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Biomedical subjects

J Herreros

Publications and source records attributed to J Herreros.

At least 19 recordsLinked to original sources
PubMed2006

[Heart transplant].

A heart transplant is at present considered the treatment of choice in cases of terminal cardiac insufficiency refractory to medical or surgical treatment. Due to factors such as the greater life expectancy of the population and the more efficient management of acute coronary syndromes, there is an increasing number of people who suffer from heart failure. It is estimated that the prevalence of the disease in developed countries is around 1%; of this figure, some 10% are in an advanced stage and are thus potential receptors of a heart transplant. The problem is that it is still not possible to offer this therapeutic form to all of the patients that require it. Consequently, it is necessary to optimise the results of the heart transplant through the selection of patients, selection and management of donors, perioperative management and control of the disease due to graft rejection. Since the first transplant carried out in 1967, numerous advances and changes have taken place, which has made it possible to increase survival and quality of life of those who have received a new heart. In this article we review the most relevant aspects of the heart transplant and the challenges that are currently faced.

Actuarial Analysis↗
PubMed2006

[Cell transplant and regenerative therapy with stem cells].

One of the fields of medicine that has raised the most expectations in recent years is cell therapy with stem cells. The isolation of human embryo cells, the apparent and unexpected potentiality of adult stem cells and the development of gene therapy lead us to imagine a hopeful future for a significant number of diseases that are at present incurable. In this article we will sketch out the panorama of stem cell research, describing the main achievements in this field as well as some of the questions that await an answer. In spite of the great expectations, it is essential that we maintain a critical and realistic spirit when it comes to analysing the scientific advances in this area.

Adult Stem Cells↗
PubMed2003

Platelet dysfunction in cardiopulmonary bypass: an experimental comparative study between a centrifugal and a new pulsatile pump.

The aim of this investigation was to study the effect of a new pulsatile pump for extracorporeal circulation (ECC) on platelet count and platelet function with respect to a Biomedicus centrifugal pump. Thirteen pigs, 8 in the pulsatile group (PG) and 5 in the centrifugal group (CG), underwent a partial extracorporeal circulation lasting 3 h. The animals were sacrificed 3 h post-ECC. The platelet study was both quantitative (platelet count) and qualitative (platelet function analysis) by assessing the closure time (CT) with a PFA-100 system. The decrease in platelet number from basal to 3 h post ECC was only significant in CG (p = 0.009). The platelet function was impaired in both groups, but the value of CT with col/ADP increased significantly only in CG (p < 0.001). The increase of CT with col/EPI was greater in CG (p = 0.07) than in PG (p = 0.2). The results indicated that the new pulsatile pump preserves platelets quantitatively and qualitatively well compared to a Biomedicus pump.

Acid-Base Equilibrium↗
PubMed2003

Apoptotic cell death and genetic control in graft coronary artery disease in heart transplant.

AIM: Apoptosis is a type of programmed cell death whereby, immunologic, genetic and biochemical mechanisms are involved in its control. On the other hand, graft coronary artery disease is the most important restrictive factor for the long-term survival of heart transplantation. The purpose of this study is to analyse both apoptotic cell lesions in transplanted patients that present coronary artery disease. METHODS: From August 1984 until December 1996, 148 heart transplants were carried out in the Clínica Universitaria de Navarra. In 102 patients, annual coronary angiography was performed, reaching a diagnosis of coronary artery disease in 30 patients. Study of apoptotic cell death was done in the tissue of endomyocardial biopsies on all patients by means of the TUNEL technique. Procedures of immunohistochemistry with antibodies antic-myc, p53 and bcl-2 were carried out and results were compared with a control group of 30 patients with homogeneous characteristics. RESULTS: All patients with coronary artery disease showed apoptotic cardiomyocytes, 13 patients to a mild degree, 14 to a moderate degree and 3 to a severe degree, while in the control group apoptosis was found only to a mild degree in 8 patients, obtaining a very significant statistical difference (p<0.0001). The expression of analysed oncoproteins was null in the 2 groups. CONCLUSION: Myocardial apoptosis is a constant finding in transplanted patients with coronary artery disease. We have not seen any correlation between the apoptotic process and genetic mechanisms.

