Evaluación de la validez de las funciones SCORE de bajo riesgo y calibrada para población española en las cohortes FRESCO

Introduction and objectives

To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population.

Differential Roles of Antimicrobials in the Acquisition of Drug Resistance through Activation of the SOS Response in Acinetobacter baumannii

The effect of antimicrobials on SOS-mediated mutagenesis induction depends on the bacterial species and the antimicrobial group. In this work, we studied the effect of different families of antimicrobial agents used in clinical therapy against Acinetobacter baumannii in the induction of mutagenesis in this multiresistant Gram-negative pathogen. The data showed that ciprofloxacin and tetracycline induce SOS-mediated mutagenesis, whereas colistin and meropenem, which are extensively used in clinical therapy, do not.     

Criterion-Related Validity of the 20-M Shuttle Run Test for Estimating Cardiorespiratory Fitness: A Meta-Analysis

The main purpose of the present meta-analysis was to examine the criterion-related validity of the 20-m shuttle run test for estimating cardiorespiratory fitness. Relevant studies were searched from twelve electronic databases up to December 2014, as well as from several alternative modes of searching. The Hunter-Schmidt’s psychometric meta-analysis approach was conducted to estimate the population criterion-related validity of the 20-m shuttle run test. From 57 studies that were included in the present meta-analysis, a total of 78 correlation values were analyzed. The overall results showed that the performance score of the 20-m shuttle run test had a moderate-to-high criterion-related validity for estimating maximum oxygen uptake (r_p = 0.66-0.84), being higher when other variables (e.g. sex, age or body mass) were used (r_p = 0.78-0.95). The present meta-analysis also showed that the criterion-related validity of Léger’s protocol was statistically higher for adults (r_p = 0.94, 0.87-1.00) than for children (r_p = 0.78, 0.72-0.85). However, sex and maximum oxygen uptake level do not seem to affect the criterion-related validity values. When an individual’s maximum oxygen uptake attained during a laboratory-based test is not feasible, the 20-m shuttle run test seems to be a useful alternative for estimating cardiorespiratory fitness. In adults the performance score only seems to be a strong estimator of cardiorespiratory fitness, in contrast among children the performance score should be combined with other variables. Nevertheless, as in the application of any physical fitness field test, evaluators must be aware that the performance score of the 20-m shuttle run test is simply an estimation and not a direct measure of cardiorespiratory fitness.

Key points

• Overall the 20-m shuttle run test has a moderate-to-high mean criterion-related validity for estimating cardiorespiratory fitness.
• The criterion-related validity of the 20-m shuttle run test is significantly higher for adults than for children. However, when the performance score is combined with other variables, the criterion-related validity value increases considerably among children.
• Sex and maximum oxygen uptake level of individuals seem not to affect the criterion-related validity of the 20-m shuttle run test.
• When individuals’ maximum oxygen uptake attained during a laboratory-based test is not feasible, the 20-m shuttle run test seems to be a useful alternative for estimating cardiorespiratory fitness.

Key words: Maximum oxygen uptake, peak oxygen uptake, PACER, Multistage fitness test, Léger test     

Mild hyperhomocysteinemia is associated with impaired renal function but not with progression of small abdominal aortic aneurysms

To study the possible role of homocysteine in aneurysmatic progression, in 1994, 112 of 141 male patients with abdominal aortic aneurysm (AAA) diagnosed by population screening were interviewed and examined. Creatinine clearance estimated and total plasma homocysteine (P-tHcy) was measured by gas chromatography-mass spectrometry. Of the 112 cases, 99 were followed with annual ultrasonography and blood pressure measurements for 1–5 years (mean 2.5 years). The mean creatinine clearance was 70.8+/-23.1 ml/min, while the mean P-tHcy was 16.0+/-10.6 mmol/l, significantly increased compared with an age- and sex-matched reference population (P<0.01). However, no trend of correlation with AAA size or aneurysmal progression was found concerning creatinine clearance and homocysteine level. There were still no trend after adjustment for age, smoking, diastolic blood pressure, and initial ankle blood pressure index. However, the homocysteine level was positively correlated with decreasing creatinine clearance (r=0.36,P<0.01), and this correlation was still present after the same adjustments. A large proportion of men with AAA have mild hyperhomocysteinemia; this does not influence aneurysmal progression and may be due to coexisting impaired renal function. The finding might explain why prospective and intervention studies cannot prove for certain that hyperhomocysteinemia influences atherosclerotic progression, or that treatment is beneficial.     

