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Luis Alvarez

Publications and source records attributed to Luis Alvarez.

17 recordsLinked to original sources
PubMed2007

Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis.

Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB(1)) and type 2 (CB(2)) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100beta- and glial fibrillary acidic protein-expressing cells. In parallel, cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.

Animals↗
PubMed2006

Validation of a minimum outcome core set in the evaluation of patients with back pain.

STUDY DESIGN: Prospective study of patients with subacute osteoporotic fracture (SOF) or chronic low back pain (CLBP). OBJECTIVE: To evaluate reliability, validity, and responsiveness of a purposefully brief outcome instrument. SUMMARY OF BACKGROUND DATA: A minimum standardized "core set" was proposed for monitoring patients with low back pain in 1998, but an assessment of metric properties was still lacking. METHODS: The Core Set, SF-36, and Oswestry questionnaires were completed by 154 patients. Test-retest reproducibility was evaluated in a subsample of 43 stable patients with CLBP. Responsiveness was evaluated by estimating effect size (ES) of pre-postsurgery changes in 50 patients with SOF and 23 with CLBP. RESULTS: The total Core Set showed good reproducibility with intraclass correlation coefficients on test-retest near the highest standard of 0.9, whereas internal consistency differed between patients with CLBP and those with SOF (Cronbach's alpha of 0.92 and 0.64, respectively). Most correlations of the Core Set with SF-36 and Oswestry, previously hypothesized as high, were >0.65, demonstrating good construct validity. Sensitivity to change of the Core Set (ES 0.4-2.3) is similar to the Oswestry (ES 0.7 and 2.3). CONCLUSIONS: These findings support the potential usefulness of the Core Set when respondent burden is a major concern. However, subscale scores need to be further tested in other populations before they can be widely recommended.

Adult↗
PubMed2006

Percutaneous vertebroplasty: functional improvement in patients with osteoporotic compression fractures.

STUDY DESIGN: Prospective, double-cohort study. OBJECTIVE: To evaluate conservative and percutaneous vertebroplasty (PV) management of osteoporotic vertebral fractures. SUMMARY OF BACKGROUND DATA: PV is an elective alternative to conservative management for the treatment of a painful osteoporotic vertebral fracture. METHODS: We performed a prospective study consisting of 101 consecutive patients who underwent PV and 27 patients who refused PV treatment and were managed conservatively. We used a data evaluation and outcomes system that was developed to evaluate the outcomes of surgical intervention. RESULTS: Patients that elected for PV as a treatment of their fractures had significantly more pain and functional impairment before the procedure than the patients of the conservative group (P < 0.001). The pain, functional, and general health scores of the PV group were improved from the preoperative mean values (P < 0.001) in all postoperative periods. Compared with the conservative treatment group, there was a significant difference at month 3. However, no statistical differences on function were observed between these groups at 6 months and 1 year posttreatment. CONCLUSIONS: PV demonstrated a rapid and significant relief of pain and improved the quality of life. PV election for treatment of painful osteoporotic vertebral fracture after 6 weeks of conservative treatment was based on pain and functional impairment.

Aged↗
PubMed2006

A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells.

Recent findings on the inhibition of angiogenesis and vascular endothelial cell proliferation by anthracycline antibiotics, which contain a quinone moiety, make this type of compound a very promising lead in cancer research/therapy. We have reported that a new cannabinoid anticancer quinone, cannabidiol hydroxyquinone (HU-331), is highly effective against tumor xenografts in nude mice. For evaluation of the antiangiogenic action of cannabinoid quinones, collagen-embedded rat aortic ring assay was used. The ability of cannabinoids to cause endothelial cell apoptosis was assayed by TUNEL staining and flow cytometry analysis. To examine the genes and pathways targeted by HU-331 in vascular endothelial cells, human cDNA microarrays and polymerase chain reaction were used. Immunostaining with anti-CD31 of tumors grown in nude mice served to indicate inhibition of tumor angiogenesis. HU-331 was found to be strongly antiangiogenic, significantly inhibiting angiogenesis at concentrations as low as 300 nM. HU-331 inhibited angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. A significant decrease in the total area occupied by vessels in HU-331-treated tumors was also observed. These data lead us to consider HU-331 to have high potential as a new antiangiogenic and anticancer drug.

Animals↗
PubMed2005

Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal).

