12 research outputs found

    The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

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    Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline

    Rapid Weight Gain in Pediatric Refugees after US Immigration

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    Prior studies of immigrants to the United States show significant weight gain after 10 years of US residence. Pediatric refugees are a vulnerable population whose post-immigration weight trajectory has not been studied. We examined the longitudinal weight trajectory of 1067 pediatric refugees seen in a single university based refugee health program between the dates of September 3, 2012 and September 3, 2014 to determine how quickly significant weight gain occurs post-arrival. The most recent BMI was abstracted from the electronic health record and charts reviewed to obtain serial BMI measurements in 3 year increments after the date of US arrival. The mean arrival BMI percentile for all refugees was 47th percentile. This increased significantly to the 63rd percentile within 3 years of US arrival (p < 0.01). This rapid increase was largely attributable to African and South and Southeast Asian refugees. The overall prevalence of age and sex adjusted obesity rose from 7.4 % at arrival to 18.3 % within 9 years of US immigration exceeding the pediatric US national obesity prevalence of 16.9 %. Pediatric refugees are at increased risk of rapid weight gain after US immigration. Targeted interventions focused on prevention of weight gain in specific populations are warranted.12 month embargo; First Online: 08 July 2016This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

    Avaliação da relação entre volume de procedimentos e a qualidade do cuidado: o caso de cirurgia coronariana no Brasil Volume and quality of care in coronary artery bypass grafting in Brazil

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    O volume de procedimentos médicos geralmente apresenta-se negativamente associado com a taxa de mortalidade hospitalar. O objetivo deste trabalho é verificar nos hospitais brasileiros a existência ou não dessa associação no caso das cirurgias de revascularização do miocárdio (CRVM), financiadas pelo Ministério da Saúde (MS). Analisaram-se as CRVM realizadas de 1996 a 1998. Os dados foram obtidos por intermédio do Sistema de Informações Hospitalares do SUS. O procedimento estatístico utilizado foi análise de sobrevida (modelo de Cox). Os hospitais foram agrupados em classes de volume de CRVM. O modelo foi ajustado pelo perfil de gravidade (risco de morrer) dos pacientes. Foram pagas 41.989 CRVM pelo MS entre janeiro de 1996 e dezembro de 1998, realizadas em 131 hospitais. A taxa de mortalidade foi de 7,2%. Observou-se um gradiente crescente nas taxas à medida que diminuiu o volume. No grupo de hospitais do SUS com maior volume de CRVM os pacientes operados apresentaram menor risco de morrer do que no de hospitais com menor volume de cirurgias. Recomenda-se que o SUS deva estimular a concentração regionalizada dos serviços para a realização de CRVM.<br>There is often a negative association between the volume of medical procedures and hospital mortality rates. The objective of this study is to determine whether this association is observed in Brazilian hospitals performing coronary artery bypass grafts (CABG) that were financed by the Ministry of Health. CABG surgeries performed from 1996 to 1998 were analyzed. Data were collected from the Ministry of Health Hospital Information System. The statistical procedure utilized was the Cox survival analysis. Hospitals were grouped in classes of volume of CABG performed. The model was adjusted to the severity of cases (risk of dying). From January 1996 to December 1998 the Ministry of Health reimbursed 41,989 CABG procedures in 131 hospitals. The overall hospital mortality rate was 7.2%. A gradient was observed in the mortality rates. The severity-adjusted risk of dying in the group of hospitals performing more procedures was lower than in the group performing fewer operations. It is recommended that the Ministry of Health strongly consider regionalized concentration of services to perform CABG

    Molecular Crowding – (in Cell Culture)

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    Macromolecular crowding (MMC) is an intrinsic and ubiquitous feature in biological cells. We find MMC in the first bacterial cell and see it culminating in the intricate extracellular matrix (ECM) that evolved in multicellular organisms. Research work on MMC started with the observation that biological cellular systems are crammed with macromolecules. The interior of cells is teeming with enzymes, transport systems, and nucleotide assemblies. In addition, eukaryotic cells possess a three-layered cytoskeleton adding confinement to an already packed cytoplasm. Likewise, the extracellular space of multicellular organisms comprises an ECM consisting of fibrillar proteins, such as collagen or elastin, surrounded by an amorphous gel-like ground substance glycoproteins and proteoglycans and their hydration shells. Together, they provide mechanical resilience to the tissues of vertebrates while forming a crowded and structural microenvironment that in turn creates confinement for other macromolecules. Surprisingly, most biochemical and cell culture experiments are still done in non-crowded, highly aqueous solutions. Here, we shall discuss the shortcomings of contemporary cell culture and emphasize the benefits of applying MMC to cell culture models of tissues. MMC can be achieved by adding water-soluble macromolecules to the culture medium. Not only is this technically feasible, it also moves in vitro biology toward a higher physiological level, allowing the design of more meaningful cell-based assays and enabling tissue engineering of matured and physiologically relevant tissue-like assemblies

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