Biomedical subjects

J Gallego

Publications and source records attributed to J Gallego.

At least 19 recordsLinked to original sources

PubMed2001

Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1.

Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to mature endothelin-1. Most homozygous ECE-1-/- embryos die in utero and show severe craniofacial, enteric, and cardiac malformations precluding ventilatory function assessment. In contrast, heterozygous ECE-1+/- embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations in mice with endothelin-1 gene disruption, we hypothesized that ECE-1-deficient mice may have impaired ventilatory control. We analyzed ventilatory responses to hypercapnia (8% CO(2)) and hypoxia (10% O(2)) in newborn and adult mice heterozygous for ECE-1 deficiency (ECE-1+/-) and in their wild-type littermates (ECE-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypoxia were significantly weaker in ECE-1+/- than in ECE-1+/+ newborn mice (percentage ventilation increase: 1 +/- 25% versus 33 +/- 29%, p = 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal in the ECE-1+/- newborn mice. No differences were observed between adult ECE-1+/- and ECE-1+/+ mice. We conclude that ECE-1 is required for normal ventilatory response to hypoxia at birth.

Animals↗

PubMed2000

[Respiratory behavior].

The notion of respiratory behaviour is grounded, among other approaches, on studies of neuronal mechanisms of voluntary breathing, clinical data, conditioning experiments and respiratory sensations. The interactions between cortical centres of voluntary breathing and respiratory neurones in the brain stem are poorly understood: voluntary control operates through the direct action of corticomotor centres on respiratory motoneurones; however these cortical structures may directly act on bulbopontine centres, and therefore indirectly on respiratory motoneurones. Recordings in animals of brain stem neuronal activity, brain imaging in humans, and transcortical stimulation of the diaphragm in humans and in animal models support either one or the other hypothesis. The mutual independence of the automatic and the voluntary controls of breathing appears in patients with impaired bulbopontine automatism and operational voluntary control (Central Congenital Hypoventilation Syndrome), and in patients with the reverse impairment (locked-in syndrome). Finally, recent studies in humans and animals show that classical conditioning affects respiratory control and sensations.

Animals↗

PubMed2000

Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial.

This study aims to establish the relative effectiveness and safety of low molecular weight heparin in elderly patients with venous thrombosis in order to find an alternative to oral anticoagulant therapy with less bleeding complications in the long-term treatment of deep venous thrombosis (DVT). One hundred consecutive elderly patients (>75 years old) with venographically demonstrated proximal DVT were included in a randomized trial. All patients were treated for ten days with adjusted doses of intravenous heparin. Informed consent was obtained and on the eight day, patients were randomly allocated to receive acenocoumarol (INR 2.0-3.0) or subcutaneous enoxaparin (4000 anti-Xa units once a day) for three months. All patients were followed-up clinically and venographically for a one year period. The results were analyzed with Fisher's exact test or chi-square test as appropriate. During the treatment and surveillance period, 6 of the 50 patients (12%) who received acenocoumarol and 8 of the 50 patients (16%) who received enoxaparin had new episodes of venous thromboembolism confirmed by objective testing (p = 0.6; 95% CI for the difference: -19.5 to 11.5). Hemorrhagic complications occurred in six of the 50 patients (12%) who received acenocoumarol and in one (2%) of those on enoxaparin (p = 0.1; 95% CI for the difference: -1.8 to 21.8). Vertebral fractures developed in 2 patients (4%) in the enoxaparin group (p = 0.5; 95% CI for the difference: -11.4 to 3.4). These results show that fixed dose enoxaparin seems to be effective and safe in the long-term treatment of proximal DVT in the elderly. In comparison with oral anticoagulants, the findings are inconclusive due to the wide confidence intervals for differences between outcomes, however they suggest that the former may have less bleeding complications with similar efficacy.

Acenocoumarol↗

PubMed1999

Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale.

