Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease

In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors. One is excess copper, causing neuronal toxicity. The other is zinc deficiency, causing neuronal damage. We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years. This leads to the conclusion that something in the developed environment is a major risk factor for AD. We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic. We present a web of evidence supporting this hypothesis. Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age‐matched controls. Zinc has critical functions in the brain, and lack of zinc can cause neuronal death. A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation. In a small blinded study we carried out, post hoc analysis revealed that 6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems. These two factors may be linked in that zinc therapy significantly reduced free copper levels. Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90519/1/1005_ftp.pd

Ab initio Direct Phasing in Macromolecular Crystallography: an Application of the Z-test

The z-criterion has been recently formulated as a tool for judging about the ab initio solvability of a crystal structure via direct methods. The criterion is reconsidered to take into account the recent powerful techniques of phase refinement in direct and reciprocal space. A report is made on a medium size crystal structure, recently solved by SIR97 by the pure application of the tangent formula

Chances and challenges of comprehensive geriatric assessment training for healthcare providers

Geriatrics is the medical specialty that deals with physical, psychological, social and functional aspects of the older adult and represents a most authentic form of personalized medicine. As such, it is successfully performed through its cornerstone instrument, the comprehensive geriatric assessment (CGA), which consistently shows its significant benefits since over 30 years. However, the high speed at which the world population ages and gets affected by chronic conditions, multimorbidity and functional impairment is not yet accompanied by a strong, competent and self-conscious geriatric culture. This unmet need contributes to the further exponential increase of disability and lack of well-being in older persons. In this paper, we give an overview of the possible reasons for the lack of adequate CGA implementation across settings and highlight the likely benefits of consequent training and education of two groups of (future) professionals in the field of aging medicine: medical students and residents on one hand and multiprofessional healthcare providers, particularly nurses and physiotherapists, on the other hand

LDL-Lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells:mitigation by statin intervention

Elevated LDL concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidative modification (oxLDL) and nitration is observed during dementia and hypercholesterolemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVEC) were maintained on transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naïve, normo- and hyperlipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40mg simvastatin intervention/day for three months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after three months. LDL isolated from statin-naïve hyperlipidaemic, AD and AD-plus subjects was more oxidised (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared to control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 Vs 3.95±0.2nmol/mg; P<0.001) and 8-isoprostane F2α (30.4±4.0 pg/ml Vs 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7nmol/mg protein) compared to untreated cells (23.8±1.2 vs nmol/mg protein). Basolateral IL-6 secretion was increased by LDL-lipids from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared to healthy subject lipids (18.6±3.6 pg/ml). LDL-Lipids isolated after statin intervention did not affect endothelial function. In summary, LDL-lipids from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVEC. In vivo intervention with statins reduces the damaging effects of LDL-lipids on HMVEC

Ab initio Direct Phasing in Macromolecular Crystallography: an Application of the Z-test

The z-criterion has been recently formulated as a tool for judging about the ab initio solvability of a crystal structure via direct methods. The criterion is reconsidered to take into account the recent powerful techniques of phase refinement in direct and reciprocal space. A report is made on a medium size crystal structure, recently solved by SIR97 by the pure application of the tangent formula

Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities

Elevated serum cholesterol concentrations in mid-life increase risk for Alzheimer's disease (AD) in later life. However, lower concentrations of cholesterol-carrying high density lipoprotein (HDL) and its principal apolipoprotein A1 (ApoA1) correlate with increased risk for AD. As HDL transports oxocarotenoids, which are scavengers of peroxynitrite, we have investigated the hypothesis that lower HDL and oxocarotenoid concentrations during AD may render HDL susceptible to nitration and oxidation and in turn reduce the efficiency of reverse cholesterol transport (RCT) from lipid-laden cells. Fasting blood samples were obtained from subjects with 1) AD without cardiovascular comorbidities and risk factors (AD); 2) AD with cardiovascular comorbidities and risk factors (AD Plus); 3) normal cognitive function; for carotenoid determination by HPLC, analysis of HDL nitration and oxidation by ELISA, and 3H-cholesterol export to isolated HDL. HDL concentration in the plasma from AD Plus patients was significantly lower compared to AD or control subject HDL levels. Similarly, lutein, lycopene, and zeaxanthin concentrations were significantly lower in AD Plus patients compared to those in control subjects or AD patients, and oxocarotenoid concentrations correlated with Mini-Mental State Examination scores. At equivalent concentrations of ApoA1, HDL isolated from all subjects irrespective of diagnosis was equally effective at mediating RCT. HDL concentration is lower in AD Plus patients' plasma and thus capacity for RCT is compromised. In contrast, HDL from patients with AD-only was not different in concentration, modifications, or function from HDL of healthy age-matched donors. The relative importance of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia should be investigated in patients with early signs of dementia

