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1.
Curr Med Imaging ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33511928

RESUMO

BACKGROUND: Ultrasonography is a diagnostic resource that serves as a complement in the evaluation of patients with carpal tunnel syndrome. The correlation of ultrasonography findings with nerve conduction studies can serve to classify new phenotypes and to evaluate therapeutic responses. OBJECTIVES: To determine the diagnostic sensitivity of ultrasound, the correlation between the cross-sectional area against the motor and sensitive latencies, and the capacity to differentiate the mild, moderate and severe degrees of the electrophysiological classification of carpal tunnel syndrome. METHODS: A cross-sectional study with prospective data collection was carried out. An ultrasonography system with a 15 MHz transducer was used. Nerve conduction studies of the median nerve were performed with conventional techniques. Data from the most symptomatic hand were used. Determination of the correlations of nerve diameter with motor and sensitive latencies of the median nerve was performed in four age groups: 40 (n=11), 40-54 (n=47), 55-70 (n=42) y >70 (n=27). Results A total of 127 patients were evaluated (average age = 58.2 years: minimum = 26; maximum = 85; SD = 13.4); female patients 109 (85.8%). According to the electrophysiological classification, mild = 40 (31.5%) were found; moderate = 60 (47.2%); and severe = 27 (21.3%). Significant differences in the area of the median nerve were found between the electrophysiological types (mild, moderate and severe; p = 0.000). The diagnostic sensitivity of ultrasonography differed for each age group. The capacity for ultrasonography to classify the degrees of electrophysiological severity was different for each age group. CONCLUSIONS: There is a well-defined and significant correlation between nerve conduction studies and median nerve diameter in patients with Carpal Tunnel Syndrome. However, the exclusive use of the ultrasonographic measurement of the cross sectional area would not be enough to confirm or rule out an entrapment of the median nerve through the carpal tunnel, nor to predict in every case their electrophysiological severity.

2.
J Biol Chem ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298522

RESUMO

Antibodies against Aß amyloid are indispensable research tools and potential therapeutics for Alzheimer's Disease. They display several unusual properties, such as specificity for aggregated forms of the peptide, the ability to distinguish polymorphic aggregate structures and the ability to recognize generic aggregation-related epitopes formed by unrelated amyloid sequences. Understanding the mechanisms underlying these unusual properties and the structures of their corresponding epitopes is crucial for the understanding why antibodies display different therapeutic activities and for the development of more effective therapeutic agents. Here we employed a novel "epitomic" approach to map the fine structure of the epitopes of 28 monoclonal antibodies against amyloid-beta using immunoselection of random sequences from a phage display library, deep sequencing and pattern analysis to define the critical sequence elements recognized by the antibodies. Although most of the antibodies map to major linear epitopes in the amino terminal 1-14 residues of Aß, the antibodies display differences in the target sequence residues that are critical for binding and in their individual preferences for non-target residues, indicating that the antibodies bind to alternative conformations of the sequence by different mechanisms. Epitomic analysis also identifies discontinuous, non-overlapping sequence Aß segments that may constitute the conformational epitopes that underlie the aggregation specificity of antibodies. Aggregation specific antibodies recognize sequences that display a significantly higher predicted propensity for forming amyloid than antibodies that recognize monomer, indicating that the ability of random sequences to aggregate into amyloid is a critical element of their binding mechanism.

