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AIM: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, ß-amyloid (Aß) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results. METHODS: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging-Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aß42, t-tau, and pTau181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups. RESULTS: The CSF Aß42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aß42 levels compared to nonapathetic ones. CONCLUSION: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Apatía/fisiología , Biomarcadores/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We analyzed peripheral blood mononuclear cells (PBMCs) and serum inflammatory biomarkers in patients with mesial temporal lobe epilepsy (drug-resistant - DR, vs. drug-sensitive - DS). Patients with epilepsy showed higher levels of serum CCL2, CCL3, IL-8 and AOPP, and lower levels of FRAP and thiols compared to healthy controls (HC). Although none of the serum biomarkers distinguished DR from DS patients, when analysing intracellular cytokines after in vitro stimulation, DR patients presented higher percentages of IL-1ß and IL-6 positive monocytes compared to DS patients and HC. Circulating innate immune cells might be implicated in DR epilepsy and constitute potential new targets for treatments.
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Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Citocinas , Monocitos , Leucocitos Mononucleares , Biomarcadores , Resistencia a Medicamentos , HipocampoRESUMEN
BACKGROUND: Tetracyclines could have neuroprotective effects in neuromuscular and neurodegenerative disorders. AIMS OF THE STUDY AND METHODS: Objective of this double-blind randomized pilot study (followed by an adjunctive open-label phase) was to evaluate whether tetracycline (500 mg/day × 14 days/month × 3 months) could be useful in patients (n = 16) with progressive external ophthalmoplegia (PEO). RESULTS: Our results do not formally support any effect of tetracycline on eye motility in PEO. However, some possible protective effects could not be completely ruled out, i.e. a further analysis suggests a possible difference between the tetracycline group and the placebo group, significant at least for oblique motility, when comparing the ratio between the end of the double-blind phase and baseline. Tetracycline could modify some oxidative stress biomarkers in patients with PEO. CONCLUSIONS: Further studies are needed to confirm such effects of tetracycline in patients with PEO, if any, and to clarify the mechanisms of action for antioxidant effects of tetracyclines in mitochondrial disorders and other diseases.
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Fármacos Neuroprotectores/uso terapéutico , Oftalmoplejía Externa Progresiva Crónica/tratamiento farmacológico , Tetraciclina/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Proyectos PilotoRESUMEN
BACKGROUND: Postmortem studies suggest excessive free radical toxicity in the substantia nigra of patients with PD. Increased lipid peroxidation and oxidative DNA damage have been reported in the CNS. Markers of oxidative stress have been identified in the blood of patients with PD. OBJECTIVE: To assess the presence of spontaneous chromosome and primary or oxidative DNA damage in peripheral blood leukocytes of patients with untreated PD. METHODS: Patients with de novo PD (20) and control subjects (16), matched for age, sex, and smoking habits, underwent cytogenetic analysis using the human lymphocyte micronucleus assay coupled with the fluorescence in situ hybridization technique and the Comet assay. RESULTS: Compared with controls, patients with PD showed an increase in the incidence of spontaneous micronuclei (p < 0.001); single strand breaks (p < 0.001); and oxidized purine bases (p < 0.05). Fluorescence in situ hybridization analysis showed micronuclei harboring acentric fragments. CONCLUSIONS: There is chromosomal, primary DNA damage and oxidative DNA damage demonstrable in lymphocytes of patients with untreated PD.
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Análisis Citogenético/estadística & datos numéricos , Leucocitos/metabolismo , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Anciano , Ensayo Cometa , Análisis Citogenético/métodos , Daño del ADN , Femenino , Humanos , Leucocitos/patología , Masculino , Micronúcleos con Defecto Cromosómico/genética , Micronúcleos con Defecto Cromosómico/metabolismo , Pruebas de Micronúcleos/métodos , Pruebas de Micronúcleos/estadística & datos numéricos , Persona de Mediana Edad , Enfermedad de Parkinson/patologíaRESUMEN
OBJECTIVE: To assess whether chronic long-term calcium antagonist therapy may increase genotoxicity, the chromosome aberration test, a widely accepted genotoxic assay, was used ex vivo in peripheral human lymphocytes of patients with or without long-term exposure to calcium antagonist therapy. METHODS AND RESULTS: In a case-control study design, we evaluated 30 ischaemic and/or hypertensive patients (22 males, eight females; age 59.4+/-1.5 years), under chronic calcium antagonist treatment (group I), for more than 3 years (4.4+/-0.34 years) and 30 age-matched subjects, without any previous exposure to calcium antagonists (group II). Venous blood samples were collected from the patients and cultures were set up for cytogenetic analysis by standard methods. For each subject, 100 metaphases were scored. The two groups showed similar values (mean +/- SEM) for percentage aberrant cells (group I 2.6+/-0.3 versus group II 2.5+/-0.3, not significant), percentage structural aberrations (group I 1.9+/-0.3 versus group II 1.8+/-0.2, not significant) and percentage numerical aberrations (group I 0.70+/-0.2 versus group II 0.73+/-0.2, not significant). CONCLUSIONS: Long-term calcium antagonist therapy is not associated with an increased incidence of chromosomal indices of genotoxic damage in humans.
