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Biomedical subjects

A Alvarez

Publications and source records attributed to A Alvarez.

At least 55 records · Page 3Linked to original sources
PubMed2003

Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.

Alzheimer Disease↗
PubMed2003

Clinical significance of anti-multiple nuclear dots/Sp100 autoantibodies.

BACKGROUND: Autoantibodies against discrete variable-sized dots observed in HEp2 cells by indirect immunofluorescence (IIF) test, called multiple nuclear dots (MND), have been closely associated with primary biliary cirrhosis (PBC). Some authors have argued that this antibody is also present in connective tissue diseases or liver diseases other than PBC as autoimmune chronic active hepatitis, particularly of the cholestatic type. We studied an unselected group of patients routinely tested for autoantibodies and positive for the MND pattern and tried to establish the correlation between the presence of this antibody and their diagnosis. METHODS: A commercial ELISA test, using a recombinant 26 kD truncated sequence of the Sp100 protein, corresponding to an immunodominant molecular region, was used to assess the clinical correlation of these autoantibodies in 110 patients showing an anti-MND immunofluorescence pattern. RESULTS: One-hundred-and-ten patients were MND positive by IIF. Of these, 100 were Sp100 positive by ELISA. In the Sp100 positive group, 34 had a diagnosis of PBC (30 definite and 4 suspected) while 15 patients had a non-PBC hepatopathy. Unexpectedly, 13 of the MND/Sp100 positive pattern corresponded to systemic lupus erythematosus (SLE) patients and 5 cases to collagen diseases. Another divergence with previous reports was that 34 of the positive patients showed very heterogeneous clinical pictures, different from hepatopathies or collagen diseases. CONCLUSIONS: Anti-Sp100 antibodies can be found in many clinical conditions. Testing for MND/Sp100 positivity is useful for the diagnosis of PBC, but only when the right clinical context is present. Other diseases cannot be excluded in first line SLE.

Antigens, Nuclear↗
PubMed2003

[Eales' disease with bilateral brain strokes and jaw-closing dystonia].

Eales' disease is an idiopathic occlusive vasculopathy of the retina, which is characterized by extensive peripheral non-perfusion, perivascular sheathing, and neovascularization. It is associated with recurrent vitreous hemorrhages. Both eyes are affected consecutively in 80% to 90% of the patients. In spite of the multiple theories that have been proposed, it continues to have unknown origin and its diagnosis relies on exclusion of other causes of retinal vasculopathy. In some occasions, these patients develop complications of the central nervous system, above all brain infarcts. We present the case of a 38 year old woman with Eales' disease who developed bilateral brain infarcts associated with occlusion or stenosis of the middle cerebral arteries. The cerebral angiography showed beading of the Silvian arteries, suggestive of an underlying inflammatory disorder. Early corticosteroid therapy could avoid contralateral retinal involvement and neurological complications. The patient also presented delayed jaw closing dystonia secondary to basal ganglia infarct which followed a benign course with spontaneous resolution in a few days.

Adult↗
PubMed2002

Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis.

We have studied the effect of N-(4-hydroxyphenyl)retinamide on either malignant human leukaemia cells or normal cells and investigated its mechanism of action. We demonstrate that 4HPR induces reactive oxygen species increase on mitochondria at a target between mitochondrial respiratory chain complex I and II. Such oxidative stress causes cardiolipin peroxidation which in turn allows cytochrome c release to cytosol, caspase-3 activation and therefore apoptotic consumption. Moreover, this apoptotic pathway seems to be bcl-2/bax independent and count only on malignant cells but not normal nor activated lymphocytes.

Antineoplastic Agents↗
PubMed2002

Elongation of the cytoplasmic domain, due to a point deletion at exon 7, results in an HLA-C null allele, Cw*0409 N.

The development of molecular techniques for HLA typing has allowed the identification of genes previously assigned as serologic blank alleles. Lack or poor cell surface expression has been found for molecules coded by HLA-A, -B, -DRB4, -DRB5, and -DPB1 genes. In this report we describe the first HLA-C gene encoding for a null cell surface molecule. HLA-Cw*0409 N shows a point deletion at position 1095 within exon 7. This mutation provokes a codon reading shift, generating a new translation stop codon 97 bp downstream to that described in alleles normally expressed. This new stop codon location implies the presence of 32 extra amino acid residues in the cytoplasmic domain. Transfection experiments suggest that elongation of the cytoplasmic domain in Cw*0409 N would be the cause of cell surface expression failure, although Cw*0409 N heavy chain is able to create stable complexes with beta2-microglobulin. HLA-C fragment length analysis in a small selected group of samples with B44-Cblk haplotypic associations allowed us to identify two additional subjects showing both a serologic silent Cw*04 allele and a point base deletion at the 3' end of the HLA-C gene. This finding indicates that the allele frequency of Cw*0409 N within serologic C blank alleles would be appreciable, although basically restricted to the (A23)-Cw*0409 N-B*4403-DR7-DQ2 haplotype.