3.
Aging Clin Exp Res ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33180283

RESUMO

BACKGROUND: Anticholinergic drugs may contribute to frailty by impairing cognitive and physical functions. Strong anticholinergic drugs in particular may have adverse effects among older adults. OBJECTIVES: Determine the association between frailty and the use of strong anticholinergic drugs among older US Veterans. METHODS: This is a cross-sectional study of community-dwelling Veterans 65 years and older who had determinations of frailty status. Prescription data for patients using strong anticholinergic medications (never/past/current) was obtained via electronic health records. A 31-item VA Frailty Index (VA-FI) was generated at the time of the assessment. We dichotomized the groups into non-frail (FI = < 0.21) and frail (FI ≥ 0.21) patients. We used binomial logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Frailty was the dependent variable and use of strong anticholinergic drugs was the independent variable. Multivariate adjustment was conducted for age, gender, race, ethnicity, marital status, and BMI. RESULTS: Population sample consisted of 17,084 Veterans who were 71.05% Caucasian, 97.34% male, and with a mean age 75.60 (SD = 8.04) years. Among the population, 9940 (58.18%) patients had no previous use of strong anticholinergic drugs, whereas 5182 (30.33%) had past exposure and 1962 (11.49%) had current exposure. In binomial logistic regression, individuals with past (OR 3.27, 95% CI 3.03-3.54, p < 0.0005) or current (OR 4.78, 95% CI 4.30-5.31, p < 0.0005) exposure showed a higher association with frailty as compared to individuals who were never exposed. CONCLUSIONS: Past and current use of strong anticholinergic drugs were associated with frailty in older Veterans. These results suggest that screening for frailty in patients with past or current exposure to strong anticholinergic medications may be necessary for proper management.

4.
J Am Med Dir Assoc ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33234447

RESUMO

OBJECTIVES: Determine the incidence rates of frailty among community-dwelling older veterans. DESIGN: Population-based retrospective cohort study. SETTING AND PARTICIPANTS: Veterans Health Administration Medical Center study included community-dwelling veterans 60 years and older with determinations of frailty from 2013 to 2014 and followed until September 2019. METHODS: A 31-item frailty index was generated at baseline and during each subsequent primary care encounters as a proportion of potential variables from electronic health record data. Period prevalence was calculated by dividing total number of cases of frailty during the baseline period. After adjusting for covariates, the association of frailty with mortality was determined using a multivariate Cox regression model. Using baseline and follow-up data, incidence rates of frailty per 1000 person/years based on event rates and mean duration of follow-up were calculated, including survivor and entire cohorts. RESULTS: Patients in this cohort were 16,761 veterans, mean age 72.18 (9.32) years, 74.00% Caucasian, 90.75% non-Hispanic, and 97.78% male. The period prevalence of frailty in this cohort was 20.84%. Over a median follow-up of 3.96 (interquartile range = 3.73) years, 25.86% of the baseline population died during follow up. Veterans with frailty had a higher all-cause mortality during follow up, adjusted hazard ratio = 3.12 (95% confidence interval 2.87-3.38), P value of < .0005. Among 10,513 veterans who survived a median follow-up of 4.81 (interquartile range = 3.12) years, 29.84% became frail. The incidence rate of frailty was 75.05 cases per 1000 person-years. Among the entire cohort of 13,268 nonfrail veterans, 29.93% became frail. The incidence rate of frailty was 84.03 cases per 1000 person-years. CONCLUSIONS AND IMPLICATIONS: This study shows high incidence of frailty in community dwelling older US veterans. Future studies should be done for identification, implementation of adequate interventions aimed at preventing frailty or reducing frailty-related complications in community dwelling older individuals.

5.
Sensors (Basel) ; 20(22)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238544

RESUMO

We introduce SodSAR, a fully polarimetric tower-based wide frequency (1-10 GHz) range Synthetic Aperture Radar (SAR) aimed at snow, soil and vegetation studies. The instrument is located in the Arctic Space Centre of the Finnish Meteorological Institute in Sodankylä, Finland. The system is based on a Vector Network Analyzer (VNA)-operated scatterometer mounted on a rail allowing the formation of SAR images, including interferometric pairs separated by a temporal baseline. We present the description of the radar, the applied SAR focusing technique, the radar calibration and measurement stability analysis. Measured stability of the backscattering intensity over a three-month period was observed to be better than 0.5 dB, when measuring a target with a known radar cross section. Deviations of the estimated target range were in the order of a few cm over the same period, indicating also good stability of the measured phase. Interforometric SAR (InSAR) capabilities are also discussed, and as a example, the coherence of subsequent SAR acquisitions over the observed boreal forest stand are analyzed over increasing temporal baselines. The analysis shows good conservation of coherence in particular at L-band, while higher frequencies are susceptible to loss of coherence in particular for dense vegetation. The potential of the instrument for satellite calibration and validation activities is also discussed.