Adolescent↗
PubMed2001

Correlating sonography, mammography, and pathology in the assessment of breast cancer size.

BACKGROUND: With the increasing use of neoadjuvant and minimally invasive therapy, the accuracy of preoperative determination of breast tumor size becomes important. Therefore, we undertook this study to compare mammography and ultrasonography (US). METHODS: A total of 180 invasive breast cancer patients were prospectively examined by mammography and US; 146 eligible patients had tumors visualized by both modalities. RESULTS: In 69% of cases, US was better than or equivalent to mammography in determining tumor size. Both underestimated tumor size; mean (median) underestimation was 3.8 +/- 0.7 mm (1.7 mm) by US and 3.5 +/- 0.9 mm (2 mm) by mammogram. Maximal tumor dimension was accurate within 5 mm in 65% of cases by mammography and 75% of cases by US. For mammographically determined size (versus pathologic size) correlation, r, was 0.4 and for US it was 0.63 and improved for only T1 and T2 tumors. CONCLUSIONS: These data suggest that US is more accurate than mammography in assessing breast cancer size.

Adult↗
PubMed2001

Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons.

Tetanus (TeNT) is a zinc protease that blocks neurotransmission by cleaving the synaptic protein vesicle-associated membrane protein/synaptobrevin. Although its intracellular catalytic activity is well established, the mechanism by which this neurotoxin interacts with the neuronal surface is not known. In this study, we characterize p15s, the first plasma membrane TeNT binding proteins and we show that they are glycosylphosphatidylinositol-anchored glycoproteins in nerve growth factor (NGF)-differentiated PC12 cells, spinal cord cells, and purified motor neurons. We identify p15 as neuronal Thy-1 in NGF-differentiated PC12 cells. Fluorescence lifetime imaging microscopy measurements confirm the close association of the binding domain of TeNT and Thy-1 at the plasma membrane. We find that TeNT is recruited to detergent-insoluble lipid microdomains on the surface of neuronal cells. Finally, we show that cholesterol depletion affects a raft subpool and blocks the internalization and intracellular activity of the toxin. Our results indicate that TeNT interacts with target cells by binding to lipid rafts and that cholesterol is required for TeNT internalization and/or trafficking in neurons.

Animals↗
PubMed2000

C-terminal half of tetanus toxin fragment C is sufficient for neuronal binding and interaction with a putative protein receptor.

Tetanus neurotoxin (TeNT) is a powerful bacterial protein toxin that cleaves VAMP/synaptobrevin, an essential protein of the synaptic vesicle fusion machinery, and consequently blocks neurotransmission. The extreme neurospecificity of TeNT is determined by the binding of its C-terminal domain (fragment C or H(C)) to neuronal receptors. Whereas polysialogangliosides are known acceptors for the toxin, the existence of additional protein receptors has also been suggested. We have reported previously on a 15 kDa cell-surface glycoprotein that interacts with TeNT in neuronal cell lines and motoneurons [Herreros, Lalli, Montecucco and Schiavo (2000) J. Neurochem., in the press]. Here, on the basis of the structural information provided by the crystallization of fragment C of TeNT, we have expressed its C-and N-terminal halves as recombinant proteins and analysed their binding abilities to rat phaeochromocytoma (PC12) cells differentiated with nerve growth factor. We found that the C-terminal subdomain of the fragment C of TeNT is necessary and sufficient for cell binding and for the interaction with the 15 kDa putative receptor. In contrast, the N-terminal half showed a very poor interaction with the cell surface. These results restrict the binding domain of TeNT to the C-terminal half of the fragment C and highlight the importance of this domain for the neurospecific interaction of the toxin with the synapse. Furthermore, these findings support the use of this portion of TeNT as a neurospecific targeting device, pointing to an involvement of the N-terminal subdomain in later steps of the intoxication pathway.

