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José A Lorente

Publications and source records attributed to José A Lorente.

10 recordsLinked to original sources
PubMed2006

The 5-HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: the PREDICT-gene study.

Previous reports and meta-analyses have yielded inconclusive results as to whether the s/s genotype at the 5-HTTLPR serotonin transporter polymorphism confers increased risk for depression. We tested the association between s/s genotype and depression in a large cohort (n = 737) of Spanish primary care consecutive attendees participating in a European study on predictors for depression in primary care (PREDICT study). Participants were administered the Composite International Diagnostic Interview (CIDI) depression subscale allowing diagnoses using ICD-10 criteria for depressive episodes. Participants were genotyped to establish 5HTTLPR genotype. Both univariable and multivariable associations between the s/s genotype and depression were tested twice using two different depressive outcomes (ICD-10 depressive episode and ICD-10 severe depressive episode). We found an association between the s/s genotype and both depressive outcomes that was independent of age, sex, family history of psychological problems among first degree relatives and presence of comorbid generalized anxiety disorder. When comparing s/s homozygous versus the rest, the adjusted odds ratio for any ICD-10 depressive episode and for severe ICD-10 depressive episode were 1.50 (95% CI: 1.0-2.2; P = 0.045) and 1.79 (95% CI: 1.1-2.8; P = 0.016), respectively. The association was significantly stronger with increasing severity of depression (chi2 for linear association=6.1; P = 0.013) suggesting a dose-dependent relationship. Our results are consistent with previous reports suggesting a small but independent effect by the s/s 5-HTTLPR genotype increasing the risk for depression.

Adult↗
PubMed2006

Ventilation-induced lung injury in rats is associated with organ injury and systemic inflammation that is attenuated by dexamethasone.

OBJECTIVE: To determine whether mechanical ventilation using high tidal volume is associated with nonpulmonary organ dysfunction that can be attenuated by dexamethasone. DESIGN: Prospective randomized animal intervention study. SETTING: Animal care facility in a university hospital. SUBJECTS: Sedated and tracheostomized male Sprague-Dawley rats. INTERVENTIONS: Three groups of rats were ventilated with different strategies: tidal volume = 9 mL/kg, positive end-expiratory pressure = 8 cm H(2)O, control group (C); tidal volume = 35 mL/kg, positive end-expiratory pressure = 0 cm H(2)O, overventilated group (OV); and tidal volume = 35 mL/kg, positive end-expiratory pressure = 0 cm H(2)O, plus administration of 6 mg/kg dexamethasone intraperitoneally (OV + dexamethasone). All rats were ventilated for 75 mins with respiratory rate = 70 breaths/min, FIO(2) = 0.35, and plateau time = 0. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and peak airway pressure were monitored. We measured arterial blood gases, aspartate aminotransferase, alanine aminotransferase, lactate, nitrates and nitrites, tumor necrosis factor-alpha, and interleukin-6 serum concentration. Lung slices were prepared for blind histologic examination. Heart tissue was analyzed for cyclooxygenase-1 and -2 expression (reverse transcription-polymerase chain reaction). Compared with the C group, the OV group showed hypotension; worsened gas exchange; increased aspartate aminotransferase, lactate, nitrates and nitrites, and interleukin-6 serum concentrations; and hyaline membrane formation in the lungs, as well as increased cyclooxygenase-1 and cyclooxygenase-2 expression in the heart. Dexamethasone prevented the pulmonary and cardiovascular injury and attenuated the increase in aspartate aminotransferase, nitrates and nitrites, interleukin-6, and cyclooxygenase-1 and cyclooxygenase-2 expression. CONCLUSIONS: High tidal volume ventilation induces cardiovascular, pulmonary, and liver injury as well as a systemic proinflammatory response. These changes are attenuated by dexamethasone, suggesting that inflammatory rather than purely hemodynamic mechanisms are involved in the changes induced by high tidal volume ventilation.

Animals↗
PubMed2005

Mitochondrial DNA error prophylaxis: assessing the causes of errors in the GEP'02-03 proficiency testing trial.