6.
Transfusion ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33241598

RESUMO

BACKGROUND: The most common large-deletion RHD allele (RHD*01N.01) includes the entire coding sequence, intervening regions and untranslated regions. The rest of large-deletion RHD alleles reported to-date consist of single-exon deletions, such as RHD*01N.67 which includes exon 1. MATERIALS AND METHODS: Samples from two donors with RhD-negative serology yielded unclear or inconclusive results when subject to confirmatory testing on RHD genotyping arrays. To determine their RHD genotypes, genomic DNA was analyzed with a combination of allele-specific PCR, long-range PCR, Sanger sequencing, and next-generation sequencing assays. RESULTS: Allele-specific PCR failed to detect products for RHD exons 1 to 3 in one sample and RHD exons 1 to 5 in the other. A quantitative next-generation sequencing assay confirmed deletion of exons 1 to 3 and 1 to 5 respectively, and detected the absence of an RHD gene in trans in both samples. Long-range PCR and Sanger sequencing enabled identification of the breakpoints for both alleles. Both deletions start within the 5' Rhesus box (upstream of the identity region for the 1-to-3 deletion, downstream of it for the 1-to-5 deletion), and end within introns. CONCLUSIONS: Resolution of unclear or inconclusive results from targeted genotyping arrays often leads to the discovery of new alleles. The 5' Rhesus box may be a hot spot for genetic recombination events, such as the large deletions described in this report.

10.
Proc Natl Acad Sci U S A ; 117(33): 19799-19808, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32759219

RESUMO

In multialternative risky choice, we are often faced with the opportunity to allocate our limited information-gathering capacity between several options before receiving feedback. In such cases, we face a natural trade-off between breadth-spreading our capacity across many options-and depth-gaining more information about a smaller number of options. Despite its broad relevance to daily life, including in many naturalistic foraging situations, the optimal strategy in the breadth-depth trade-off has not been delineated. Here, we formalize the breadth-depth dilemma through a finite-sample capacity model. We find that, if capacity is small (∼10 samples), it is optimal to draw one sample per alternative, favoring breadth. However, for larger capacities, a sharp transition is observed, and it becomes best to deeply sample a very small fraction of alternatives, which roughly decreases with the square root of capacity. Thus, ignoring most options, even when capacity is large enough to shallowly sample all of them, is a signature of optimal behavior. Our results also provide a rich casuistic for metareasoning in multialternative decisions with bounded capacity using close-to-optimal heuristics.


Assuntos
Tomada de Decisões , Heurística , Comportamento de Escolha , Humanos , Modelos Teóricos , Racionalização
11.
Gerontol Geriatr Med ; 6: 2333721420924956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596419

RESUMO

Frailty is a state of vulnerability to stressors resulting in higher morbidity, mortality, and utilization in older adults. Frailty and type 2 diabetes mellitus share similar pathophysiological mechanisms which metformin may target. The purpose of this study was to determine whether exposure to metformin is associated with frailty in veterans. This is a cross-sectional study of veterans 65 years and older with type 2 diabetes who were screened for frailty between January 2016 and August 2017. We constructed a 44-item Frailty Index including multiple variables using a deficit accumulation framework. After adjustment for covariates, the association was calculated using binomial logistic regression models with frailty status as the outcome variable, and metformin exposure as the independent variable. Patients were 98.3% male and 56.7% White with a mean age of 72.9 (SD = 6.8) years. The proportion of robust, prefrail and frail patients was 2.9% (n = 22), 46.7 % (n = 356) and 50.5% (n = 385), respectively. In binomial logistic regression, exposure to metformin was associated with lower risk for frailty, adjusted odds ratio (OR) = .55 (95% confidence interval [CI] = .39-.77), p ≤ .001. This study shows that exposure to metformin was associated with lower risk for frailty in community-dwelling veterans.