An anti-CD45RO immunotoxin kills latently infected human immunodeficiency virus (HIV) CD4 T cells in the blood of HIV-positive persons.

Highly active antiretroviral therapy has decreased the morbidity and mortality of human immunodeficiency virus (HIV) infection, but latently infected cells remain for prolonged periods. CD4(+) CD45RO(+) T cells are a major latent virus reservoir in HIV-infected persons. Replication-competent, latently HIV-infected T cells can be generated in vitro by infecting peripheral blood mononuclear cells with HIV and then eliminating the HIV-producing cells with an anti-CD25 immunotoxin (IT). The CD25(-) latently infected cells then can be eliminated with an anti-CD45RO IT. This study determined whether this IT also could kill latently infected CD4 T cells from HIV-infected persons with or without detectable plasma viremia. The results show that ex vivo treatment of cells from HIV-positive persons by anti-CD45RO IT reduces the frequency of both productively and latently infected cells. In contrast, CD4(+) CD45RA(+) naive T cells and a proportion of CD4(+) CD45RO(lo) memory T cells are spared.     

Tuberculosis recurrences: reinfection plays a role in a population whose clinical/epidemiological characteristics do not favor reinfection

BACKGROUND: Tuberculosis (TB) recurrences can be due to either reactivation by the same strain (standard assumption) or reinfection by a new strain. Reinfection has mainly been studied in selected populations with a high risk of reexposure to TB. Our aim was to analyze the role of reinfection in TB recurrences in unselected populations, without the clinical/epidemiological circumstances that favor the involvement of a new different strain of Mycobacterium tuberculosis in the recurrence. METHODS: A molecular typing analysis was performed with 92 sequential isolates of M tuberculosis from 43 patients with recurrent TB, during a 12-year period. The subjects were both positive and negative for the human immunodeficiency virus, most did not adhere to anti-TB therapy, and they lived in an area with a moderate incidence of TB. Recurrence was considered as being caused by reinfection when the molecular fingerprints for the strains involved in the sequential episodes of TB were different. RESULTS: In 14 (33%) of the 43 patients, different M tuberculosis strains were involved in the first and in subsequent episodes of TB. Reinfection was found for patients who were both positive and negative for the human immunodeficiency virus, and most patients did not adhere to anti-TB therapy. Differences between the reinfection and reactivation groups were not significant (P =.77) according to the time interval between episodes. CONCLUSIONS: Reinfection plays an important role in recurrent TB in a population without the clinical/epidemiological circumstances that are usually assumed to favor it. Reinfection should, thus, be considered as a cause of TB recurrences in a wider context than before.     

Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.     

Physical activity affects plasma coenzyme Q10 levels differently in young and old humans

Coenzyme Q (Q) is a key lipidic compound for cell bioenergetics and membrane antioxidant activities. It has been shown that also has a central role in the prevention of oxidation of plasma lipoproteins. Q has been associated with the prevention of cholesterol oxidation and several aging-related diseases. However, to date no clear data on the levels of plasma Q during aging are available. We have measured the levels of plasmatic Q₁₀ and cholesterol in young and old individuals showing different degrees of physical activity. Our results indicate that plasma Q₁₀ levels in old people are higher that the levels found in young people. Our analysis also indicates that there is no a relationship between the degree of physical activity and Q₁₀ levels when the general population is studied. However, very interestingly, we have found a different tendency between Q₁₀ levels and physical activity depending on the age of individuals. In young people, higher activity correlates with lower Q₁₀ levels in plasma whereas in older adults this ratio changes and higher activity is related to higher plasma Q₁₀ levels and higher Q₁₀/Chol ratios. Higher Q₁₀ levels in plasma are related to lower lipoperoxidation and oxidized LDL levels in elderly people. Our results highlight the importance of life habits in the analysis of Q₁₀ in plasma and indicate that the practice of physical activity at old age can improve antioxidant capacity in plasma and help to prevent cardiovascular diseases.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.