We analyzed the control region of the mitochondrial DNA (mtDNA) from maternally related individuals originating from the Azores Islands (Portugal) in order to estimate the mutation rate of mtDNA and to gain insights into the process by which a new mutation arises and segregates into heteroplasmy. Length and/or point heteroplasmies were found at least in one individual of 72% of the studied families. Eleven new point substitutions were found, all of them in heteroplasmy, from which five appear to be somatic mutations and six can be considered germinal, evidencing the high frequency of somatic mutations in mtDNA in healthy young individuals. Different values of the mutation rate according to different assumptions were estimated. When considering all the germinal mutations, the value of the mutation rate obtained is one of the highest reported so far in family studies. However, when corrected for gender (assuming that the mutations present in men have the same evolutionary weight of somatic mutations because they will inevitably be lost) and for the probability of intraindividual fixation, the value for the mutation rate obtained for HVRI and HVRII (0.2415 mutations/site/Myr) was in the upper end of the values provided by phylogenetic estimations. These results indicate that the discrepancy, that has been reported previously, between the human mtDNA mutation rates observed along evolutionary timescales and the estimations obtained using family pedigrees can be minimized when corrections for gender proportions in newborn individuals and for the probability of intraindividual fixation are introduced. The analyses performed support the hypothesis that (1) in a constant, tight bottleneck genetic drift alone can explain different patterns of heteroplasmy segregation and (2) in neutral conditions, the destiny of a new mutation is strictly related to the initial proportion of the new variant. Another important point arising from the data obtained is that, even in the absence of a paternal contribution of mtDNA, recombination may occur between mtDNA molecules present in an individual, which is only observable if it occurs between mtDNA types that differ at two or more positions.

Azores↗
PubMed2005

Predictors of outcomes of percutaneous vertebroplasty for osteoporotic vertebral fractures.

STUDY DESIGN: Retrospective review of all percutaneous vertebroplasties performed in the authors' institution from November 1994 to June 2002. OBJECTIVE.: To determine the factors affecting the outcome of percutaneous vertebroplasty for the treatment of persistent painful osteoporotic fractures. SUMMARY OF BACKGROUND DATA: Percutaneous vertebroplasty is an efficient procedure to treat pain due to osteoporotic vertebral fracture. However, the patient population that is most likely to benefit from this procedure is uncertain, and the inclusion and exclusion criteria for an ideal candidate have varied widely in the literature. METHODS: A retrospective review of 278 percutaneous vertebroplasty procedures for osteoporotic fractures at 423 levels was performed. Sociodemographic, clinical, radiologic, and procedural data were analyzed as parameters for prognosis significance by univariate and multivariate analysis with logistic regression to estimate the strength of influence of each variable. RESULTS: The presence of two or less symptomatic vertebrae (P < 0.03), the American Society of Anesthesiologists status I (P < 0.001), the presence of signal changes on magnetic resonance imaging (P < 0001), and the collapse of the vertebral body less than 70% (P < 0.001) were assessed as parameters for prognostic significance. Multivariate analysis also showed a significant correlation between the American Society of Anesthesiologists score and height loss of the vertebral body and the final outcome. The presence of signal changes on magnetic resonance imaging showed the highest odds ratio adjusted. CONCLUSIONS: Appropriate patient selection is essential for achieving clinical success. Better results can be expected in patients with an American Society of Anesthesiologists score of I and when the level managed is confirmed by magnetic resonance imaging and the vertebral body height loss is less than 70%.

Adult↗
PubMed2005

Molecular basis of cholestatic diseases of surgical interest.

Cholestasis constitutes one of the most common and severe manifestations of acquired or inherited liver disease. When manifest in early infancy, it is often life-threatening and usually requires surgical management. In many cases, liver transplantation is the only effective therapy. Extensive knowledge about the molecular mechanisms underlying several pediatric cholestatic disorders has been gained in recent years from studies in both experimental models and clinical forms. In this review, we focus on recent contributions to the knowledge of molecular basis of main pediatric cholestatic disorders, such as biliary atresia, Alagille syndrome, and familial intrahepatic cholestasis. For some of them, putative targets of therapeutic interest, such as interferon-gamma and Farnesoid X receptor, have been proposed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Measurement of triclabendazole and its metabolites in liver flukes: method development and full validation.