12.
Am J Manag Care ; 26(5): 200-206, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32436677

RESUMO

OBJECTIVES: To determine whether health literacy, numeracy, and graph literacy are associated with all-cause hospitalizations or mortality in community-dwelling veterans. STUDY DESIGN: Retrospective cohort study. METHODS: A total of 470 community-dwelling veterans underwent evaluations of health literacy, numeracy, and graph literacy with validated instruments in 2012 and were followed until 2018. At the end of follow-up, the associations with all-cause hospitalizations and mortality were determined with the Andersen-Gill model and Cox regression multivariate analysis, respectively. RESULTS: There were no associations of health literacy, numeracy, or graph literacy with all-cause hospitalization or mortality after multivariate adjustment. In subgroup analysis, subjective numeracy was associated with hospitalizations in African Americans. Higher objective and subjective numeracy were associated with future hospitalizations only for those with a history of hospitalization. Higher graph literacy was associated with lower mortality in those with a history of hospitalization. CONCLUSIONS: This study did not show associations of health literacy, numeracy, or graph literacy scores with lower risk of all-cause hospitalization or mortality. Further research is needed with random sampling in a broader spectrum of healthcare settings to better understand what roles health literacy, numeracy, and graph literacy might play in healthcare utilization and clinical outcomes.

13.
J Inorg Biochem ; 208: 111080, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32330762

RESUMO

Polypyridyl ruthenium complexes have been intensively investigated for their remarkable antiproliferative properties and some are currently being tested in clinical trials. Here, we investigated the impact of illumination on the biological properties of a series of new cyclometalated ruthenium compounds with increased π-conjugation. We determined that various of these complexes display a bivalent biological activity as they are highly cytotoxic by themselves in absence of light while their cytotoxicity can significantly be elevated towards an IC50 in the nanomolar range upon illumination. In particular, we showed that these complexes are particularly active (IC50 < 1 µM) on two gastric cancer cell lines (AGS, KATO III) that are resistant towards cisplatin (IC50 > 25 µM). As expected, light activation leads to increased production of singlet oxygen species in vitro and accumulation of reactive oxygen species in vivo. Importantly, we established that light exposure shifts the mode of action of the complexes towards activation of a caspase 3-dependent apoptosis that correlates with increased DNA damage. Altogether, this study characterizes novel ruthenium complexes with dual activity that can be tuned towards different mode of action in order to bypass cancer cell resistance mechanisms.

14.
Gene ; 745: 144636, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32244056

RESUMO

Since the discovery of the double helix and the introduction of genetic engineering, the possibility to develop new strategies to manipulate the genome has fascinated scientists around the world. Currently scientists have the knowledge andabilitytoedit the genomes. Several methodologies of gene editing have been established, all of them working like "scissor", creating double strand breaks at specific spots. The introduction of a new technology, which was adapted from the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas bacterial immune system, has revolutionized the genetic therapy field, as it allows a much more precise editing of gene than the previously described tools and, therefore, to prevent and treat disease in humans. This review aims to revisit the genome editing history that led to the rediscovery of the CRISPR/Cas technology and to explore the technical aspects, applications and perspectives of this fascinating, powerful, precise, simpler and cheaper technology in different fields.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Terapia Genética/métodos , Imunidade Adaptativa/genética , Animais , Bactérias/genética , Bactérias/imunologia , Sistemas CRISPR-Cas/imunologia , Contenção de Riscos Biológicos , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Modelos Animais de Doenças , Terapia Genética/efeitos adversos , Humanos , RNA Guia/genética
15.
Rev. Fac. Med. Hum ; 20(2): 322-327, abr.- jun. 2020.
Artigo em Inglês, Espanhol | LILACS-Express | LILACS | ID: biblio-1120786

