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1.
J Neurochem ; 164(1): 57-76, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36326588

RESUMO

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late-onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics, and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these data sets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic data set derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late-onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins, and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetic metabolic pathways were significantly over-represented across the AD multi-omics data sets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modeled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.


Assuntos
Doença de Alzheimer , Humanos , Camundongos , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Lipidômica , Estudo de Associação Genômica Ampla , Multiômica , Camundongos Knockout , Lipídeos , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo
2.
Mov Disord ; 38(2): 338-342, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36448620

RESUMO

BACKGROUND: Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. OBJECTIVE: The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. METHODS: We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). RESULTS: We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. CONCLUSIONS: The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Atrofia de Múltiplos Sistemas , Atrofias Olivopontocerebelares , Humanos , Atrofia de Múltiplos Sistemas/patologia , alfa-Sinucleína/metabolismo , Variações do Número de Cópias de DNA , Hibridização in Situ Fluorescente
4.
Int J Mol Sci ; 17(8)2016 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-27529242

RESUMO

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a "liquid biopsy" for carrier detection and genetic counseling in DMD.


Assuntos
MicroRNAs/sangue , MicroRNAs/genética , Repetições de Microssatélites/genética , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Segregação de Cromossomos/genética , Feminino , Variação Genética , Heterozigoto , Humanos , Desequilíbrio de Ligação/genética , Masculino , México , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
5.
Neurogenetics ; 16(2): 123-31, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25535174

RESUMO

Autism spectrum disorders (ASD) comprise neurodevelopmental disorders with clinical onset during the first years of life. The identification of peripheral biomarkers could significantly impact diagnosis and an individualized, early treatment. Although the aetiology of ASD remains poorly understood, there is increasing evidence that neurotrophins and their receptors represent a group of candidate genes for ASD pathophysiology and biomarker research. Total messenger RNA (mRNA) from whole blood was obtained from adolescents and adults diagnosed as ASD (n = 21) according to DSM-IV criteria and confirmed by the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) algorithms, as well as healthy controls (n = 10). The mRNA expression of neurotrophins (BDNF, NT3 and NT4) and their receptors (TrkA, TrkB and p75 (NTR) ) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, social cognition abilities of ASD patients and controls were determined according to three Theory of Mind (ToM) tests (Reading the Mind in the Eyes, Faux pas, and Happé stories). The NT3 and NT4 mRNA expression in the whole blood was significantly lower in ASD compared to healthy controls, while p75(NTR) was higher (P < 0.005). In addition, lower scores in three of the ToM tests were observed in ASD subjects compared to controls. A significant (P < 0.005) ToM impairment in Happé stories test was demonstrated in ASD. Nevertheless, no correlations were observed between neurotrophins and their receptors expressions and measures of ToM. Given their potential as peripheral blood-based biomarkers, NT3, NT4 and p75 (NTR) mRNA expression patterns may be useful tools for a more personalized diagnostics and therapy in ASD. Further investigations with larger numbers of samples are needed to verify these results.


Assuntos
Transtorno do Espectro Autista/sangue , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Fator de Crescimento Neural/genética , Teoria da Mente , Adolescente , Adulto , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neurotrofina 3/genética , RNA Mensageiro/sangue , Receptor trkA/genética , Receptor trkB/genética , Adulto Jovem
6.
Int J Mol Sci ; 16(3): 5334-46, 2015 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-25761239

RESUMO

Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.


Assuntos
Distrofina/genética , Frequência do Gene , Distrofia Muscular de Duchenne/genética , Mutação , Éxons , Terapia Genética , Humanos , México , Distrofia Muscular de Duchenne/terapia
7.
Molecules ; 20(6): 11154-72, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26091074

RESUMO

Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 and matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 1, myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression.