Using a combination of nuclear magnetic resonance (NMR) spectroscopy experiments and molecular dynamics, we have analyzed the structure and dynamics of a complex between the bisnaphthalimide drug LU-79553 and the DNA duplex d(ATGCAT)(2). LU-79553 is a DNA-binding topoisomerase II inhibitor that is particularly effective against human solid tumors that are refractory to other drugs. We have found that the two naphthalimide chromophores of the drug bisintercalate at the TpG and CpA steps of the DNA hexanucleotide, stacking mainly with the purine G and A bases from opposite strands. The 3, 7-diazanonylene linker lies in the major groove of the DNA molecule, with its two amino groups hydrogen-bonded to the symmetry-related guanine bases. Unexpectedly, we have detected an unprecedented exchange process between two equivalent and intercalated states of the naphthalimide rings in the drug-DNA complex. The interconversion process takes place by rotational ring flipping, has an activation energy of 22 kcal mol(-)(1) for the two rings, and does not affect the aminoalkyl linker region of the drug. The exchange rate is intermediate to fast on the chemical shift time scale at 36 degrees C (1800 s(-)(1)) but slow at 2 degrees C (20 s(-)(1)). We have also observed limited flexibility for the drug linker on the picosecond time scale on the basis of NMR data and a time-averaged restrained molecular dynamics simulation. The implications of the structural and dynamic features of the DNA-LU-79553 complex on the binding specificity and on the antitumor activity of bisnaphthalimide agents are discussed.

Amides↗

PubMed1999

The folding of centromeric DNA strands into intercalated structures: a physicochemical and computational study.

We have carried out a physicochemical and computational analysis on the stability of the intercalated structures formed by cytosine-rich DNA strands. In the computational study, the electrostatic energy components have been calculated using a Poisson-Boltzmann model, and the non-polar energy components have been computed with a van der Waals function and/or a term dependent on the solvent-accessible surface area of the molecules. The results have been compared with those obtained for Watson-Crick duplexes and with thermodynamic data derived from UV experiments. We have found that intercalated DNA is mainly stabilized by very favorable electrostatic interactions between hydrogen-bonded protonated and neutral cytosines, and by non-polar forces including the hydrophobic effect and enhanced van der Waals contacts. Cytosine protonation electrostatically promotes the association of DNA strands into a tetrameric structure. The electrostatic interactions between stacked C.C+ pairs are strongly attenuated by the reaction field of the solvent, and are modulated by a complex interplay of geometric and protonation factors. The forces stabilizing intercalated DNA must offset an entropic penalty due to the uptake of protons for cytosine protonation, at neutral pH, and also the electrostatic contribution to the solvation free energy. The latter energy component is less favorable for protonated DNA due to the partial neutralization of the negative charge of the molecule, and probably affects other protonated DNA and RNA structures such as C+-containing triplexes.

Centromere↗

PubMed1999

Behavioural correlates of conditioned ventilatory responses to hypoxia in rats.

To examine the possible contribution of behavioural arousal to ventilatory conditioning, we performed a differential conditioning experiment using two odours as the paired conditioned stimulus (CS + ) and unpaired conditioned stimulus (CS-) and a hypoxic mixture (7.5% O2) as the unconditioned stimulus (US) in 24 adult male rats. Vanillin was the CS + and rose the CS - in half the rats, and vice versa in the other half. Each rat underwent 26 paired CS + /hypoxia trials and 26 CS - trials in alternation, followed by two CS + only and two CS - trials to test for conditioning. Analysis of breathing variables and behavioural scores during the test showed two qualitatively different conditioned responses. The initial conditioned response was characterised by short breath durations (TT), frequent sniffing episodes, and arousal responses. Following this, a specific, conditioned increase in tidal volume (VT) and levelling off of sniffing and motor activities occurred. The early TT-response and late VT-response to CS + both contributed to an increase in ventilation (VI). The present data show that the association of an odour and hypoxia elicits a biphasic ventilatory conditioned response, of which the first component is integrated into conditioned arousal.

Animals↗

PubMed1999

Ventilatory responses to hypercapnia and hypoxia in Mash-1 heterozygous newborn and adult mice.

Normal control of breathing is characterized by maintenance of CO2 and O2 arterial pressures at constant levels by appropriate ventilatory responses to changes in CO2 production and O2 consumption. Abnormal development of this regulatory system during embryogenesis may produce early impairments in chemosensitivity, as in congenital central hypoventilation syndrome. The present study addresses the role of the mammalian achaetescute homologous gene (Mash-1) in the development of respiratory control. We analyzed ventilatory responses to hypercapnia (8% CO2, 21% O2, 71% N2) and hypoxia (10% O2, 3% CO2, 87% N2) in newborn and adult Mash-1 heterozygous mice (Mash-1+/-) and their wild-type littermates (Mash-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypercapnia were significantly weaker in newborn male Mash-1+/- compared with Mash-1+/+ mice as a result of a weaker breath-duration response. No differences were observed between adult Mash-1+/- and Mash-1+/+ mice. Our data suggest that Mash-1 may be involved in respiratory control development via mechanisms linked to the X chromosome.