Animals↗
PubMed2000

Tetanus toxin fragment C binds to a protein present in neuronal cell lines and motoneurons.

Tetanus Toxin Fragment C Binds to a Protein Present in Neuronal Cell Lines and Motoneurons Tetanus neurotoxin is one of the most powerful protein toxins known, acting in vivo at femtomolar doses. Two main factors determine its high potency: a protease activity restricted to a single intracellular substrate and its absolute neurospecificity. Whereas the enzymatic properties of tetanus toxin have been thoroughly defined, the nature of its neuronal receptor(s) and their involvement in the intracellular trafficking of tetanus toxin are poorly understood. Using binding and crosslinking experiments, we report here on the characterisation of an N-glycosylated 15-kDa interacting protein, which behaves as an integral membrane protein. This putative receptor specifically interacts with the binding domain (fragment C) of tetanus toxin and not with several related botulinum neurotoxins in spinal cord motoneurons and neuronal-like cell lines. Sialic acid-specific lectins antagonise the binding of tetanus toxin to the cell surface and to the 15-kDa protein, supporting the central role of sialic acid residues in the recognition process. Altogether, these results indicate the existence of a neuronal protein receptor for tetanus toxin whose identification is likely to constitute a key step in the analysis of the molecular machinery involved in the toxin internalisation and retrograde transport.

Animals↗
PubMed1999

Calcium-dependent oligomerization of synaptotagmins I and II. Synaptotagmins I and II are localized on the same synaptic vesicle and heterodimerize in the presence of calcium.

Synaptotagmins constitute a large family of membrane proteins characterized by their distinct distributions and different biochemical features. Genetic evidence suggests that members of this protein family are likely to function as calcium sensors in calcium-regulated events in neurons, although the precise molecular mechanism remains ill defined. Here we demonstrate that different synaptotagmin isoforms (Syt I, II, and IV) are present in the same synaptic vesicle population from rat brain cortex. In addition, Syt I and II co-localize on the same small synaptic vesicle (SSV), and they heterodimerize in the presence of calcium with a concentration dependence resembling that of the starting phase of SSV exocytosis (EC50 = 6 +/- 4 microM). The association between Syt I and Syt II was demonstrated by immunoprecipitation of the native proteins and the recombinant cytoplasmic domains and by using fluorescence resonance energy transfer (FRET). Although a subpopulation of SSV containing Syt I and IV can be isolated, these two isoforms do not show a calcium-dependent interaction. These results suggest that the self-association of synaptotagmins with different calcium binding features may create a variety of calcium sensors characterized by distinct calcium sensitivities. This combinatorial hypothesis predicts that the probability of a single SSV exocytic event is determined, in addition to the gating properties of the presynaptic calcium channels, by the repertoire and relative abundance of distinct synaptotagmin isoforms present on the SSV surface.

Amino Acid Sequence↗
PubMed1999

Functional characterisation of tetanus and botulinum neurotoxins binding domains.

Tetanus and botulinum neurotoxins constitute a family of bacterial protein toxins responsible for two deadly syndromes in humans (tetanus and botulism, respectively). They bind with high affinity to neurons wherein they cause a complete inhibition of evoked neurotransmitter release. Here we report on the cloning, expression and use of the recombinant fragments of the heavy chains of tetanus neurotoxin and botulinum neurotoxin serotypes A, B and E as tools to study the neurospecific binding of the holotoxins. We found that the recombinant 50 kDa carboxy-terminal domains of tetanus and botulinum neurotoxins alone are responsible for the specific binding and internalisation into spinal cord cells in culture. Moreover, we provide evidence that the recombinant fragments block the internalization of the parental holotoxins in a dose-dependent manner, as determined by following the neurotoxin-dependent cleavage of their targets VAMP/synaptobrevin and SNAP-25. In addition, the recombinant binding fragments cause a significant delay in the paralysis induced by the corresponding holotoxin on the mouse phrenic nerve-hemidiaphragm preparation. Taken together, these results show that the carboxy-terminal domain of tetanus and botulinum neurotoxins is necessary and sufficient for the binding and internalisation of these proteins in neurons and open the possibility to use them as tools for the functional characterisation of the intracellular transport of clostridial neurotoxins.