The trematode parasite Fasciola hepatica is still the cause of considerable loss in livestock production all over the world. The knowledge of the pharmacological properties of the available flukicidal drugs is critical to control this parasite. Triclabendazole is an halogenated benzimidazole anthelmintic with potent flukicidal activity. A simple reversed-phase high-performance liquid chromatographic analytical method has been developed, validated and applied for the quantitative determination of the flukicidal drug triclabendazole and its sulpho- and hydroxy-metabolites in the liver fluke, F. hepatica. Triclabendazole, triclabendazole sulphoxide, triclabendazole sulphone, hydroxy-triclabendazole, hydroxy-triclabendazole sulphoxide and hydroxy-triclabendazole sulphone were measured simultaneously in this trematode parasite. Linearity, resolution, precision, accuracy, recovery, limits of detection and quantification of the method were determined. Drug extraction from the parasite's tissue homogenate was effectively performed using liquid extraction (acetonitrile), avoiding clean up by solid phase extraction, prior to analysis by reversed-phase high-performance liquid chromatography. The resolution of all the halogenated benzimidazole thiol molecules assayed was obtained on a C(18) reversed-phase (5 microm, 250 mm x 4.6 mm) column using acetonitrile and ammonium acetate as the mobile phase and ultraviolet detection at 300 nm. Regression analyses were linear over the concentration range examined (from 0.272 to 16.331 nmol/100 mg trematode protein) and the correlation coefficients of the calibration curves ranged between 0.996 and 1.000. The calculated limits of detection of the proposed method for the parent drug and its metabolites ranged between 0.007 and 0.079 nmol/100 mg trematode protein. The extraction efficiency for the different analytes from the parasite material was greater than 71%. The results obtained indicated that the developed chromatographic method was selective, accurate and easy to reproduce. The developed procedure was successfully applied to quantify triclabendazole/metabolites in F. hepatica incubated under ex vivo conditions, demonstrating to be efficient for the determination of the most extensively used flukicidal drug available for veterinary medicine, and its metabolites. The analytical method described here is an useful tool for the measurement of this flukicidal compound in different studies addresses to evaluate drug influx/eflux and metabolism in its main target parasite.

Animals↗
PubMed2004

Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.

Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas.

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Delta9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.

Animals↗
PubMed2004

Potentially serious infections in the aging person: diagnosis, treatment and prevention.

Infections in the elderly patient are a challenge, since the classical signs of infection are absent or ill defined. The present paper describes the presentation, diagnosis, clinical manifestations and treatment for a selected group of potential serious infections including influenza, bacterial pneumonia, urinary tract infections as well as infections caused by multiresistant bacteria, like vacomycin-resistant enterococcus and methicillin resistant S. aureus. We conclude with the need for prevention in the older person with the use of vaccines, specifically the influenza and pneumococcal vaccine as well as the prevention of urinary infections. Influenza is a significant cause of morbidity, whose ill effects can be prevented in many older persons with the use of a vaccine. The use in prophylaxis and treatment of antiviral agents like amantadine, rimatadine, and oseltamivir is presented. Bacterial pneumonia is one of the leading causes of death in the USA among the older persons. The emergence of drug resistant Streptococcus pneumoniae leads to the consideration as empiric therapy the newer fluoroquinolones or the use of third or fourth generation cephalosporis. Of importance is the use of pneumococcal vaccine among people age 60 or above. The frequency of urinary tract infections among the elderly is of primary although in many instances important do not require treatment. When infection of the urinary tract is diagnosed, most authors use a fluoroquinolone as empiric theraphy. The emergence of multiresistant bacteria like methicillin resistant S. aureus and or vancomycin resistant enterococci leads to the need to consider new agents like quinipristin-dalfopristin, linezolid and deptomycin in the management of such patients.

Age Factors↗
PubMed2003

Quantitative chromatographic determination of several benzimidazole anthelmintic molecules in parasite material.

A specific, precise and accurate high-performance liquid chromatographic (HPLC) analytical method has been developed for the quantitative determination of different benzimidazole (BZD) anthelmintics in parasite material (Moniezia benedeni). Mebendazole (MBZ), oxibendazole (OBZ), flubendazole (FLBZ), albendazole (ABZ) ricobendazole (RBZ), albendazole sulphone (ABZSO(2)), fenbendazole (FBZ), oxfendazole (OFZ) and fenbendazole sulphone (FBZSO(2)) were measured simultaneously in M. benedeni, a sheep and cattle cestode parasite used as a model of the biological matrix. The recovery, linearity, precision, accuracy, limits of detection and quantification of the method were determined. Drug extraction from the parasite's tissue homogenate was performed using methanol (liquid phase extraction), and after solvent evaporation, the residual material was cleaned up by solid phase extraction prior to analysis by reversed-phase HPLC. The resolution of all the BZD molecules assayed was obtained on a C(18) reversed-phase (5 microm, 250 mm x 4.6 mm) column using acetonitrile and ammonium acetate as the mobile phase and ultraviolet (UV) detection at 292 nm. Regression analyses for all the BZD compounds assayed were linear at concentrations ranging from 1.61 to 64.21 nmol/100mg protein (triplicate determinations) showing correlation coefficients greater than 0.9922. The developed method is efficient for the simultaneous determination of several benzimidazole anthelmintic molecules in parasite material and useful for the ex vivo and in vivo characterisation of the kinetics of drug uptake/diffusion in target parasites, which seems to be relevant to optimise parasite control both in human and veterinary medicine.