Assuntos
Heterozigoto , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/diagnóstico , Sensibilidade e Especificidade
8.
J Neural Transm (Vienna) ; 121(9): 1117-28, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24500031

RESUMO

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins-as crucial moderators of neuroplasticity-impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = -2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η (2) = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Globais do Desenvolvimento Infantil/sangue , Adolescente , Fatores Etários , Análise de Variância , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Criança , Ensaio de Imunoadsorção Enzimática , Humanos , Inteligência , Testes de Inteligência , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/sangue
9.
Pharmaceuticals (Basel) ; 16(5)2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37242456

RESUMO

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

10.
bioRxiv ; 2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37205496

RESUMO

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

11.
Proteomics ; 12(1): 145-56, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22065602

RESUMO

Glial cells in the peripheral nervous system, such as Schwann cells, respond to nucleotides, which play an important role in axonal regeneration and myelination. Metabotropic P2Y receptor agonists are promising therapeutic molecules for peripheral neuropathies. Nevertheless, the proteomic mechanisms involved in nucleotide action on Schwann cells remain unknown. Here, we studied intracellular protein changes in RT4-D6P2T Schwann cells after treatment with nucleotides and Nucleo CMP Forte (CMPF), a nucleotide-based drug. After treatment with CMPF, 2-D DIGE revealed 11 differential gel spots, which were all upregulated. Among these, six different proteins were identified by MS. Some of these proteins are involved in actin remodelling (actin-related protein, Arp3), membrane vesicle transport (Rab GDP dissociation inhibitor ß, Rab GDI), and the endoplasmic reticulum stress response (protein disulfide isomerase A3, PDI), which are hallmarks of a possible P2Y receptor signalling pathway. Expression of P2Y receptors in RT4-D6P2T cells was demonstrated by RT-PCR and a transient elevation of intracellular calcium measured in response to UTP. Actin reorganisation was visualized after UTP treatment using phalloidin-FITC staining and was blocked by the P2Y antagonist suramin, which also inhibited Arp3, Rab GDI, and PDI protein upregulation. Our data indicate that extracellular UTP interacts with Schwann P2Y receptors and activates molecular machinery that induces changes in the glial cell cytoskeleton.


Assuntos
Proteoma/metabolismo , Agonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y/metabolismo , Uridina Trifosfato/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Monofosfato de Citidina/farmacologia , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Expressão Gênica , Neurilemoma , Proteoma/genética , Ratos , Receptores Purinérgicos P2Y/genética , Eletroforese em Gel Diferencial Bidimensional , Regulação para Cima/efeitos dos fármacos
12.
Medicina (B Aires) ; 82(1): 74-80, 2022.
Artigo em Espanhol | MEDLINE | ID: mdl-35037864

RESUMO

The aim of this study was to describe the long term prognosis of 34 patients with Takayasu arteritis and the results of surgical and endovascular treatment. A total of 5 central surgeries and 53 endovascular procedures were performed including 18 bypass surgeries (33.8%) and 35 angioplasties (66.2%). The median follow-up was 7.5 years, interquartile range [IQR] 2.6-12.5. Among the 18 bypass surgeries 6 (33.3%) had events, while in the 35 patients with endovascular treatment there were 16 events (45.7%). The overall 1-, 3-, 5-, and 10-year death and arterial complication-free survival rates were 80% (95% CI between 74 and 89%), 68% (95% CI between 58 and 79%), 65% (95% CI between 54 and 76%) and 47% (95% CI between 41 and 62%). Both revascularization techniques were initially successful. In long term follow-up there was a high restenosis recurrence rate with endovascular treatment requiring repeated revascularization to the same vessel in 41% of the cases. Surgery had higher mortality in patients with aortic and ascending aortic valve disease, combined coronary artery disease and carotid disease. In long term follow up Takayasu arteritis frequently requires revascularization and restenosis or new lesions are common. Surgical treatment had better results with less restenosis than angioplasty.


Se analizaron los resultados del tratamiento quirúrgico y endovascular a 7.5 años, rango intercuartilo (RIC) entre 2.6 y 12.5 años de seguimiento en 34 pacientes con arteritis de Takayasu. Se realizaron en total 5 cirugías cardíacas centrales y 53 procedimientos vasculares,18 cirugías de bypass (33.9%) y 35 angioplastías (66.1%). Entre los 18 procedimientos quirúrgicos realizados, 6 (33.3%) presentaron eventos, mientras que en los 35 con intervención percutánea hubo 16 eventos (45.7%). La supervivencia actuarial y otras complicaciones vasculares (método de Kaplan y Meier) a 1,3,5 y 10 años fue: 80% (IC 95% entre 74 y 89%), 68% (IC 95% entre 58 y 79%), 65% (IC 95% entre 54 y 76%) y 47% (IC 95% entre 41 y 62%).Tanto la revascularización endovascular como la quirúrgica fueron inicialmente exitosas. En el seguimiento del tratamiento endovascular hubo una alta tasa de eventos con necesidad de revascularización repetida a un mismo vaso en el 41% de los casos. La cirugía tuvo mayor mortalidad en pacientes con valvulopatía aórtica, de aorta ascendente y enfermedad coronaria y carotidea combinada. La arteritis de Takayasu requiere frecuentemente revascularización debido a reestenosis y lesiones de novo. En su evolución alejada, el procedimiento quirúrgico ofreció mejores resultados con menor reestenosis.


