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Biomedical subjects

A Alvarez

Publications and source records attributed to A Alvarez.

At least 91 records · Page 5Linked to original sources
PubMed2000

A pharmacogenomic approach to Alzheimer's disease.

Single nucleotide polymorphisms (susceptibility genetics) and genomic point mutations (mendelian genetics) can be used in Alzheimer's disease (AD) for diagnostic, predictive and therapeutic purposes. Using a matrix genetic model, including APOE, PS1 and PS2 allelic variants, we have studied the distribution of 36 different genotypes in the AD population (N= 479) and the genotype-related cognitive response to a multifactorial therapy in AD patients with mild-to-moderate dementia. The 10 most frequent AD genotypes are the following: 1) E33P112P2 + (17.75%), 2) E33P112P2- (15.55%), 3) E33P111P2+ (10.85%), 4) E34P112P2+ (9.60%), 5) E34P112P2- (7.56%), 6) E33P111P2- (7.10%), 7) E34P111P2+ (4.80%), 8) E33P122P2+ (4.38%), 9) E34P111P2- (4.18%), and 10) E34P122P2+ (3.55%). APOE-4/4-related genotypes represent less than 3% in the following order: E44P112P2 + > E44P111P2+ = E44P111P2- > E44P112P2+ > E44P122P2+ = E44P122P2. Multifactorial therapy with CDP-choline (1,000 mg/day) + piracetam (2,400 mg/day) + anapsos (360 mg/day) did improve mental performance during the first 6-15 months in a genotype-specific fashion. The best responders in the APOE series were patients with APOE-3/4 genotype (r= +0.013), while the worst responders were APOE-4/4 patients (r= -0.93). PS1-related genotypes responded in a similar manner; and patients with a defective PS2 gene exon 5 (PS2+) always showed a poorer therapeutic response than PS2- patients. All these data suggest that the therapeutic outcome in AD exhibits a genotype-specific pattern, and that a pharmacogenomic approach to AD might be a valuable strategy for drug development and monitoring.

Adjuvants, Immunologic↗
PubMed2000

Acetylcholinesterase-amyloid-beta-peptide interaction and Wnt signaling involvement in Abeta neurotoxicity.

Previous studies have indicated that acetylcholinesterase (AChE) promotes amyloid-beta-peptide (Abeta) fibril formation and AChE-Abeta complexes increase Abeta-dependent neurotoxicity. Here we present evidence for the: i) identification of the AChE motif that promotes amyloid formation, ii) in vivo effect of AChE on brain plaque formation, and iii) connection between AChE-Abeta neurotoxicity and the Wnt signal transduction pathway. Computer modeling, stereotaxic infusions and cell biological techniques were used to study the above problems. Results indicated that a 3.4 kDa AChE peptide promotes Abeta fibril formation. AChE infusion into rat hippocampus determines the appearance of anti-Abeta and thioflavine-S positive plaques, and AChE-Abeta toxicity on hippocampal cultures was blocked by lithium, an activator of the Wnt cascade. We suggest that AChE-Abeta/Abeta dependent neurotoxicity may result in loss of function of Wnt signaling components, and open the possibility that lithium may be considered as a candidate for therapeutic intervention in Alzheimer's disease pathology.

Acetylcholinesterase↗
PubMed2000

P64k meningococcal protein as immunological carrier for weak immunogens.

Previously, the P64k meningococcal protein, an antigen of 64 kDa expressed in Escherichia coli, has been extensively characterized. We have successfully conjugated several synthetic peptides and meningococcal group C polysaccharide to P64k. In three out of four model peptides, the murine humoral immune response against the homologous peptide, evaluated after three doses of conjugate, was higher in the animals immunized with the coupled peptide than in those that received free peptide. The fourth and largest was immunogenic by itself. Similarly, the antigroup C polysaccharide levels reached by conjugated polysaccharide were significantly higher than those produced against unconjugated polysaccharide. As a carrier for one of the peptides, P64k was compared with bovine serum albumin (BSA) and tetanus toxoid (TT), being able to induce slightly higher or similar antipeptide antibody levels than these well-establish protein carriers. Our results suggest that recombinant P64k protein could be a readily available immunological carrier, as efficient as other commonly used large carrier molecules.

Amino Acid Sequence↗
PubMed2000

Biologic parameters that correlate with the prognosis of human gliomas.