Animals↗
PubMed2003

Transfection of MS-36 melanoma cells with gef gene inhibits proliferation and induces modulation of the cell cycle.

The gef gene, found in Escherichia coli DNA, encodes a small (50 amino acids) protein which is related to cell-killing functions. We used the MS-36 melanoma cell line as an experimental model to examine the usefulness of the gef gene as a new strategy for cancer therapy. We transfected MS-36 cells using the pMAMneo vector, and induced gef gene expression with dexamethasone. This decreased the proliferation rate of MS-36TG by as much as 85% in comparison with MS-36 parental cells. The decrease in cell growth was accompanied with significant modifications of the cell cycle and morphology. The G1-phase gradually disappeared, with accumulation in the S-phase. However, studies with annexin V-FITC and 7-aminoactinomycin D failed to demonstrate induction of apoptosis. Morphological changes were an increase in cell size and the number of filopodia, and especially the appearance of pore-like alterations in the cell membrane which were not seen in parental cells. Our results demonstrate that the gef gene, a system independent of the administration of a prodrug, significantly reduces the proliferation of MS-36 cells. This gene may therefore be considered a new candidate for cancer gene therapy.

Apoptosis↗
PubMed2003

[Hemostatic coronary risk factors in a healthy population of Maracaibo, Venezuela].

The purpose of the present work was to determine the plasma concentrations of fibrinogen and Von Willebrand Factor (VWF) as well as platelet aggregation, in an apparently healthy population of 306 men and 41 women, 33 to 65 years of age, workers of the national oil industry (PDVSA, Maracaibo), as a base investigation in a 5-year prospective national collaborative study. The participants were previously subjected to a thorough clinical examination with cardiovascular evaluation and laboratory tests. Clottable fibrinogen and VWF concentrations were determined in platelet poor plasma, the last one by immunoclectrophoresis, and a multimeric analysis of VWF was performed on those plasmas with concentrations higher than 150 U/dL by SDS agarose electrophoresis, followed by cellulose membrane transference. Platelet aggregation was studied in platelet rich plasma with no addition of stimulants and after collagen and ristocetin were added. Forty per cent of men and 65.8% of women, showed fibrinogen concentrations above 300 mg/dL (p < 0.01) and 12.2% of men and 15.4% of women had VWF values higher than 150 U/dL, with normal multimeric distribution. Fourteen individuals presented spontancous platelet aggregation and increased aggregation in 12 and 13 of them, after induction with collagen and ristocetin respectively. Comparing these findings with those of previous collaborative studies from other countries, the present results could mean that an important proportion of the population here studied, could be at risk for a future coronary event; however, as these are the base findings in Maracaibo, the significance of our results will be better evaluated at the end of the five year study.

Adult↗
PubMed2002

The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy.

PURPOSE: Although conventional surgery is presently used to treat seizures of temporolimbic and neocortical origin, deep-seated lesions are often associated with morbidity. Stereotactic radiosurgery is a noninvasive procedure that effectively treats patients with vascular malformations and brain tumors, but its efficacy for epileptogenic foci is limited, especially in children. METHODS: Between 1995 and 1999, four candidates who had medically uncontrolled seizures and localized seizure foci were selected for stereotactic radiosurgery, with a mean age of 9.75 years at the time of surgery (range, 4-17 years). Seizure foci were identified on the basis of ictal and interictal video-EEG. Magnetic resonance (MR) images were obtained before and after surgery. Ictal single-photon emission computed tomography (SPECT) was performed by using stabilized hexamethyl-propyleneamine oxime (HMPAO; 300 microcuries/kg) with early injection after electrographic ictal onset. The clinical features of the patients are given. All radiosurgical procedures were performed with the gamma knife unit with the Leksell stereotactic frame, stereotactic MRI imaging, and the Gamma Plan workstation. Seizure outcome was scored according to Engel's classification. RESULTS: Two patients had hypothalamic hamartoma (HH), and two had neocortical epilepsy. At mean follow-up of 39.2 months (range, 26-69 months), two patients were seizure free, one with a HH and one with a suggestive developmental tumor in the insular cortex by MRI findings. The other patient with HH had 90% reduction of seizures. One patient with a widespread seizure focus that involved the motor strip was unimproved. The two patients with HH also exhibited markedly improved neurobehavioral status after surgery. There were no significant complications of radiosurgical therapy. CONCLUSIONS: Our findings suggest that gamma knife surgery is a potentially valuable treatment modality for children with medically intractable epilepsy due to a well-localized seizure focus that is difficult to excise by conventional techniques or for whom they are deemed unsuitable. More widespread application in childhood epilepsy should be investigated in larger series.

Adolescent↗