Assuntos
Doença da Artéria Coronariana , Procedimentos Endovasculares , Arterite de Takayasu , Angioplastia , Humanos , Arterite de Takayasu/cirurgia , Resultado do Tratamento
13.
Commun Biol ; 5(1): 670, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794204

RESUMO

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Alelos , Glucosilceramidase/genética , Heterozigoto , Humanos , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética
14.
BMC Psychiatry ; 11: 103, 2011 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-21702894

RESUMO

BACKGROUND: Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. METHODS: We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. RESULTS: We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. CONCLUSION: Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.


Assuntos
Anquirinas/genética , Transtorno Bipolar/genética , Transtorno Depressivo/genética , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
16.
Rev Esp Salud Publica ; 84(4): 389-407, 2010.
Artigo em Espanhol | MEDLINE | ID: mdl-21141266

RESUMO

BACKGROUND: Variability in cardiovascular drugs is of great interest because of its high population use, its high expenditure and the availability of strong evidence supporting its use. The aim of this study is to describe variation in dispensation, price and pharmaceutical expenditure for 11 subgroups of cardiovascular drugs by healthcare areas. METHODS: This was a population study describing dispensation for 11 subgroups of cardiovascular drugs among healthcare areas in 2005. POPULATION: 93 healthcare areas of the 8 participant Autonomous Regions. ANALYSIS: Descriptive analysis of dispensation (Defined Daily Dose (DDD) per 1,000 pensioners and day (DDD/1000P/Day), average price (euros per DDD), pharmaceutical expenditure (euros per 100 pensioners) and standardized consumption ratios. Small-area variation analysis was used to analyze observed variability. RESULTS: Consumption of cardiovascular drugs oscillated between 324 DDD/1000p/Day for drugs with action on the renin-angiotensin system, and 6.5 DDD/1000p/Day for anti-aldosterone diuretics. Variation in consumption for areas in the 5th and 95th percentiles went from 1.8 times (digitalics) to 17.2 times (flavonoids), although most of the groups showed an extremal quotient of around 5. Variation in average prices was lower than in consumption (1.1 times for doxazosin and 3.7 for flavonoids) and variations in pharmaceutical expenditure was similar to variation in consumption (from 2.0 timesfor digitalics to 13.0 times for flavonoids). CONCLUSIONS: Major variations in the consumption of cardiovascular drugs between healthcare areas, together with discreet variations in price mean there are big differences in pharmaceutical expenditure from one population to another.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Custos de Medicamentos , Uso de Medicamentos , Farmacoepidemiologia , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Glicosídeos Digitálicos/uso terapêutico , Diuréticos/uso terapêutico , Doxazossina/uso terapêutico , Humanos , Hipolipemiantes/uso terapêutico , Nitratos/uso terapêutico , Pensões , Inibidores da Agregação Plaquetária/uso terapêutico , Análise de Pequenas Áreas
17.
Animals (Basel) ; 10(10)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053679

RESUMO

The aim of this study is to assess the effects of parity number on sow reproductive performance and the chemical and immunological composition of colostrum and immunoglobin concentrations in the sera of the sows. Colostrum samples were collected at 0, 6 and 24 h after the births of the first piglets from 56 sows with different numbers of parturitions (ranging 1-6). The piglets born alive to primiparous sows had lower birth weights (p < 0.05) than piglets from second and fourth parturition sows. The colostrum composition was influenced (p < 0.05) by parity number: primiparous sows had higher concentrations of dry matter, fat, lactose and non-fat-solids. No parity-dependent differences were found concerning total protein amount. Colostrum composition was drastically affected (p < 0.001) by sampling time-the highest concentrations of dry matter and protein and lowest concentrations of fat and lactose were found immediately after parturition (0 h). The study revealed no effect of parity (p ≥ 0.05) on the concentrations of immunoglobulins in colostrum. The immunoglobulin with the highest level in sow serum at day 110 of gestation was IgG, while IgA showed the lowest values and greater variability with respect to parity from an immunological point of view. Regarding the relationship between serum Ig levels at the end of gestation and colostrum Ig, serum IgG showed a strong correlation with colostrum IgG and IgM, while colostrum IgG was strongly related with colostrum IgM, but not with IgA. IgA did not correlate with any other immunoglobulin. The different behaviors of the immunoglobins in colostrum were probably due to IgG coming almost exclusively from the sows' sera, whereas IgA is mainly synthetized by the mammary gland.