Animals↗
PubMed1998

[The effect of isoflurane on coronary autoregulation in hypothermia].

OBJECTIVES: To analyze the effect of isoflurane on myocardial metabolism and coronary hemodynamics during the reheating phase after heart surgery. PATIENTS AND METHODS: Sixteen patients (12 women and 4 men), with cardiac output greater than 0.5 undergoing aortic and/or mitral valve surgery, were studied prospectively. A retrograde thermodilution catheter was placed in the heart and a Swan-Ganz catheter was inserted in the pulmonary artery to determine coronary blood flow and pulmonary wedge pressure, respectively, as well as myocardial and systemic parameters. After surgery, and with hemodynamic variables stable and rectal temperature at 34 +/- 0.5 degrees C, 0.4% isoflurane was administered at the end of expiration. Variables were recorded before administering isoflurane and 20 minutes afterwards. RESULTS: Isoflurane administration decreased coronary perfusion pressure, coronary vascular resistance, regional myocardial oxygen consumption and myocardial oxygen output. Increases in coronary oxygen saturation and in large coronary vein saturation were also observed. No patient experienced significant changes in ST segment, enzymes or decreased clearance of lactic acid. CONCLUSIONS: Administering 0.4% isoflurane at the end of expiration effected coronary vasodilation without altering oxygenation or myocardial metabolism. Moreover, no electrocardiographic, enzymatic or metabolic signs of myocardial ischemia were observed.

Adult↗
PubMed1997

Characterization of presynaptic proteins involved in synaptic vesicle exocytosis in the nervous system of Torpedo marmorata.

Synaptobrevin, SNAP-25 and syntaxin (SNAP receptor proteins) are molecular components that play a key role in the exocytotic machinery of synaptic vesicles. Their presence, distribution and interactions are reported in central and peripheral nervous systems of the electric fish Torpedo marmorata. These three proteins form a protein complex in all the nervous system regions tested, including the electric lobe and the electric organ which is innervated by pure cholinergic nerve terminals. Immunoblot analysis revealed a double protein pattern of SNAP-25 in the anterior brain and cerebellum, although a single protein band corresponding to SNAP-25 was observed in the electromotor system. Moreover, SNAP-25 showed a differential distribution in the electromotor system. It was present along nerve fibres and terminals that innervated the electric organ but it was not detected in nerve terminals at the electric lobe. Immunoisolation experiments using anti-synaptobrevin antibodies showed a tissue-specific co-existence of SNAP-25 and syntaxin with synaptobrevin in the immunoisolated organelles. In conclusion, the molecular components of the exocytotic machinery are shown to be conserved in Torpedo, although some differences mainly on SNAP-25, suggest a potential diversity in the regulation of neurosecretion.

Animals↗
PubMed1997

Vascular cryopreservation in microsurgery.

Cyropreservation of blood vessels has been carried out for some decades with variable results. A rabbit model was used to compare cryopreserved femoral artery allografts (n = 12 arteries), fresh autografts (n = 15 arteries), and fresh allografts (n = 16 arteries) at 1 and 3 months postoperatively. Patency rates were highest in the fresh autografts (86.7 percent), followed by the cryopreserved allografts (66.7 percent at 1 month and 83.3 percent at 3 months) and fresh allografts (62.5 percent at 1 month and 75 percent at 3 months). The fresh allografts showed the greatest alterations in endothelial cells and intima and muscle layer, followed by cryopreserved allografts, and then fresh autografts. Changes observed included pseudoendothelium formation, thickened intima, and thinner muscle layer. Cellular infiltrate appeared on the vessel walls only in the cryopreserved allografts (25 percent), but this did not have an effect on vascular patency. Fresh autografts remain the graft of choice for vascular defects, but cryopreserved allografts serve as the most appropriate option when the former are unavailable.