We report the results of the Spanish and Portuguese working group (GEP) of the International Society for Forensic Genetics (ISFG) Collaborative Exercise 2002-2003 on mitochondrial DNA (mtDNA) analysis. Six different samples were submitted to the participating laboratories: four blood stains (M1-M2-M3-M4), one mixture blood sample (M5), and two hair shaft fragments (M6). Most of the labs reported consensus results for the blood stains, slightly improving the results of previous collaborative exercises. Although hair shaft analysis is still carried out by a small number of laboratories, this analysis yielded a high rate of success. On the contrary, the analysis of the mixture blood stain (M5) yielded a lower rate of success; in spite of this, the whole results on M5 typing demonstrated the suitability of mtDNA analysis in mixture samples. We have found that edition errors are among the most common mistakes reported by the different labs. In addition, we have detected contamination events as well as other minor problems, i.e. lack of standarization in nomenclature for punctual and length heteroplasmies, and indels. In the present edition of the GEP-ISFG exercise we have paid special attention to the visual phylogenetic inspection for detecting common sequencing errors.

Blood Stains↗
PubMed2005

Neutralization of tumor necrosis factor in preclinical models of sepsis.

Tumor necrosis factor (TNFalpha), a cardinal early mediator of the innate host inflammatory response, has been an attractive target for therapeutic intervention in human sepsis. However, pooled data from 12 completed randomized controlled trials show only a very modest impact on mortality in a highly heterogeneous population of patients. To gain insight into the preclinical in vivo biology of TNFalpha that might aid in better identifying appropriate patient populations for therapeutic intervention, we undertook a systematic review of published reports of preclinical studies assessing the consequences of neutralization of TNFalpha in models of acute infection or inflammation. We identified 143 reports incorporating 484 unique experimental comparisons in seven different animal species. The effects of neutralization of TNFalpha in these were quite variable. Neutralization of TNFalpha was beneficial in endotoxemia, or after systemic challenge with gram-negative organisms, Staphylococcus aureus, or Group B streptococci. On the other hand, neutralization was detrimental in infections caused by Streptococcus pneumoniae, Candida spp., or intracellular pathogens such as Listeria and Mycobacterium tuberculosis, and in models of pneumonia. Treatment was more efficacious when delivered before infectious challenge, and the therapeutic signal increased as the baseline mortality in the placebo group increased. Evidence of neutralization of TNFalpha bioactivity, and of attenuation of inflammation, was typically accompanied by evidence of impairment of antimicrobial defenses. Multiple specific and nonspecific therapeutic strategies were identified. We conclude that the beneficial effects of TNF in systemic inflammation occur at the cost of impaired antimicrobial defenses, and that a better understanding of the consequences of neutralization of TNFalpha in vivo could aid in better defining optimal patient populations for therapeutic intervention.

Animals↗
PubMed2005

Large tidal volume mechanical ventilation induces vascular dysfunction in rats.

BACKGROUND: Experimental studies have shown that mechanical ventilation using high tidal volumes (V(T)) damages the lungs, causing pulmonary edema. We tested the hypothesis that high V(T) ventilation in rats induces major vascular dysfunction. METHODS: Healthy Sprague-Dawley rats, weighing (mean +/- SD) 340 +/- 15 g, were ventilated with either V(T) = 9 mL/kg and positive end-expiratory pressure (PEEP) = 8 (n = 8) or V(T) = 35 mL/kg and PEEP = 0 (n = 8). The high V(T) used in the injurious ventilation group is in the V(T) range used in other studies to induce lung damage in a short period of time in rats. Lungs were removed for examination under light microscopy and vascular rings from the thoracic aorta were studied for isometric tension recording. RESULTS: Relaxations to acetylcholine (p < 0.001) and sodium nitroprusside (p < 0.05) and contractions to norepinephrine were markedly decreased (p < 0.001) in the high V(T) group, as compared with the low V(T) group. CONCLUSION: Injurious mechanical ventilation in normal rats is associated with vascular dysfunction characterized by decreased relaxation to an endothelium-dependent vasodilator and to a nitrous oxide donor and by decreased response to norepinephrine.

Analysis of Variance↗
PubMed2003

The 2000-2001 GEP-ISFG Collaborative Exercise on mtDNA: assessing the cause of unsuccessful mtDNA PCR amplification of hair shaft samples.

We report the results of Spanish and Portuguese working group (GEP) of International Society of Forensic Genetics (ISFG) Collaborative Exercise 2001-2002 on mitochondrial DNA (mtDNA) analysis. 64 laboratories from Spain, Portugal and several Latin-American countries participated in this quality control exercise. Five samples were sent to the participating laboratories, four blood stains (M1-M4) and a sample (M5) consisting of two hair shaft fragments. M4 was non-human (Felis catus) in origin; therefore, the capacity of the labs to identify the biological source of this sample was an integral part of the exercise. Some labs detected the non-human origin of M4 by carrying out immuno-diffussion techniques using antihuman serum, whereas others identified the specific animal origin by testing the sample against a set of animal antibodies or by means of the analysis of mtDNA regions (Cyt-b, 12S, and 16S genes). The results of the other three human blood stains (M1-M3) improved in relation to the last Collaborative Exercises but those related to hairs yielded a low rate of success which clearly contrasts with previous results. As a consequence of this, some labs performed additional analysis showing that the origin of this low efficiency was not the presence of inhibitors, but the low quantity of DNA present in these specific hair samples and the degradation. As a general conclusion the results emphasize the need of external proficiency testing as part of the accreditation procedure for the labs performing mtDNA analysis in forensic casework.