Animals↗

PubMed1999

Using gadolinium-enhanced three-dimensional MR angiography to assess arterial inflow stenosis after kidney transplantation.

OBJECTIVE: Our objective was to evaluate use of gadolinium-enhanced three-dimensional (3D) MR angiography in the assessment of suspected arterial inflow stenosis after kidney transplantation. SUBJECTS AND METHODS: Twenty-eight consecutive patients receiving kidney transplants (26 single-kidney transplants and two en block transplants) with suspected arterial inflow stenosis were examined with two MR angiography sequences: gadolinium-enhanced 3D fast spoiled gradient-recalled (SPGR) imaging and 3D phase-contrast imaging. Twenty-four of these patients then were examined using the gold standards: either digital subtraction angiography (DSA) (n = 23) or surgery (n = 1). MR angiography and DSA studies were independently and prospectively analyzed for the presence of arterial stenoses (mild [<50%], severe [50-90%], or critical [>90%]) in the iliac, anastomotic, and renal artery segments. Two independent observers retrospectively evaluated the MR angiography sequences for ability to detect or exclude significant (> or = 50%) arterial stenoses. RESULTS: In 22 single-kidney transplants, DSA showed eight significant stenoses in 66 arterial segments. MR angiograms adequately showed 66 of 66 segments (prospective observers) and 64 of 66 segments (each retrospective observer), which were subsequently evaluated. The sensitivity and specificity of MR angiography in revealing significant stenoses were 100% and 98% (prospective analysis), 88% and 98% (retrospective observer 1), and 86% and 100% (retrospective observer 2). Concordance between observers showed kappa values exceeding .85 for all comparisons except the analysis of phase-contrast series (kappa = .62). In one en block transplant, DSA showed that stenosis was greater than 90%, although it had been graded at less than 50% with MR angiography. CONCLUSION: Gadolinium-enhanced 3D MR angiography accurately evaluated arterial inflow in single-kidney transplants.

Angiography, Digital Subtraction↗

PubMed1998

Biochemical parameters for the diagnosis of mitochondrial respiratory chain deficiency in humans, and their lack of age-related changes.

It is now widely acknowledged that a large number of human diseases originate from respiratory-chain dysfunctions. Because the molecular bases of these diseases are still poorly known, a biochemical approach has to be used in the screening procedures for the diagnoses of these conditions. Assessment of respiratory-chain function in human samples faces several problems: (i) the small size of available samples, (ii) the determination of discriminating parameters, and (iii) the interfering factors, such as age and physical activity. The present study focuses on isolated mitochondria prepared from a minute amount (100-200 mg) of skeletal-muscle biopsies from 201 patients between 0 and 65 years. Whereas 42 patients presented an isolated complex (C)I, CII, CIII or CIV deficiency, no respiratory-chain dysfunction or indirect evidence for a mitochondrial disorder could be attested in 159 of these patients. In this reference group, there was little correlation between enzyme activities and age, whatever the age class considered, 0-3 or 0-65 years of age. However, a confident handling of data points was largely hampered by the marked scattering of enzyme activities measured in the reference population. Activity ratios between the various respiratory-chain complexes presenting a much reduced scattering may be considered as diagnostic tools. As to the effect of age, no correlation with any of the enzyme-activity ratios could be shown. Use of age-matched controls for the diagnosis of respiratory-chain disorders may therefore be avoided, enzyme-activity ratios being highly discriminating and age-independent parameters.

Adolescent↗

PubMed1998

Arteriovenous fistula as a complication of lumbar disc surgery: case report.

Arteriovenous fistula (AVF) is a rare, late complication of lumbar disc surgery. It is often not suspected and the symptoms are diagnosed as heart failure or deep venous thrombosis. We report a case in which the patient developed leg swelling and high-output congestive heart failure due to a left ilioiliac AVF after lumbar laminectomy.

Adult↗

PubMed1998

The effects of restraint on ventilatory responses to hypercapnia and hypoxia in adult mice.