RESUMO

Actualmente hay una alta incidencia de accidentes de tránsito en el mundo, muchos de ellos provocan una discapacidad grave en las personas. Estas lesiones en las extremidades provocan alta morbilidad llegando incluso a una amputación. Esto se agrava en pacientes VIH/SIDA, sobre todo en el tratamiento y la evolución. Se presenta un caso clínico de un paciente con lesión severa del mediopie que termina en amputación y se hace una revisión del manejo quirúrgico del paciente traumatológico con VIH/SIDA


Currently there is a high incidence of traffic accidents in the world, many of them cause severe disability in people. These limb injuries cause high morbidity even reaching an amputation. This is aggravated in HIV/AIDS patients, especially in treatment and evolution. A clinical case of a patient with severe midfoot injury that ends in amputation is presented and a surgical management review of the trauma patient with HIV/AIDS is made.

16.
Acta Neuropsychiatr ; : 1-10, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039744

RESUMO

BACKGROUND: Peripheral gene expression of several molecular pathways has been studied in major depressive disorder (MDD) with promising results. We sought to investigate some of these genes in a treatment-free Latino sample of Mexican descent. MATERIAL AND METHODS: The sample consisted of 50 MDD treatment-free cases and 50 sex and age-matched controls. Gene expression of candidate genes of neuroplasticity (BDNF, p11, and VGF), inflammation (IL1A, IL1B, IL4, IL6, IL7, IL8, IL10, MIF, and TNFA), the canonical Wnt signaling pathway (TCF7L2, APC, and GSK3B), and mTOR, was compared in cases and controls. RNA was obtained from blood samples. We used bivariate analyses to compare subjects versus control mean mRNA quantification of target genes and lineal regression modelling to test for effects of age and body mass index on gene expression. RESULTS: Most subjects were female (66%) with a mean age of 26.7 (SD 7.9) years. Only GSK3B was differentially expressed between cases and controls at a statistically significant level (p = 0.048). TCF7L-2 showed the highest number of correlations with MDD-related traits, yet these were modest in size. DISCUSSION: GSK3B encodes a moderator of the canonical Wnt signaling pathway. It has a role in neuroplasticity, neuroprotection, depression, and other psychiatric phenotypes. We found that adding population diversity has the potential to elicit distinct peripheral gene expression markers in MDD and MDD-related traits. However, our results should only be considered as hypothesis-generating research that merits further replication in larger cohorts of similar ancestry.

17.
Int J Geriatr Psychiatry ; 35(1): 37-44, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31608502

RESUMO

INTRODUCTION: Frailty is a state of vulnerability to stressors resulting in higher morbidity, mortality, and utilization in older adults. Depression and frailty often coexist, suggesting a bidirectional relationship that may increase the effects of each individual condition on clinical outcomes and health-care utilization in older adults. OBJECTIVE: To determine the effects of concurrent frailty and depression on all-cause hospitalizations. METHODS/DESIGN: Prospective cohort study, conducted at a Veterans Affairs (VA) Medical Center. The participants were male, community-dwelling veterans 65 years and older. From 4 January through 30 December 2016, a 46-item frailty index was generated from data obtained from the VA electronic health record. Trained staff conducted in-depth reviews of electronic health records ascertaining depression status. Patients were followed through 31 December 2017 for all-cause hospitalizations following the initial assessment of frailty. After adjusting for covariates, the association of frailty and depression with all-cause hospitalizations was determined with the Andersen-Gill model, accounting for repeated hospitalizations. RESULTS: Five hundred fifty-three male patients were part of the study, mean age 76.3 (SD = 8.2) years. One hundred eighty-one patients (32.7%) had depression diagnoses. During a median follow-up period of 530 days (interquartile range [IQR] = 245), 123 patients (22.2%) had 240 hospitalizations. Frailty status was not associated with future hospitalizations (adjusted hazard ratio [HR] = 1.61; 95% CI, 95-2.74; P > .05). Depression was associated with higher all-cause hospitalizations (adjusted HR = 1.57; 95% CI, 1.09-2.26); P = .0157). CONCLUSIONS: Depression but not frailty was significantly associated with higher rates of all-cause hospitalization. Implementing interventions that target older adults with both frailty and depression may reduce the burden of both conditions and reduce hospitalizations.