Accreditation↗
PubMed2003

Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis.

Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Results of the 1999-2000 collaborative exercise and proficiency testing program on mitochondrial DNA of the GEP-ISFG: an inter-laboratory study of the observed variability in the heteroplasmy level of hair from the same donor.

The Spanish and Portuguese working group (GEP) of international society for forensic genetics (ISFG) 1999-2000 collaborative exercise on mitochondrial DNA (mtDNA) included the analysis of four bloodstain samples and one hair shaft sample by 19 participating laboratories from Spain, Portugal and several Latin-American countries. A wide range of sequence results at position 16,093 of the HV1 (from T or C homoplasmy to different levels of heteroplasmy) were submitted by the different participating laboratories from the hair shaft sample during the first phase of this exercise. During the discussion of these results in the Annual GEP-ISFG 2000 Conference a second phase of this exercise was established with two main objectives: (i) to evaluate the incidence of the HV1 sequence heteroplasmy detected in Phase I across different sample types from the same donor including blood, saliva, and hair shafts, (ii) to perform a technical review of the electropherograms to evaluate the relative levels of heteroplasmies obtained by the different laboratories and also to examine the source of possible errors detected in Phase I. Anonymous review of the raw sequence data permitted the detection of three transcription errors and three errors due to methodological problems. Highly variable levels of heteroplasmy were found in the hair shaft and more stability in blood and saliva. Three laboratories found variable levels of heteroplasmy at position 16,093 across adjacent fragments from the same hair shaft. Two laboratories also described more than one heteroplasmic position from a single hair. The relevance of these findings for the interpretation of mtDNA data in the forensic context is also discussed.

Blood Stains↗
PubMed2002

Interaction between hemoglobin and glutathione in the regulation of blood flow in normal and septic pigs.

BACKGROUND: Hemoglobin (Hb) induces vasoconstriction by heme group binding nitric oxide in an irreversible fashion. Recent in vitro studies indicate that the thiol groups in Hb reversibly bind nitric oxide and participate in trans-nitrosylation reactions with other thiols. Sepsis is a pathophysiologic state characterized by vasodilation mediated, at least in part, by an excessive release of nitric oxide. The role of nitrosothiols (RSNOs) in these changes is unknown. OBJECTIVES: We tested the following in a porcine model of sepsis: (i) whether glutathione (GSH) reverses the hemodynamic effects of Hb; (ii) whether GSH induces an increase in blood flow in sepsis; (iii) whether RSNO plasma concentration increases in sepsis and is related to hypotension. DESIGN: Nonrandomized animal controlled study. SETTING: Animal research facility in a university hospital. SUBJECTS: Anesthetized pigs were monitored with a pulmonary artery catheter and ultrasonic blood flow probes in the mesenteric artery and the portal vein for measurement of systemic, mesenteric, and portal blood flows (Q(TOT), Q(MES), and Q(POR), respectively). Four groups of pigs were studied: nonseptic, septic, nonseptic treated with Hb (stroma-free purified porcine hemoglobin), and septic treated with Hb (n = 6 in each group). INTERVENTIONS: Sepsis was induced at 0 min by the administration of live Escherichia coli. Hb (400 mg/kg/hr) was administered at 240 mins, followed by glutathione (1 g iv). MEASUREMENTS AND MAIN RESULTS: Hb induced a pressor response and a decrease in Q(TOT), Q(MES), and Q(POR). Glutathione reversed the effects of Hb on Q(MES) and Q(POR). In septic pigs not treated with Hb, GSH induced an increase in Q(POR). RSNO plasma concentration increased after the induction of sepsis and correlated significantly with blood pressure. CONCLUSIONS: These results indicate the reversibility of the effects of Hb by GSH, probably by interactions between nitric oxide and the reduced sulfhydryl groups in Hb, and suggest a role of RSNOs in the cardiovascular changes of sepsis.

Analysis of Variance↗