18.
Animals (Basel) ; 10(4)2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272724

RESUMO

The aim of this study was to evaluate whether piglets absorb immunoglobin G (IgG) from goat colostrum and the potential effects of its ingestion on suckling piglets. Thirty-eight piglets with body weights ranging from 1000 to 1700 g were assigned to one of the three experimental treatments: Control group (C), where piglets were allowed to suckle normally, and porcine and goat groups. The piglets from the last two groups were removed from the sows after birth and received an oral 20 mL dose every 3 h of porcine (PC) or goat colostrum (GC), respectively, during first 12 h of life. Then, they were returned to newly farrowing sows to continue suckling until 20 d. The apparent efficiency of absorption (AEA) of IgG at 12 h was calculated as total serum IgG divided by ingested IgG. No diarrhea or symptoms of intolerance were observed at any time. On day 20, body weight and the number of dead piglets were similar in all three treatments (p > 0.05). At 12 h, the concentration of goat IgG in the serum of piglets fed GC was 8.11 mg/mL. AEA was 20.9% for goat IgG and 26.3% for porcine IgG (p > 0.05). Therefore, goat colostrum seems a promising alternative to study new feed supplements or artificial rearing of newborn piglets.

19.
Neurosurgery ; 88(1): E42-E48, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818240

RESUMO

BACKGROUND: Meningiomas are the most common tumors occurring in the central nervous system, with variable recurrence rates depending on World Health Organization grading. Atypical (Grade II) meningioma has a higher rate of recurrence than benign (Grade I) meningioma. The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. OBJECTIVE: To investigate clinical and histopathological predictors of tumor recurrence and radio-resistance in atypical meningiomas. METHODS: This cohort study retrospectively reviewed all patients in St. Michael's Hospital CNS tumor patient database who underwent surgical resection of a Grade II meningioma from 1995 to 2015. Cases with neurofibromatosis type II, multiple satellite tumors, spinal cord meningioma, radiation-induced meningioma, and perioperative death were excluded. Patient demographics, neuropathological diagnosis, tumor location, extent of resection, radiation therapy, and time to recurrence or progression were recorded. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. RESULTS: Among 181 patients, the combination of necrosis and brain invasion was associated with an increased recurrence risk (hazard ratio [HR] = 4.560, P = .001) and the lowest progression-free survival (PFS) relative to other pathological predictors. This trend was maintained after gross total resection (GTR, P = .001). RT was associated with decreased PFS (P = .001), even in patients who received GTR (P = .001). CONCLUSION: The combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. Our findings question the sensibility of brain invasion as an absolute criterion for Grade II status.


Assuntos
Neoplasias Meníngeas/patologia , Meningioma/patologia , Recidiva Local de Neoplasia , Tolerância a Radiação , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirurgia , Meningioma/radioterapia , Meningioma/cirurgia , Necrose , Intervalo Livre de Progressão , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco
20.
J Alzheimers Dis ; 72(4): 1077-1087, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31744003

RESUMO

BACKGROUND: Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer's disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. OBJECTIVE: To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. METHODS: Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ4 & ɛ4 and ɛ4/ɛ4 groups depending on ɛ4 copy number within APOE. Presence of AMB was assessed using NPI-Q. RESULTS AND CONCLUSION: AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOEɛ4 alleles as compared to No ɛ4 & ɛ4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral/genética , Corpos de Lewy/genética , Transtornos dos Movimentos/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/patologia , Angiopatia Amiloide Cerebral/patologia , Bases de Dados Factuais , Feminino , Genótipo , Humanos , Corpos de Lewy/patologia , Masculino , Transtornos dos Movimentos/patologia
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