Much clinical and biologic data have been processed in the search for useful objective parameters to predict brain tumor behavior. Seventy cases of astrocytic glioma collected by a single clinical team were studied using a full complement of clinical procedures: follow up (7 years), histologic analysis, DNA content estimation, and cell kinetics by flow cytometry. Proliferating cell nuclear antigen (PCNA) was determined by immunocytochemical-coupling flow cytometry (PFC) and also by counting under light microscopy (PIHC). A statistical evaluation was carried out to establish the usefulness of several parameters for glioma prognosis. The cases were histologically classified as 14 low-grade astrocytomas, 20 anaplastic astrocytomas, and 36 glioblastomas multiforme. The survival curve showed significant differences between histologic groups. Diploid populations were more frequent in low-grade astrocytomas, and aneuploid tumors often had increased S-phase and proliferative fractions. The PCNA-labeled index (PCNA-LI) increased with malignancy and correlated with histologic grading (P = 0.01). The PCNA-LI and age segregated low- from high-grade astrocytomas (including anaplastic astrocytoma and glioblastoma multiforme), but none of the variables considered differentiated anaplastic astrocytoma from glioblastoma multiforme. The Cox regression test displayed significant values for age, histologic diagnosis, and PCNA determinations when considered in tandem. Discriminant analysis obtained a function integrating age and specifically PIHC-LI to help in the prognosis of doubtful cases. The results emphasize the importance of parameters integrating different variables in an attempt to provide an accurate prognosis, the most significant being age, histopathologic diagnosis, and the proliferative fraction determined by PCNA.

Adult↗
PubMed2000

The cytolytic effect of a glycoconjugate extracted from corms of saffron plant (Crocus sativus) on human cell lines in culture.

Corms of Crocus sativus L. (Iridaceae) contain a glycoconjugate that shows cytotoxic activity on tumoral cells in culture. Studies of intracellular calcium fluctuations, and release of lactate dehydrogenase in human cervical epitheloid carcinoma cells, showed that this compound caused plasma membrane damage, allowing movements of both calcium and macromolecules, and leading to cell lysis. Analysis of DNA fragmentation showed that cell death was not mediated by apoptosis. This molecule is active against human tumoral cells derived from fibrosarcoma, cervical epithelioid carcinoma and breast carcinoma, with IC50 values of 7, 9 and 22 micrograms/ml, respectively. The proteoglycan is about 8 times more cytotoxic for malignant cells than for their normal counterparts. In addition, 100 micrograms/ml of proteoglycan produced 50% in vitro lysis of normal human erythrocytes, whereas 320 micrograms/ml induced about 60% cell death on cultured human hair follicles. Altogether, these results suggests a distinctive cytotoxic activity of this molecule on different human cell types.

Antineoplastic Agents, Phytogenic↗
PubMed2000

[(99m)Tc]-sestamibi parathyroid scintigraphy in chronic haemodialysis patients: static and dynamic explorations.

BACKGROUND: The place of parathyroid gland imaging by [(99m)Tc](technetium)-sestamibi scintigraphy in uraemic patients with secondary hyperparathyroidism remains a matter of debate. The purpose of the present study was (i) to assess its value with respect to plasma intact parathyroid hormone (iPTH) levels and to surgical parathyroidectomy (PTx), and (ii) to explore the possibility of suppressing parathyroid [(99m)Tc]-sestamibi uptake by calcitriol. METHODS: In a first cross-sectional, static study 52 chronic haemodialysis (HD) patients with plasma iPTH levels between 14 and 2791 pg/ml (normal, 10-65 pg/ml) had a [(99m)Tc]-sestamibi scan, and 21 of them underwent surgical PTx. In a second longitudinal, dynamic study 14 chronic HD patients with advanced secondary hyperparathyroidism received short-term calcitriol treatment in an attempt to suppress [(99m)Tc]-sestamibi imaging of parathyroid glands. Calcitriol was given intravenously for 2 weeks, 2 microg after each haemodialysis session. Scintigraphy was carried out before and at the end of this inhibition test. RESULTS: [(99m)Tc]-Sestamibi scan led to imaging of one or more (maximum three) parathyroid glands in most, but not all, HD patients with plasma iPTH values >600 pg/ml. Based on surgical findings, overall sensitivity of [(99m)Tc]-sestamibi scan in correctly locating parathyroid glands was only 50%, whereas specificity was 100%. In contrast, its sensitivity was 100% in locating single glands in the subgroup of five patients with recurrent hyperparathyroidism. The calcitriol inhibition test showed suppression of [(99m)Tc]-sestamibi uptake by at least one parathyroid gland in eight patients (57%), with complete suppression in five of them (36%). Basal plasma iPTH or decrease of plasma iPTH in response to calcitriol was not predictive of suppressible [(99m)Tc]-sestamibi uptake in the individual case, although mean iPTH was markedly higher in patients with non-suppressible parathyroid glands. CONCLUSION: Because of its relatively low sensitivity the [(99m)Tc]-sestamibi scan is of limited help in the exploration of uraemic patients with severe secondary hyperparathyroidism before a first surgical PTx. However, it is very useful in locating the remaining parathyroid gland(s) in case of reoperation. The novel calcitriol inhibition test of [(99m)Tc]-sestamibi uptake could help to better distinguish parathyroid glands with non-suppressible, autonomous activity from glands whose activity might be amenable to long-term suppression.