Assuntos
Depressão/epidemiologia , Fragilidade/epidemiologia , Hospitalização/estatística & dados numéricos , Veteranos/psicologia , Veteranos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Idoso Fragilizado/estatística & dados numéricos , Humanos , Vida Independente , Masculino , Estudos Prospectivos , Medição de Risco , Fatores de Risco
18.
Neuroscience ; 439: 332-341, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31349005

RESUMO

Extracellular adenosine triphosphate (ATP) participates in maintaining the vascular tone in the CNS, particularly in the retina, via the tonic activity of ligand gated activated P2X1 receptors. P2X1 receptors are characterized by their high affinity for ATP and their strong desensitization to concentrations of ATP that are 200-fold lower than their EC50. The mechanism behind P2X1 tonic activity remains unclear. In this study, we expressed human P2X1 (hP2X1) homomeric receptors in Xenopus oocytes to explore the relationship between ATP release from oocytes at rest, hP2X1, and Ca2+-activated Cl- channels. Our results indicate that Xenopus oocytes release ATP at rest via vesicular exocytosis, and this process is a constitutive phenomenon independent of extracellular Ca2+. Our results also indicate that hP2X1 receptors are able to sustain a tonic activity of Ca2+-activated Cl- channels. In the presence of extracellular Ca2+ the activity of hP2X1 receptors is greatly amplified by its coupling with Ca2+-activated Cl- channels. Future studies addressing the relationship between hP2X1 receptors and Ca2+-activated Cl- channels in vascular smooth muscle cells should provide information about additional mechanisms that regulate the vascular tone and their potential as pharmaceutical targets. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

19.
Eur J Gastroenterol Hepatol ; 32(1): 116-119, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651656

RESUMO

OBJECTIVE: Cholangiocarcinoma (CCA) affects all ethnicities worldwide. The Hispanic population being the leading ethnic minority in the United States, its importance to the healthcare system cannot be understated. This study aims to assess the occurrence and outcomes of CCA in Hispanic patients in the United States. METHODS: This is a case-control study using the National Inpatient Sample 2014. All patients with ICD-9 CM codes for CCA were included. Hispanic patients were identified from the ethnic categories within the database. The primary outcomes were the occurrence and odds of CCA in the Hispanic population when compared with other ethnicities. Secondary outcomes were inpatient mortality, morbidity, ICU stay, multiorgan failure, and resource utilization. RESULTS: A total of 13 965 patients with CCA were identified, of which 2750 were propensity-matched to controls (1480 Hispanic). The inpatient occurrence of CCA in Hispanics relative to the national population was 2.73/100 000 persons, compared to 4.82/100 000 persons (39.9/100 000 relative to inpatient population) of all other ethnicities. After adjusting for confounders on multivariate analysis, Hispanic patients displayed adjusted propensity-matched odds of 1.28 (P < 0.01) of having CCA when compared with other ethnicities. Hispanics did not display different propensity-matched odds of inpatient mortality, morbidity, hospital length of stay, or resource utilization compared to non-Hispanic patients. CONCLUSION: This study demonstrated that the odds of CCA in admitted patients are higher for the Hispanic population. This difference with the prevalence potentially suggests the presence of social factors such as disparities in cancer prevention or detection in this group.

20.
J Alzheimers Dis ; 73(1): 229-246, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31771065

RESUMO

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAß), and the mechanism of an age-related increase in iAß in adult AD-model mouse neurons. A new end-specific antibody for Aß45 and another for aggregated forms of Aß provide new insight into the composition of iAß and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAß levels containing aggregates of Aß45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAß was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAß and rapidly increased following a brief metabolic stress with glutamate. AßPP-CTF, Aß45, and aggregated Aß colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAß by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aßs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAß processing may lead to application of countermeasures to prolong dementia-free health span.

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