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Bloqueadores de los Canales de Calcio/uso terapéutico , Aberraciones Cromosómicas , Hipertensión/tratamiento farmacológico , Linfocitos/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Estudios de Casos y Controles , Células Cultivadas , Daño del ADN/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/sangre , Masculino , Metafase/efectos de los fármacos , Metafase/genética , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Factores de RiesgoRESUMEN
Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.
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Antiparkinsonianos/farmacocinética , Benzofenonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Levodopa/farmacocinética , Enfermedad de Parkinson/metabolismo , Antiparkinsonianos/sangre , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacología , Benzofenonas/farmacología , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Levodopa/sangre , Levodopa/metabolismo , Levodopa/farmacología , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Nitrofenoles , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/tratamiento farmacológico , Tolcapona , Tirosina/análogos & derivados , Tirosina/sangre , Tirosina/farmacocinéticaRESUMEN
Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.
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Antiparkinsonianos/uso terapéutico , Ritmo Circadiano/fisiología , Levodopa/uso terapéutico , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Administración Oral , Antiparkinsonianos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Levodopa/farmacocinética , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Desempeño Psicomotor/efectos de los fármacos , Temblor/tratamiento farmacológico , Temblor/etiología , Tirosina/análogos & derivados , Tirosina/sangre , CaminataRESUMEN
Due to high mercury levels in many Mediterranean aquatic organisms, people who live in this area and consume large amounts of seafood are exposed to a toxicological hazard. A group of 51 fishermen exposed to mercury through eating contaminated seafood from the northern Tyrrhenian Sea underwent cytogenetic monitoring. This work is part of a research project consisting of the evaluation of micronuclei (MN), chromosomal aberrations (CA) and sister-chromatid exchanges (SCE) in peripheral blood lymphocytes. Here we present data on mercury levels in blood and on micronucleus frequencies in peripheral blood lymphocytes of fishermen. The range of mercury concentrations in blood was 10.08-304.11 ng/g fresh weight, the average was 88.97 +/- 54.09 ng/g. Micronucleus frequency was defined with at least 2000 binucleated cells scored for each person; the average was 8.74 +/- 2.56 expressed on 1000 binucleated cells. A statistical correlation was found between MN frequency and total mercury concentration in blood (p = 0.00041, r = 0.674), as well as between MN frequency and age (p = 0.017). No other parameters taken into account correlated with MN frequency.
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Aberraciones Cromosómicas , Monitoreo del Ambiente , Contaminación de Alimentos , Mercurio/toxicidad , Alimentos Marinos/efectos adversos , Contaminantes del Agua/análisis , Adulto , Factores de Edad , Anciano , Animales , Células Cultivadas , Explotaciones Pesqueras , Humanos , Modelos Lineales , Linfocitos , Masculino , Mar Mediterráneo , Mercurio/sangre , Pruebas de Micronúcleos , Persona de Mediana Edad , Intercambio de Cromátides Hermanas , Contaminantes del Agua/efectos adversosRESUMEN
As cancer development usually results from exposure to several environmental risk factors in interaction with the genetic susceptibility of the host, it could be of interest to investigate if neurodegeneration, as occurs in Parkinson's disease (PD) patients can be attributed at least partially, to environmental risk factors. There is growing evidence that oxidative stress could play a significant role as a risk factor in the aetiology and pathogenesis of neurodegenerative diseases, emphasising the need for new individual and human-based approaches. The aim of our research is to explore the relation between chromosome instability and oxidative stress biomarkers in Parkinson's disease using a variety of strategies. We determined peripheral markers for oxidative damage in PD by testing for spontaneous and induced chromosomal damage, DNA strand breaks, oxidised pyrimidines and altered purines both in peripheral blood and cultured lymphocytes. We also measured glutathione S-transferase activity in the plasma of patients and controls. Compared to healthy controls, PD patients show higher frequencies of micronuclei (17.2 +/- 4.8 vs. 9.0 +/- 3.4, p < 0.001) and a significant increase in the levels of single strand breaks (SSB). Significant differences were also obtained in the distribution of oxidised purine bases between the two groups. Preliminary data obtained by fluorescence in situ hybridization analysis showed that the percentage of centromere negative micronuclei is higher than that of centromere positive micronuclei. Glutathione S-transferase activity in plasma from PD patients and controls was also measured and the enzymatic activity in PD patients was lower than in healthy controls.