Calcitriol↗
PubMed2000

Non-Hodgkin's lymphoma following untreated essential thrombocythemia.

The coexistence of essential thrombocythemia (ET) and non-Hodgkin's lymphoma (NHL) is an extremely rare event, with only two such cases having been reported in the medical literature. We describe here a 25-year old woman who developed high-grade B-cell NHL of the stomach three years after the diagnosis of ET, for which she had received no treatment, due to her young age and the lack of thrombotic risk factors other than thrombocytosis. The lymphoma showed a favorable response to CHOP chemotherapy, whereas the thrombocytosis remained unchanged throughout the patient's clinical course. The possible etiologic and pathogenetic mechanisms leading to the association of these two disorders are discussed. Given the relative frequency of ET and the fact that the present case represents only the third reported instance of NHL developing in such patients, the coincidental ocurrence of both diseases is a possibility that cannot be excluded.

Adult↗
PubMed2000

Influence of serum from healthy or breast tumor-bearing women on the growth of MCF-7 human breast cancer cells.

Sera from women healthy (HW) or with breast (BCW), ovarian or endometrial cancer, were added (10%) to the culture media of MCF-7 cells and cell proliferation assessed 4 days later to verify: a) whether sera from BCW, obtained before or 8 days after tumor ablaction, influence the proliferation of these cells, b) whether the effects of serum from BCW are specific for mammary tumor cells. Sera from BCW, but not sera from women with ovarian or endometrial cancer, increased MCF-7 cell proliferation in comparison with sera from HW. After surgical ablation of the breast tumors, serum's ability to increase MCF-7 cell proliferation decreased significantly. These effects cannot be explained by differences on serum levels of estradiol or melatonin. These results suggest the presence of growth-promoting substances of possible tumoral origin in serum of BCW, a fact that should be considered as support for the surgical treatment of tumor masses.

Adenocarcinoma, Papillary↗
PubMed2000

Relative sensitivity of direct antiglobulin test, antibody's elution and flow cytometry in the serologic diagnosis of immune hemolytic transfusion reactions.

BACKGROUND AND OBJECTIVE: Current immunohematology practice dictates that serologic diagnosis of immune hemolytic transfusion reactions (IHTR) is based on the finding of a positive post-transfusion direct antiglobulin test (DAT). However, since DAT may fail to detect antibody-coated cells when they constitute a minor population amid a large number of non-sensitized ones, we investigated whether antibody detection in eluates or by flow cytometry is more sensitive than DAT in this context. DESIGN AND METHODS: Ten samples of red blood cells sensitized with allo- or autoantibodies were diluted in non-sensitized red blood cells to final concentrations ranging from 10% to 0.1%. DAT, antibody detection in eluates, and immunofluorescence by flow cytometry were performed on each mixture. RESULTS: DAT failed to detect sensitized cells in all but two cases in that only the 10% dilution yielded a positive DAT. Antibody detection in eluates and by flow cytometry was able to detect up to 1% sensitized cells in most cases. INTERPRETATION AND CONCLUSIONS: Antibody detection in eluates and by flow cytometry is more sensitive than DAT for detecting minor populations of IgG-coated cells. These techniques should be included in the routine investigation of suspected cases of IHTR.

Antibodies↗
PubMed2000

[Pathological laughter after the brainstem infarction].

We report a case of 'fou rire prodromique' heralding a brainstem infarct with favorable prognosis after thrombolysis. Different clinical forms of pathological laughter, the pathophysiological mechanisms and clinico-anatomical correlations of this rare phenomenon are discussed.

Anticoagulants↗
PubMed2000

Danazol treatment of idiopathic myelofibrosis with severe anemia.

BACKGROUND AND OBJECTIVE: Severe anemia is an important problem in patients with idiopathic myelofibrosis (IM). When other therapeutic measures are unsuccessful or not applicable, 40-50% favorable responses are obtained with androgen therapy. Oxymetholone is the drug usually employed, but good results have also been reported with danazol, although the experience is limited to a few patients. The aim of the present study was to evaluate the effect of danazol on the anemia of IM. DESIGN AND METHODS: Seven out of 22 consecutive IM patients were eligible for danazol treatment because of severe anemia not treatable with (four cases) or refractory to (three cases) other therapies. Danazol (600-800 mg/day) was given orally for six months and thereafter progressively tapered to the minimum effective dose in responding patients or discontinued in non-responders. Complete response was considered cessation of transfusion requirements with normalization of hemoglobin (Hb) values; partial response was defined as a > 30% reduction in transfusional needs or an increase > 10 g/L in the Hb. The effect on platelet counts was also analyzed. RESULTS: One patient splenectomized three years earlier achieved a complete response and three a partial response, giving an overall response rate of 57 %. A significant increase in platelet counts was also observed in three responders. The responses were first seen between three and six months after the start of treatment, which was usually well tolerated. INTERPRETATION AND CONCLUSIONS: Danazol, given at an appropriate dosage for a sufficient time, is an effective treatment for a substantial proportion of IM patients with severe anemia without marked splenomegaly or who have been previously splenectomized.