Alleles↗
PubMed2002

[Ischemic cadiopathy in patients undergoing chronic hemodialysis].

UNLABELLED: We report a retrospective study of patients on chronic hemodialysis in whom a diagnosis of ischemic heart disease had been established. We compared the findings on coronary cineangiography and the treatment (medical only, surgical revascularisation [CABG] and percutaneous transluminal coronary angioplasty [PTCA]) with the early and late evolution. From a population of 2,287 patients on chronic hemodialysis treatment during the 5 year period 1994-1999, 83 patients who underwent coronary cineangiography after starting dialysis were selected. Their mean age was 63 +/- 9.4 (39-80) and the mean time on hemodialysis was 6 years (6 months-19 years). RESULTS: 65 patients (78%) had severe coronary lesions, 40% of whom had three vessel disease. 14 patients had medical treatment only (group 1), 23 had CABG (group 2) and 28 PTCA (group 3). Mortality within 30 days of intervention was 13% in group 2 and 21.4% in group 3. Global survival at two years was 82% in group 2 and 69% in group 3. Survival without angina at 6 and 24 months were 69% and 46% in group 2 and 55% and 22% in group 3 respectively. Survival without acute myocardial infarction at 6 and 24 months was 95% and 95% in group 2 and 89% and 64% in group 3. Data analysis using Cox proportional risk model showed that PTCA posed a higher risk of angina and death than CABG. CONCLUSION: Surgery yielded better early and later results than angioplasty even in those patients with severe coronary artery disease.

Adult↗
PubMed2001

Antithrombin III prevents early pulmonary dysfunction after lung transplantation in the dog.

BACKGROUND: Ischemia-reperfusion injury with the resulting inflammatory response is a devastating complication of lung transplantation; much of the tissue damage could be diminished by control of the inflammatory response. Recent studies have show that antithrombin III (AT III) has an anti-inflammatory effect in addition to its established role in the regulation of blood coagulation. Thus, we hypothesized that the administration of AT III might help to prevent ischemia-reperfusion injury after lung transplantation. METHODS AND RESULTS: The study was performed in a dog model of orthotopic lung transplantation. Dogs were randomly assigned to receive either vehicle (controls) or AT III. We observed that in control dogs, during the 180-minute period after lung transplantation, the arterial O(2) partial pressure decreased and both the alveolar-arterial O(2) difference and the pulmonary vascular resistance increased. By contrast, these parameters remained unchanged in the group of dogs receiving AT III. Dogs with transplants receiving AT III did not show an increase in cell adhesion molecules, and histological examination revealed almost an absence of inflammatory response. The administration of AT III produced a marked increase in serum prostacyclin (PGI(2)) levels, whereas in control dogs, the PGI(2) levels did not change. The beneficial effect of AT III was not observed when dogs received indomethacin to prevent the stimulation of PGI(2) release by AT III. CONCLUSIONS: Our results demonstrate that AT III prevents ischemia-reperfusion injury in a dog model of lung transplantation and that this effect is conditioned by an increase in PGI(2) production.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Immunogenicity of recombinant class 1 protein from Neisseria meningitidis refolded into phospholipid vesicles and detergent.

The possibility of eliciting bactericidal antibodies against a recombinant class 1 protein (P1) from Neisseria meningitidis, joined to the first 45 amino acids of the neisserial LpdA protein (PM82), was examined. P1 was produced in Escherichia coli as intracellular inclusion bodies, from which it was purified and reconstituted by (a) inclusion into phospholipid vesicles and detergent and (b) refolding in 0.1% SDS. When Balb/c mice were immunised, high titres of subtype-specific bactericidal antibodies against P1 were obtained in both cases. These results suggest that in spite of being a denaturing agent, it is possible to use SDS to reconstitute the P1 protein in a conformation that exposes the immunodominat regions.

Animals↗
PubMed2001

A Cdk5-p35 stable complex is involved in the beta-amyloid-induced deregulation of Cdk5 activity in hippocampal neurons.