The aim of this experiment was to determine whether ventilatory measurements in adult restrained mice provide a valid assessment of chemosensitivity. We used whole-body plethysmography to compare breathing patterns in eight restrained and eight unrestrained outbred Swiss mice during air breathing, hypercapnia, and hypoxia. The mice in the restrained group were each placed in a loosely restraining wire-mesh cage. The unrestrained mice could move freely inside the plethysmograph. All the mice received three hypercapnic stimuli (8.5% CO2) and three hypoxic isocapnic stimuli (10% O2, 3.5% CO2). As compared to unrestrained mice, restrained mice had significantly lower breath durations (TT, 445+/-110 ms vs. 323+/-32 ms) and higher ventilation (VE) levels (15.7+/-2.6 microl/(sec x g) vs. 22.2+/-4.5 microl/(sec x g)), whereas no difference was observed for tidal volume (VT). The increases in frequency and ventilation from baseline to hypercapnia were not significantly different in restrained and unrestrained mice. The VE response to hypoxia was marginally higher in restrained mice. We conclude that chemosensitivity to hypercapnia, and to a lesser extent to hypoxia, can be measured in restrained adult mice, but that the baseline breathing pattern cannot.

Animals↗

PubMed1998

The effect of attentional load on the breathing pattern in children.

Experiments designed to establish the effects of video games on breathing patterns have led to contradictory results. Several authors reported that video games tended to increase breathing frequency (i.e. to reduce breath duration), whereas others reported the opposite. We postulated that video games contain different psychophysiological components which may have opposite effects on breathing pattern. On the one hand, arousal and emotion may tend to stimulate breathing. On the other, focusing attention on the game may prompt subject to inhibit any movement--including breathing--which might be a potential nuisance variable. The aim of this study was to assess the specific effects of the attentional load in an experimental environment characterized by its low emotional impact. We measured breathing variables, cardiac frequency and cortisol levels in 10 healthy children (mean age = 9.2 +/- 1.5 years) who were familiar with the environment, the experimenter and the video game. Breath duration rose significantly, from 2.56 to 3.16 s, as a function of game difficulty. Cortisol levels, heart rate and the thoracic contribution to breathing displayed no significant changes. Taken together, these data suggest that focusing attention on the game tended to inhibit breathing and that previous contradictory reports in this respect were due to the confounding effects of emotion.

Attention↗

PubMed1998

Effects of voluntary changes in breathing frequency on respiratory comfort.

Previous experiments on voluntary breathing have suggested that spontaneous breathing is partly determined by the minimization of respiratory sensations. However, during instructed breathing, respiratory sensations may be confounded with difficulty in achieving the prescribed pattern. In the present experiment, we tested the hypothesis that the subjective assessment of respiratory comfort and the difficulty in following breathing instructions are closely related. A total of 15 subjects adjusted breathing frequency to prescribed values ranging from 40 to 250% of individual spontaneous levels. Then, they scored the difficulty of this task and the discomfort associated with the target frequency. Difficulty scores sharply increased above 100% (spontaneous level) and discomfort scores displayed a similar shape. A significant positive correlation between discomfort and difficulty was found, thus suggesting a possible influence of the difficulty to follow ventilatory instructions on respiratory sensation scores.

Adult↗

PubMed1998

Iron supplementation aggravates periventricular cystic white matter lesions in newborn mice.

Periventricular leukomalacia (PVL) is the main cause of neurological impairment in premature newborns. The pathogenesis of PVL remains unclear but may involve glutamate excitotoxicity and free radical production. Oxygen and iron, which are widely used in premature newborns, are oxidizing agents with a potential for promoting free radical production. We previously described a mouse model of excitotoxic neonatal white matter lesions mimicking several aspects of human PVL. In the present study, we used this mouse model to investigate whether iron pretreatment or 100% oxygen exposure worsened excitotoxic lesions. We found that iron pretreatment but not hyperoxia significantly increased white matter lesions, suggesting that high doses of iron may aggravate PVL in premature newborns.

Animals↗

PubMed1998

Classical conditioning to hypoxia using odors as conditioned stimuli in rats.

The authors performed a differential conditioning experiment in 30 rats, using 2 odors as the conditioned stimuli (CS+ and CS-) and hypoxia (8% O2) as the unconditioned stimulus. Vanillin was the CS+ and rose the CS- in half of the rats, and vice versa in the other half. Fifteen paired CS+/hypoxia trials and 15 CS- only trials were performed in random order, followed by 3 CS+ only and 3 CS- only trials to test for conditioning. The increase in ventilation from prestimulus levels averaged 116 +/- 85% in response to CS+ versus 55 +/- 36% in response to CS-. This effect was supported by the significant Pre-Post Stimulus x CS Type interaction for this variable (p < .003). The data confirm the sensitivity of breathing to conditioning processes and also indirectly support the hypothesis that feedforward responses may complement feedback reflex pathways in respiratory homeostasis.