Adult↗
PubMed2000

Pharmacological treatment of Alzheimer disease: from psychotropic drugs and cholinesterase inhibitors to pharmacogenomics.

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more "molecular approach" based on new data on the pathogenic events underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into main categories: primary events (genetic factors, neuronal apoptosis), secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction). All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis. This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment. Stem-cell activation, genetically manipulated cell transplantation, gene therapy and antisense oligonucleotide technology constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration. The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.

Journal Article↗
PubMed1999

Gastric antisecretory and antiulcer activities of an ethanolic extract of Bidens pilosa L. var. radiata Schult. Bip.

Bidens pilosa var. radiata Schult. Bip. is used in folk medicine to treat stomach disorders including peptic ulcers. The ethanolic extract (0.5-2 g/kg) decreased the gastric juice volume, acid secretion, as well as pepsin secretion in pylorus ligated rats. B. pilosa extract showed antiulcer activity against indomethacin-induced gastric lesions. The extract effectively inhibited gastric haemorrhagic lesions induced by ethanol, and with an effective dose of 2 g/kg being more potent than sucralfate (400 mg/kg). In contrast, ranitidine (50 mg/kg) failed to reduce these lesions. These results indicate that B. pilosa ethanolic extract exerts a cytoprotective effect in addition to its gastric antisecretory activity that could be due, partly at least, to the presence of flavonoids of which quercetin was identified by HPLC.

Animals↗
PubMed1999

Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death.

The key target of this study was the tau protein kinase II system (TPK II) involving the catalytic subunit cdk5 and the regulatory component p35. TPK II is one of the tau phosphorylating systems in neuronal cells, thus regulating its functions in the cytoskeletal dynamics and the extension of neuronal processes. This research led to demonstration that the treatment of rat hippocampal cells in culture with fibrillary beta-amyloid (Abeta) results in a significant increase of the cdk5 enzymatic activity. Interestingly, the data also showed that the neurotoxic effect of 1-20 microM Abeta on primary cultures markedly diminished with co-incubation of hippocampal cells with the amyloid fibers plus the cdk5 inhibitor butyrolactone I. This inhibitor protected brain cells against Abeta-induced cell death in a concentration dependent fashion. Moreover, death was also prevented by a cdk5 antisense probe, but not by an oligonucleotide with a random sequence. The cdk5 antisense also reduced neuronal expression of cdk5 compared with the random oligonucleotide. The studies indicate that cdk5 plays a major role in the molecular path leading to the neurodegenerative process triggered by the amyloid fibers in primary cultures of rat hippocampal neurons. These findings are of interest in the context of the pathogenesis of Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1999

[A cost-effectiveness analysis of strategies for the diagnosis-treatment of Helicobacter pylori-associated peptic ulcer in primary care].

OBJECTIVES: To undertake an economic evaluation of three strategies for diagnosing and treating Helicobacter pylori (HP)-related peptic ulcers (PU), and to find the most efficacious and efficient combination of medication for the most cost-effective strategy. DESIGN: Cost-effectiveness analysis based on retrospective information (systematic review of the literature) and Markov models for the simulation of a hypothetical cohort of patients with PU. PATIENTS: Patients seeking medical care at the primary level for an acute PU attack. The costs and health effects of the management of an attack were evaluated in a hypothetical cohort of adults (> 18 years old) with symptomatic peptic ulcer confirmed endoscopically and not associated with consumption of non-steroidal anti-inflammatory drugs (NSAIDs). INTERVENTIONS: Three strategies for handling PU patients were compared: pre- and post-treatment diagnosis of HP, pre-treatment diagnosis and empirical treatment. Then the most efficient strategy for comparing 6 combinations of antibiotics was used. RESULTS: The empirical treatment strategy was markedly less costly (saving of between 15000 and 39000 pesetas per patient treated) than the diagnosis strategies, and obtained equivalent effectiveness under all analytical hypotheses. In comparing drug combinations, the classic triple therapies based on bismuth subcitrate were more effective and less costly than other therapies. CONCLUSIONS: Empirical treatment with combinations of irradicatory drugs was the most efficient strategy for tackling the diagnosis/therapy of patients with HP-related PU. In terms of efficiency, the choice between the various combinations of irradicatory drugs with over 80% success depends basically on the cost of the drugs.

Adult↗