Animals↗
PubMed1997

Cisplatin, mitomycin, and vindesine followed by intraoperative and postoperative radiotherapy for stage III non-small cell lung cancer: final results of a phase II study.

Sixty-two patients with stage III non-small cell lung cancer (NSCLC) were treated with neoadjuvant chemotherapy consisting of cisplatin 120 mg/m2 day 1, mitomycin 8 mg/m2 day 1, and vindesine 3 mg/m2 days 1 and 14. Each cycle was repeated every 4 weeks for a total of 1 to 6 cycles (median, 3 cycles). Resection was attempted 4 to 5 weeks after the last course of chemotherapy. Intraoperative radiation therapy (IORT) (10-15 Gy) was delivered during surgery and postoperative external beam radiotherapy (EBRT) (46 Gy) was begun 4 weeks after surgery. Fifty-five patients (25 IIIA, 30 IIIB) were evaluable. Only partial responses occurred (64%), and 29 patients (53%) underwent resection. Complete resection rates were 85% (12/14) and 40% (6/15) in stage IIIA and IIIB, respectively (p = 0.01). In 3 of 29 patients (10%), no tumor was found in the resected specimen. There was one chemotherapy-related death and three postoperative-related deaths. The median survival time was 10 months, and the 5-year survival rate was 29 and 7% for stage IIIA and stage IIIB, respectively (p = 0.3). High complete resection rates and modest increase in 5-year survival have been observed in stage IIIA NSCLC. Although a number of stage IIIB patients can be made technically resectable, the low complete resectability rate reflects the lack of survival benefit in these patients.

Adult↗
PubMed1997

Localization of putative receptors for tetanus toxin and botulinum neurotoxin type A in rat central nervous system.

Clostridial neurotoxins (tetanus and botulinum toxins) are potent blockers of neurotransmitter release. These toxins act specifically on the nervous system by interacting with still non-identified protein receptors together with gangliosides. Whereas many biochemical data are available on their binding properties to neuronal membranes in vitro, there is poor morphological evidence of their binding to mammalian central nervous system. In the present study, the binding of tetanus and botulinum neurotoxin type A to rat brain sections is reported. Both toxins bound to nerve terminals with a broad distribution in brain. Tetanus toxin additionally bound to nerve fibres. The staining patterns were clearly shown to be due to the interaction of the heavy chains, which contain the binding moiety, with the tissue. In an attempt to investigate the nature of the acceptors present in the tissue, some sections were pre-incubated with periodic acid. This treatment resulted in the additional binding of botulinum neurotoxin type A to nerve fibres. Since the extended staining of nerve terminals was not modified by this pretreatment, it is suggested that protein receptors of clostridial neurotoxins are located at the nerve terminals, which may be common constituents of the synapses.

Animals↗
PubMed1997

Role of endomyocardial biopsy in the diagnosis of chronic rejection in human heart transplantation.

To assess the pathologic findings observed in the setting of post-transplant graft atherosclerosis, we have studied 18 endomyocardial biopsies (EMB) from 18 heart-transplanted patients collected at the same time that a coronary angiography (CA) showed changes consistent with graft atherosclerosis. Twenty-two EMB from patients with heart transplant with normal CA were used as controls. In spite of the small size of the sample, the number of acute rejection (AR) episodes correlated with the appearance of graft atherosclerosis (p < 0.001). Heart biopsies in graft atherosclerosis showed myointimal proliferation, thickening and folding of the wall of precapillary arteries, myocyte hypertrophy, and interstitial and perivascular fibrosis. Type III and type IV collagen, laminin, and fibronectin were increased in areas of interstitial and perivascular fibrosis, as well as in the vessel's wall. Fibronectin accumulation was more evident in the subendothelium and inner media of affected vessels. These changes were never found all together in control biopsies. Even though the inespecificity of some of those findings, we conclude that chronic graft atherosclerosis in a heart transplant may be suspected by endomyocardial biopsy when most of these alterations are seen together, especially if small precapillary arteries are present in the specimen.

Acute Disease↗