Animals↗

PubMed1997

Centromeric pyrimidine strands fold into an intercalated motif by forming a double hairpin with a novel T:G:G:T tetrad: solution structure of the d(TCCCGTTTCCA) dimer.

The solution structures of the oligodeoxynucleotides d(CCCGTTTCC) and d(TCCCGTTTCCA) have been determined by two-dimensional NMR spectroscopy. These oligomers are part of a DNA box in human centromeric alpha satellite targeted by the centromere protein B (CENP-B). Both CENP-B and its recognition box in alphoid DNA are conserved in mammals, suggesting an important biological role. At acidic pH, d(CCCGTTTCC), d(TCCCGTTTCCA) and the full d(TCCCGTTTCCAACGAAG) CENP-B box strand all fold and dimerize in solution forming a stable bimolecular structure containing two GTTT hairpin loops that interact through a novel T : G : G : T tetrad. The stem region of the dimer is a four-stranded intercalated motif in which the hairpin monomers are parallel and held together by C : C+ hydrogen-bonding and intercalation. The loops are at the same end of the dimer and lie across the narrow grooves of the tetraplex. They are remarkably structured and stabilized by base-base cross-stacking, sugar-base stacking, and parallel G:G and antiparallel G:T pairing. In the d(TCCCGTTTCCA)2 structure, the intercalated motif is continued at the other end of the dimer with unpaired but stacked adenine and thymine bases. The possible biological implications of these structures are discussed.

Autoantigens↗

PubMed1997

Maternal protein restriction early in rat pregnancy alters brain development in the progeny.

We assessed the effects of a dietary protein restriction (5% vs. 20% casein in diet) initiated at conception and imposed during the first 2 weeks of rat gestation on postnatal brain development. At the end of the malnutrition period, protein-restricted animals exhibited significantly smaller fetal body weight and brain cortical thickness than controls. At birth and thereafter, body weight was normalized in the progeny. Similarly, brain weight and cytoarchitecture were normal in postnatal animals. In contrast, we observed, during the first 2 postnatal weeks, several abnormalities of brain development which affected all the studied areas for most of the studied parameters: (i) delayed astrocytogenesis as shown by a reduced GFAP staining; (ii) delayed production of hyaluronan in the extracellular matrix studied with binding of biotinylated hyaluronectin; (iii) abnormal neuronal differentiation as shown by reduced expression of MAP-5 and increased expression of MAP-1; (iv) abnormal synaptogenesis as shown by the increased expression of synaptophysin in the basal ganglia; (v) decreased programmed cell death. In adult prenatally protein-restricted animals, all the above parameters were normalized excepted MAP-1 labeling which remained high. In addition, we observed slight alterations of the ventilatory response to hypoxia in adult animals. The present study demonstrates that early protein malnutrition during embryonic development induces multiple, transient alterations of brain development. However, the almost complete normalization in adults of brain architecture and differentiation as well as our physiological data strongly suggest a remarkable plasticity of the developing brain following an early aggression.

Aging↗

PubMed1997

Influence of thoracoabdominal pattern of breathing on respiratory resistance.

The purpose of this study was to test the hypothesis that voluntary changes in thoracoabdominal pattern of breathing may increase total respiratory resistance. Thirty-one normal subjects were asked to control their thoracoabdominal pattern of breathing by using a visual feedback. Thoracic and abdominal volume changes were measured by inductance plethysmography. Respiratory resistance and elastance were measured by forced oscillometry. The mean (+/-SD) percent thoracic contributions to tidal volume during thoracic or abdominal breathing were 75 (+/-11) and 25% (+/-9), respectively. These changes induced small but significant increases in resistance (P < 0.005) and elastance (P < 0.002). The increased resistance was observed in 22 subjects for thoracic breathing (P < 0.016) and in 21 subjects for abdominal breathing (P < 0.043). The mean value (+/-SD) of individual increases in resistance during thoracic or abdominal breathing, compared with normal breathing, were 9.2 +/- 17.5 and 9.4 +/- 19.9%, respectively. The fact that departing from spontaneous pattern increases respiratory resistance is consistent with the notion that breathing pattern is optimally adjusted on the basis of mechanical criteria.

Abdomen↗