were unaltered (rats received appropriate uptake blockers prior to neurotoxic infusions). Sham-operated animals received solute only. Rats were then either exposed daily for 10 days to a second larger aggressive male in the latter's home cage, or simply transferred to an empty cage (control procedure). Rats with reduced serotonin failed to show the increased freezing behaviour during the pre-defeat phase of the social interaction test characteristic of sham animals. There was no change in the residents' behaviour. Core temperature increased during aggressive interaction in sham rats, and this did not adapt with repeated stress. By contrast, stress-induced hyperthermia was accentuated in serotonin-reduced rats as the number of defeat sessions increased. Basal core temperature was unaffected by serotonin depletion. Heart rate increased during social defeat, but this did not adapt with repeated stress; serotonin depletion had no effect on this cardiovascular response. Basal corticosterone was increased in serotonin-depleted rats, but the progressive reduction in stress response over days was not altered. C-fos expression in the brain was not altered in control (non-stressed) rats by serotonin reduction in the areas examined, but there was increased expression after repeated social stress in the medial amygdala of 5-HT depleted rats. These experiments show that reduction of serotonin alters responses to repeated social stress in male rats, and suggests a role for serotonin in the adaptive process.

5,7-Dihydroxytryptamine↗