The cdk5 and its activator p35 constitute one of the main tau-phosphorylating systems in neuronal cells. Under normal conditions for neurons, its activity is required for modulating tau involvement in neuronal polarity and in development of the mammalian central nervous system. Recently, we reported that the treatment of rat hippocampal cells in culture with fibrillary beta-amyloid (Abeta) results in deregulation of the protein kinase cdk5. The neurotoxic effects of Abeta fibrils were prevented by inhibition of cdk5 activity by butyrolactone I or by using antisense oligonucleotides that control the expression of this kinase. Here, we show that the Abeta-promoted increase of cdk5 activity is associated with changes in tau phosphorylation patterns and in the intraneuronal distribution of tau. In addition to hippocampal cells, deregulation of cdk5 was observed in other cell types. However, butyrolactone I prevented Abeta-induced cell death only in neuronal cells in which cdk5 activation was sensitive to Abeta fibrils. This lost of cdk5 regulation in hippocampal cells exposed to Abeta fibrils appears to be associated with an increase in the cdk5-p35 complex stability. Complex stabilization was sensitive to phosphorylation of cdk5. However, no changes in cdk5 and p35 mRNAs were observed, suggesting that the main effects on cdk5 occur at the posttranslational level. These studies indicate that cdk5 phosphorylation and the formation of an abnormally active cdk5-p35 complex are directly involved in the molecular paths leading to the neurodegenerative process of rat hippocampal neurons triggered by Abeta fibrils.

Amyloid beta-Peptides↗
PubMed2001

Induction of cell proliferation by cyclosporine A in primary cultures of rat hepatocytes.

Cyclosporine A (CsA) has been reported to be able to promote cell proliferation, although the precise mechanism by which CsA stimulates cell growth remains uncertain. In the present study, we examined, in hepatocyte cultures, the effect of CsA on parameters related to the cell cycle as well as the levels of proteins involved in the control and progression of the cycle. Flow cytometry analysis detected an increase in the percentage of cells involved in the S phase of the cycle, which correlated with increases in the levels of cyclins D1 and E (two G1-progression regulators), as well as in those of PCNA (proliferating cell nuclear antigen), and without modification in p27, an inhibitory protein of CDKs. We also examined in nucleus the levels of nuclear factor kappaB (a nuclear factor involved in the transcription of the cyclin D1 gene) and found that this transcription factor increased in the presence of CsA. We conclude that the increases in cyclin D1, PCNA, and cyclin E, together with the invariable level of p27, clearly show that CsA induces hepatocytes to proliferate. These results reinforce the idea of the growth-promoting effect of CsA in cultured hepatocytes.

Animals↗
PubMed2001

Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals.

The phosphatidylinositol (PI)-3 kinase-Akt/PKB survival pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective effect against neurotoxins that produce oxidative stress and neurodegeneration has not been investigated. We analyzed the effect of this pathway on the action of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Overexpression of a membrane-targeted, N-myristylated fusion protein of enhanced green fluorescence protein (EGFP) and mouse Akt1 attenuated the apoptotic effect of the neurotoxin in PC12 cells. This effect was not due to protection of mitochondrial complex I activity or restoration of energy charge. Following MPP+-treatment, myr-EGFP-Akt1-transfected cells exhibited an unaltered mitochondrial membrane potential and lower ROS levels than control cells. These results provide a new site of action of Akt/PKB at the level of the oxidative detoxifying cell machinery and suggest that this effect may be responsible in part for the resistance of myr-EGFP-Akt1-expressing cells to oxidative stress and MPP+-induced apoptosis.

1-Methyl-4-phenylpyridinium↗
PubMed2001

Single-agent therapy with oral mercaptopurine for nonlymphoid blast crisis of chronic myeloid leukemia.

Currently, no effective treatment is available for the nonlymphoid blast crisis (BC) of chronic myeloid leukemia (CML) and because of this the prognosis for such patients remains invariably poor. In an attempt to determine the results provided by palliative treatment with oral 6-mercaptopurine (6-MP) in the above hematological condition, 30 such patients were analyzed for hospital stay, days of intravenous (i.v.) antibiotics, transfusion requirements, response rate, and survival. Thirty patients with nonlymphoid BC matched for their initial characteristics and treated with different i.v. regimens were used for comparison purposes. Patients managed with 6-MP spent less days in hospital (median: 9, range: 0-46 vs median: 42, range: 5-140; P<0.0001), needed antibiotics for less days (median: 0. range: 0-46 vs median: 20, range: 0-57; P<0.0001), and received less platelet transfusions (median: 0, range: 0-20 vs median: 6, range: 0-63; P=0.004) than those treated with i.v. chemotherapy. Although no complete or partial remission was achieved by patients receiving 6-MP vs six in the i.v. chemotherapy group, no significant difference was observed when the survival of both groups was compared (median: 4.7 months, range: 0.1-22.7 vs median: 3.8 months, range: 0.2-12, respectively). These results indicate that 6-MP therapy constitutes a good palliative treatment for patients with nonlymphoid BC of CML. However, new treatment strategies for this hematological condition are required.

Administration, Oral↗
PubMed2001

Prediction of early bronchopleural fistula after pneumonectomy: a multivariate analysis.