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Biomarcadores/análisis , Aberraciones Cromosómicas , Daño del ADN , Estrés Oxidativo , Enfermedad de Parkinson/fisiopatología , Anciano , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Femenino , Glutatión Transferasa/metabolismo , Humanos , Hibridación Fluorescente in Situ , Linfocitos , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Purinas/metabolismo , Pirimidinas/metabolismo , Factores de RiesgoRESUMEN
Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.
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Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/fisiopatología , Enfermedad de la Neurona Motora/metabolismo , Enfermedad de la Neurona Motora/fisiopatología , Animales , Atrofia Bulboespinal Ligada al X/genética , ADN Mitocondrial/genética , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedad de la Neurona Motora/genética , Receptores Androgénicos/genéticaRESUMEN
A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients. APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis. We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers. This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.
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Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/genética , Estrés Oxidativo , Polimorfismo Genético/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/sangre , Apolipoproteínas E/metabolismo , Disfunción Cognitiva/sangre , Disfunción Cognitiva/metabolismo , Femenino , Genotipo , Humanos , Masculino , Factores de Riesgo , Superóxido Dismutasa/metabolismoRESUMEN
Astrocytes have long been considered as just providing trophic support for neurons in the central nervous system, but recently several studies have highlighted their importance in many functions such as neurotransmission, metabolite and electrolyte homeostasis, cell signaling, inflammation, and synapse modulation. Astrocytes are, in fact, part of a bidirectional crosstalk with neurons. Moreover, increasing evidence is stressing the emerging role of astrocyte dysfunction in the pathophysiology of neurological disorders, including neurodegenerative disease, stroke, epilepsy, migraine, and neuroinflammatory diseases.
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One major goal of drug development would be the establishment of biomarkers as objective indicators of normal biological and pathogenetic processes, or pharmacological response to a therapeutic intervention. A potential approach is to investigate proteins in CSF linked to key neuropathological features of Alzheimer's disease (AD). Recently CSF phosphorylated-Tau (p-Tau) levels have been reported to reflect neurofibrillary changes within the brain of patients with AD, however the use of serial CSF investigations in order to monitor the disease progression is not applicable. PET with FDG reveals characteristic patterns in AD patients, however so far no correlation between in vivo metabolic information and pathological features has been reported. In the present study, we tested whether CSF Tau levels correlate with metabolic rate for glucose consumption in a cohort of 28 AD patients. We found a statistically significative correlation between both CSF total and p-TAU protein and relative metabolic indexes obtained from 18FDG-PET scans in parietal, temporal and occipital lobes bilaterally. These results indicate the existence of a correlation between impairment of cerebral metabolism, estimated throughout FDG-PET, and CSF Tau protein levels.
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Enfermedad de Alzheimer/metabolismo , Cerebro/metabolismo , Glucosa/metabolismo , Tomografía de Emisión de Positrones , Proteínas tau , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Biomarcadores/metabolismo , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/estadística & datos numéricos , Estadística como Asunto , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/químicaRESUMEN
Mitochondrial DNA (mtDNA) haplogroup-specific polymorphisms were previously related to several neurodegenerative diseases, including Alzheimer's disease (AD). However, the precise role of mtDNA haplogroups in the neurodegenerative cascade leading to AD is still unclear. In this work we have genotyped predefined European mtDNA haplogroups in 209 patients with AD and 191 matched controls. In order to minimise the risk of "genetic contamination", which could lead to false associations between gene markers and disease, we were careful to enrol in the study only patients and controls of clear Tuscan origin (with at least three generations of Tuscanborn relatives). The frequency of the haplogroups did not differ between the two groups, and no correlation with gender, ApoE genotype, age of onset or disease status was observed. Further studies will be required to define the contribution of mtDNA haplogroups, if any, to the pathogenesis of AD. A correct population selection, in order to minimise the risk of genetic contamination, is essential in these studies.
