RESUMEN
BACKGROUND: Premature and/or intrauterine growth-restricted neonates have an increased risk of developing postnatal renal injuries in later life. Studies on renal physiology in these neonates at a corrected age of 30-40 days are scarce and mostly relate to preterm infants. The data from these studies often lack the results of correlation analyses between biochemical parameters and nephron number-data which could provide additional insight and/or improve recognition of individuals at higher risk of renal failure. METHODS: Urinary total protein and albumin levels and N-acetyl-ß-D-glucosaminidase and cathepsin B activity were evaluated in preterm and intrauterine growth-restricted infants at a corrected age of 30-40 days and compared to data from a healthy control neonate population. The data were then associated with predominant susceptibility factors of renal damage related to low nephron number, such as gestational age, birth weight, total renal volume and renal cortex volume. RESULTS: Compared to the control neonate population, we found significantly increased levels of all biochemical parameters tested in the intrauterine growth-restricted neonates, whereas in the preterm infants we observed a significant increase in cathepsin B activity, total protein level and, to a lesser extent, albumin level. Cathepsin B activity showed a significant, strong and inverse correlation with all surrogate markers of nephron number and was also strongly and positively correlated with urinary albumin level. CONCLUSIONS: At this postnatal age, we found that lower nephron number in low birth weight neonates was associated to tubular impairment/injury that could be concurrent with a dysfunction of glomerular permeability. Urinary cathepsin B activity may be a candidate marker for the early prediction of renal susceptibility to damage in low birth weight neonates.
Asunto(s)
Biomarcadores/orina , Retardo del Crecimiento Fetal/diagnóstico , Recien Nacido Prematuro , Enfermedades Renales/diagnóstico , Nefronas/diagnóstico por imagen , Acetilglucosaminidasa/orina , Albuminuria/orina , Peso al Nacer , Catepsina B/orina , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/patología , Humanos , Imagenología Tridimensional , Lactante , Corteza Renal/patología , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/orina , Masculino , Proteinuria/orinaRESUMEN
BACKGROUND: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radical-mediated damage. OBJECTIVE: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age ≥65 years), and younger adults with normal cognition (YCN, age <65 years). Plasma levels and activities of antioxidants were also measured. METHODS: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. RESULTS: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 ± 0.21 U/mg protein for AD, 0.93 ± 0.28 U/mg protein for MCI, 1.17 ± 0.78 U/mg protein for OCN subjects, and 1.23 ± 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini-Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. CONCLUSION: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.
Asunto(s)
Aconitato Hidratasa/sangre , Enfermedad de Alzheimer/sangre , Disfunción Cognitiva/sangre , Linfocitos/metabolismo , Anciano , Biomarcadores/sangre , Western Blotting , Progresión de la Enfermedad , Femenino , Radicales Libres/metabolismo , Humanos , Masculino , Escala del Estado Mental , Mitocondrias/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Vitamina E/sangreRESUMEN
PURPOSE: The role of oxidative stress is increasingly recognized in cognitive disorders of the elderly, notably Alzheimer's disease (AD). In these subjects brain(18)F-FDG PET is regarded as a reliable biomarker of neurodegeneration. We hypothesized that oxidative stress could play a role in impairing brain glucose utilization in elderly subjects with increasing severity of cognitive disturbance. METHODS: The study group comprised 85 subjects with cognitive disturbance of increasing degrees of severity including 23 subjects with subjective cognitive impairment (SCI), 28 patients with mild cognitive impairment and 34 patients with mild AD. In all subjects brain FDG PET was performed and plasma activities of extracellular superoxide dismutase (eSOD), catalase and glutathione peroxidase were measured. Voxel-based analysis (SPM8) was used to compare FDG PET between groups and to evaluate correlations between plasma antioxidants and glucose metabolism in the whole group of subjects, correcting for age and Mini-Mental State Examination score. RESULTS: Brain glucose metabolism progressively decreased in the bilateral posterior temporoparietal and cingulate cortices across the three groups, from SCI to mild AD. eSOD activity was positively correlated with glucose metabolism in a large area of the left temporal lobe including the superior, middle and inferior temporal gyri and the fusiform gyrus. CONCLUSION: These results suggest a role of oxidative stress in the impairment of glucose utilization in the left temporal lobe structures in elderly patients with cognitive abnormalities, including AD and conditions predisposing to AD. Further studies exploring the oxidative stress-energy metabolism axis are considered worthwhile in larger groups of these patients in order to identify pivotal pathophysiological mechanisms and innovative therapeutic opportunities.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Glucosa/metabolismo , Estrés Oxidativo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Encéfalo/metabolismo , Catalasa/sangre , Disfunción Cognitiva/sangre , Femenino , Fluorodesoxiglucosa F18 , Glutatión Peroxidasa/sangre , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiofármacos , Superóxido Dismutasa/sangreRESUMEN
Alzheimer disease (AD) is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaques (rich in amyloid-ß peptide), neuronal fibrillary tangles (rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In this study, we show that levels of oxidative stress markers are significantly increased in the mitochondria isolated from lymphocytes of subjects with mild cognitive impairment (MCI) compared to cognitively normal individuals. Further, an increase in mitochondrial oxidative stress in MCI is associated with MMSE score, vitamin E components, and ß-carotene. Further, a proteomics approach showed that alterations in the levels of thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit ß might be important in the progression and pathogenesis of AD. Increased understanding of oxidative stress and protein alterations in easily obtainable peripheral tissues will be helpful in developing biomarkers to combat this devastating disorder.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Biomarcadores/análisis , Disfunción Cognitiva/diagnóstico , Linfocitos/metabolismo , Mitocondrias/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva/metabolismo , Progresión de la Enfermedad , Electroforesis en Gel Bidimensional , Femenino , Humanos , Focalización Isoeléctrica , Masculino , Espectrometría de Masas , Estrés Oxidativo/fisiología , ProteómicaRESUMEN
Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. α-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.
Asunto(s)
Disfunción Cognitiva/sangre , Tocoferoles/sangre , Tocotrienoles/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Femenino , Humanos , MasculinoRESUMEN
Alzheimer's disease (AD) is histopathologically characterized by the presence of senile plaques, neurofibrillary tangles, and synapse loss. The main component of senile plaques is amyloid ß-peptide (Aß), which has been shown to induce oxidative stress in in vitro and in vivo studies. AD is associated with elevated levels of oxidative damage in brain and peripheral lymphocytes. Further Aß has been found to be accumulated in mitochondria, which might contribute to the reported alterations in the mitochondrial morphology, and impaired mitochondrial energy metabolism in AD brain. Biomarkers are desperately needed for earlier diagnosis of AD and to monitor efficacy of new therapies. Hence, in the present study we show that markers of oxidative damage are elevated in mitochondria isolated from AD lymphocytes suggesting that these oxidative stress indices potentially could serve as a viable biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Peroxidación de Lípido/fisiología , Linfocitos/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Carbonilación Proteica/fisiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Femenino , Humanos , MasculinoRESUMEN
This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on dayâ+1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 + âcell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No gradeâ ≥ 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.