BACKGROUND: The aim of this study was to determine independent risk factors for early bronchopleural fistula (BPF) after pneumonectomy and to assess the efficacy of bronchial coverage in preventing this complication. METHODS: We reviewed 242 consecutive patients undergoing pneumonectomy for lung cancer. The bronchial stump was covered with autologous tissue in 178 patients (74%). Perioperative data were recorded to identify risk factors of BPF by univariate and multivariate analyses. RESULTS: Overall morbidity and mortality rates were 59% and 5.4%, respectively. The incidence of BPF was 5.4%. By univariate analysis, patients with chronic obstructive pulmonary disease (COPD; p = 0.017), hyperglycemia (p = 0.003), hypoalbuminemia (p = 0.017), previous steroid therapy (p < 0.001), poor predicted postpneumonectomy forced expiratory volume in 1 second (FEV1; p = 0.012), long bronchial stumps (p < 0.001), and mechanical ventilation (p = 0.015), were related with higher risk of BPF. In the multiple logistic regression model, the independent risk factors of BPF were the bronchial stump coverage and length, side of pneumonectomy, predicted postpneumonectomy FEV1, COPD, and mechanical ventilation. CONCLUSIONS: Bronchial stump coverage is highly recommended in all cases to minimize the risks of BPF. A shorter length of the bronchial stump and early extubation may prevent the development of BPF. Careful attention must be paid to those patients with COPD and poor predicted postpneumonectomy FEV1.

Adult↗
PubMed2001

Anti-inflammatory effect of Pimenta racemosa var. ozua and isolation of the triterpene lupeol.

Pimenta racemosa var. ozua (Myrtaceae) is a tropical plant, used in different inflammatory processes by the folk medicine of the Caribbean region. From the methanol extract of the leaves a terpenic compound identified as lupeol has been isolated for the first time in this species. The anti-inflammatory activity of the extract has been evaluated against two experimental models of acute inflammation: paw edema in rats, using carrageenan or dextran as phlogogen agents, and ear edema in mice, inducing the inflammation with 12-o-tetradecanoylphorbol acetate (TPA). Myeloperoxidase activity (MPO) was also assayed as an indicator of leukocytary migration in the inflamed ears. In the carrageenan test, the methanol extract (125 and 250 mg kg(-1) p.o.) had a dose-dependent and significant effect at different time intervals. On the contrary, when the dextran was injected in paw, the extract did not reduce the inflammation provoked. This behavior was similar to indomethacine (25 mg kg(-1)) used as a standard drug. In the TPA-induced ear edema, the methanol extract (0.5, 1 and 3 mg ear(-1)) significantly reduced the inflammation. In the MPO assay a significant inhibition of the enzyme was observed in the inflamed tissue in all the samples assayed. These results show that the methanol extract from the leaves of Pimenta racemosa var. ozua, is effective against acute inflammation processes, by oral route and when topically applied. The anti-inflammatory behavior of the extract was similar to that exhibited by the selective cyclo-oxygenase inhibitor, indomethacin. On the other hand, the reduction of MPO activity shows that the action mechanism is clearly related with the neutrophil migration.

Animals↗
PubMed2001

Airway complications after lung transplantation: a review of 151 anastomoses.

OBJECTIVE: To analyze the incidence, treatment and follow up of airway complications after lung transplantation. METHODS: From October 1993 to April 2000, 104 lung transplants were performed in 101 patients. One hundred and fifty one bronchial anastomoses at risk were included in the study (29 single lung and 61 sequential double lung). Donor lungs were flushed both antegradely and retrogradely with Eurocollins. In the recipients, either a single or a sequential bilateral lung transplantation was performed when indicated. The bronchial anastomosis was telescoped and covered with peribronchial tissue in all cases. Postoperative fiberoptic bronchoscopic examinations were dictated by clinical grounds. Recipient variables were recorded and analyzed to assess possible differences between both complicated and non-complicated groups. RESULTS: Eight bronchial anastomotic complications (5.3%) occurred in six patients (6.8%). All complicated cases developed in sequential bilateral lung recipients (P=0.08): stenosis (n=5), granulation tissue (n=2), and bronchial dehiscence (n=1). Treatment consisted of lobectomy and subsequent completion pneumonectomy in one patient, rigid bronchoscopy dilation in two, balloon bronchodilation in two, laser debridement and stenting in one, and conservative therapy in two cases. One patient with severe sepsis and bronchial dehiscence died on day +30. The rest of the patients remain well so far. Airway complications were related to longer intubation periods (P<0.01). Other perioperative donor and recipient factors including the incidence of infections and acute rejection episodes, and actuarial survival, did not differ between groups. CONCLUSION: In our experience, the incidence of airway complications after lung transplantation is 5.3%. The careful surgical technique and organ preservation, the close surveillance of rejection and infection, and early postoperative extubation might play a role in reducing this incidence. Either surgical therapy or bronchoscopic dilation and stenting methods may contribute to resolve these complications.

Adolescent↗