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Enfermedad de Alzheimer/genética , ADN Mitocondrial/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Apolipoproteínas E/genética , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Factores SexualesRESUMEN
The sera obtained from 105 non transfused adult heterozygous thalassaemic subjects and from 119 members of 25 thalassaemic families have been tested with radioimmunoassay methods for the presence of HBsAg and anti-HBs. 11 out of 105 thalassaemic patients (10.4%) showed HBsAg in their serum and 41 (40%) anti-HBs antibodies. Family studies revealed that the incidence of HBsAg was 8.9% in 89 thalassaemic members and 10% in 30 non thalassaemic relatives. The incidence of anti-HBs was 34.8% and 13.3% respectively. The frequency of HBsAg in thalassaemic subjects, independently of blood transfusion as shown by our data, suggests some difficulty in eliminating the antigen. So these subjects become rather easily carriers of the antigen and source of the infection particularly in the family.
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Anticuerpos Antivirales/análisis , Anticuerpos contra la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/análisis , Talasemia/inmunología , Adulto , Transfusión Sanguínea , Portador Sano , Humanos , Radioinmunoensayo , Talasemia/genéticaRESUMEN
OBJECTIVE: It is well known that free radicals contribute to endothelial dysfunction and are involved in the pathogenesis and development of cardiovascular diseases, such as atherosclerosis. The aim of this study was to provide evidence for enhanced oxidative stress in coronary artery disease (CAD). METHODS: Plasma levels of 8-isoprostane (8-epiPGF(2alpha)), marker of lipid peroxidation, were measured in 68 subjects (age: 60 +/- 2 years, mean +/- SEM). Subjects included 30 healthy control subjects and 38 patients with angiographically proven CAD. In addition, the total antioxidant power (PAO) was evaluated in a subgroup (40 subjects, 12 healthy and 28 CAD). RESULTS: Levels of 8-epiPGF(2alpha) increased with the number of affected vessels (one- and multi-vessel disease versus control subjects, P < 0.001) and considering different risk determinants for atherosclerosis (i.e. hypertension, gender, hypercholesterolaemia, P < 0.01). In multivariate regression models the number of affected vessels was independently correlated with 8-epiPGF(2alpha) (P < 0.05). PAO values significantly decreased with increased number of affected vessels (P < 0.05) and in hypertensive patients when compared with those without hypertension (P < 0.05). In multivariate regression models the number of affected vessels resulted an independent determinant for PAO (P < 0.05). Concentration of 8-epiPGF(2alpha) and PAO also correlated with the number of cardiovascular risk factors (P < 0.01 and P = 0.07, respectively). CONCLUSION: These findings indicate that elevated levels of plasma 8-epiPGF(2alpha) and reduced antioxidant capacity are associated with the extent and the severity of CAD and with the occurrence and number of different atherogenic risk factors. This observation may assist in providing more information as to how oxidative stress may predispose to atherogenesis and suggest attractive therapeutic strategies in the prevention and treatment of cardiovascular disease.
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Enfermedad de la Arteria Coronaria/metabolismo , Estrés Oxidativo/fisiología , Antioxidantes/metabolismo , Biomarcadores/sangre , Dinoprost/análogos & derivados , Dinoprost/sangre , Femenino , Humanos , Peroxidación de Lípido/fisiología , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
This study was aimed at assessing whether peripheral blood lymphocytes of patients with Alzheimer's disease (AD) show significant levels of aneuploidy and high percentages of cytogenetic events in vitro, indicating a predisposition to aneuploidy spontaneously, or after chemical treatment in vitro. A group of affected individuals and a group of unaffected, age-, sex- and smoking-habit-matched controls were identified. Lymphocytes were cultured for analysis of the following cytogenetic parameters: premature centromere division (PCD), satellite associations of acrocentric chromosomes (SA) and micronuclei (MN). In a subset of subjects, the fluorescence in situ hybridization (FISH) technique was combined with the MN assay, by means of a pancentromeric DNA probe for the detection of the presence of centric material. To evaluate the sensitivity to aneuploidogenic agents, in vitro treatment of lymphocytes of affected individuals was performed by adding griseofulvin, a chemical whose supposed target is microtubule-associated protein(s). Both the spontaneous frequency of MN and the frequency of PCD was significantly higher in patient cells than in controls. Furthermore, after application of the FISH technique, we found that the majority of MN were composed of whole chromosomes (because of the phenomenon of chromosome loss). Metaphase analysis for the detection of associative events between satellite regions of acrocentric chromosomes showed no differences between the two groups under study. Analysis of sensitivity to the aneuploidogen griseofulvin showed that the patient group was characterized by lower levels of MN induction compared with controls. Our data confirm that peripheral blood lymphocytes of AD patients are prone to undergo aneuploidy spontaneously in vitro and support the hypothesis that microtubule impairment might be associated with the disease.
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Enfermedad de Alzheimer/genética , Aneuploidia , Linfocitos/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Causalidad , Células Cultivadas , Femenino , Griseofulvina/farmacología , Humanos , Masculino , Pruebas de Micronúcleos , Persona de Mediana EdadRESUMEN
To further investigate our finding of high levels of spontaneous aneuploidy in somatic cells of Alzheimer's disease (AD) patients (Migliore et al. 1997), we studied the molecular cytogenetics of eight patients with sporadic AD and six healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral blood lymphocytes from the AD patients and unaffected controls were used to measure micronucleus induction or other aneuploidy events, such as the presence of malsegregation in interphase nuclei (representing chromosome loss and gain). Dual-color fluorescence in situ hybridization (FISH) with differential labeled DNA probes was applied. We used a probe specific for the centromeres of chromosomes 13 and 21 combined with a single cosmid for the Down's syndrome region (21q22.2) to obtain information on spontaneous chromosome loss and gain frequencies for both chromosomes (13 and 21). FISH data showed that AD lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently labeled micronuclei) for both chromosomes, as well as higher frequencies of aneuploid interphase nuclei, again involving both chromosomes, compared to control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than for chromosome 13 in AD patients. This preferential occurrence of chromosome 21 in malsegregation in somatic cells of AD patients raises the hypothesis that mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in AD patients, as well as in elderly Down's syndrome patients.
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Enfermedad de Alzheimer/genética , Aneuploidia , Segregación Cromosómica/genética , Cromosomas Humanos Par 21/genética , No Disyunción Genética , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , División Celular/efectos de los fármacos , Segregación Cromosómica/efectos de los fármacos , Cromosomas Humanos Par 13/genética , Citocalasina B/farmacología , Síndrome de Down/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Linfocitos , Masculino , Pruebas de Micronúcleos , Persona de Mediana EdadRESUMEN
Huntington's disease (HD) is characterized by chorea, cognitive and behavioral changes. Amantadine, a non-competitive NMDA receptor antagonist, has shown an antidyskinetic effect on levodopa-induced dyskinesias, which are known to have strict pathogenetic analogies with choreic hyperkinesias. The antidyskinetic efficacy of amantadine and its effects on cognitive and behavioural symptoms were evaluated. Eight HD patients received oral amantadine (100 mg tid) unblinded for a 1-year period. A significant reduction of dyskinesias was reported ( p<0.01). No changes were observed in neuropsychologic and psychiatric assessments after 6 and 12 months of therapy. These data may have relevance to the treatment of HD with amantadine.
Asunto(s)
Amantadina/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Enfermedad de Huntington/tratamiento farmacológico , Anciano , Discinesia Inducida por Medicamentos/metabolismo , Femenino , Humanos , Enfermedad de Huntington/metabolismo , Hipercinesia/inducido químicamente , Levodopa/efectos adversos , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly with a complex etiology due to the interaction between genetic and environmental factors. At least 15% of cases are inherited as an autosomal dominant mutation, but the majority are sporadic. We evaluated cytogenetic alterations, both spontaneous and chemical-induced [aluminium (Al) and griseofulvin (GF)], by means of the micronucleus (MN) test in lymphocytes or skin fibroblasts of 14 patients with sporadic and eight with familial Alzheimer's disease (FAD), respectively. The spontaneous MN frequencies of sporadic (20.8 +/- 9.2) and familial (20.7 +/- 4.6) AD patients are significantly higher than those of the respective control groups (9.0 +/- 6.8 and 6.7 +/- 3.4). In all AD patients, GF significantly increased the spontaneous MN frequency of somatic cells to a lesser extent (P < 0.05) as compared with the control group. Al treatment did not induce MN in AD patients. The results of the present study indicate that different types of somatic cells from sporadic and familial AD patients show comparable levels of spontaneous cytogenetic anomalies, and MN induction is partially reduced or lacking according to the type of chemical treatments.