The role of prognostic stratification on prescription of anticoagulants in older patients with atrial fibrillation : a multicenter, observational, prospective European study (EUROSAF)

Background: Literature suggests that different risks of mortality could influence physicians in prescribing or not anticoagulants in older patients with atrial fibrillation (AF). The Multidimensional Prognostic Index (MPI) can be considered a tool for the detection of multidimensional frailty. The aim of this cross-sectional study was to evaluate whether prescription patterns of oral anticoagulants exist, based on MPI values. Methods: Older hospitalised patients (age >= 65 years) with non-valvular AF were included across 24 European centres. MPI was calculated using validated and standardised tools derived from a comprehensive geriatric assessment. Other functional and clinical information were collected to calculate indexes specific for haemorrhagic and thromboembolic risk in AF. Results: Altogether, 2,012 participants affected by AF (mean age was 83.2 +/- 7.5, range: 65-104 years), with a higher presence of women (57.0%), were included. Overall, 440 took vitamin K antagonists VKAs (22.0%), 667 (33.4%) direct oral anticoagulants (DOACs), whilst 44.6% did not take any anticoagulant treatment. Prescription of anticoagulants was associated with MPI values, with people taking anticoagulants having lower mean MPI values. Anticoagulant therapy was not used in 53.1% of the group with the highest risk of mortality, compared with 32.3% of those in the group with the lowest mortality risk. People with higher scores in MPI were less frequently treated with anticoagulant therapy, after adjusting for several potential confounders. Conclusions: The EURopean study of Older Subjects with Atrial Fibrillation (EUROSAF) suggested that almost half of the older persons with AF do not receive anticoagulants and that MPI is an important determinant in prescribing or not anticoagulants.Peer reviewe

The Multidimensional Prognostic Index (MPI) for the prognostic stratification of hospitalized older patients with COVID-19: a prospective multicenter observational cohort study. Objectives, study design and expected outcomes (MPI_COVID-19)

The emergent coronavirus-19 disease (COVID-19) pandemic posed and still poses serious issues in the management of the inpatients and in the resource allocation, in particular for those patients requiring Intensive Care Unit (ICU) management. Epidemiological data clearly suggest that multimorbid older patients have the poorest prognosis. However, it is conceivable that age and number of comorbidities alone do not reflect the real condition and the expected prognosis of the patients affected by COVID-19. A different approach based on comprehensive geriatric assessment (CGA) could help to better identify older patients more at risk of dismal outcomes and who, at some point of their clinical course, will need the ICU admission. The Multidimensional Prognostic Index (MPI) is a well-accepted tool derived from a standard CGA which allows to measure prognosis of older patients in different clinical settings including hospital. Therefore, we designed a multicenter, prospective, observational study to evaluate the role of MPI in predicting risk of ICU admission and in-hospital mortality among 500 COVID-19-positive older subjects admitted to geriatric and internal medicine wards. In addition, risk of re-hospitalization, institutionalization and death after 3 months from discharge will be assessed. The MPI yields a straightforward value from 0 to 1 and might be able to adequately stratify complex, vulnerable COVID-19 patients for best possible decision-making and treatment allocation

The Multidimensional Prognostic Index in general practice: One-year follow-up study.

BACKGROUND Older patients' health problems in general practice (GP) can often not be assigned to a specific disease, requiring a paradigm shift to goal-oriented, personalised care for clinical decision making. PURPOSE To investigate the predictive value of the comprehensive geriatric assessment (CGA)-based Multidimensional Prognostic Index (MPI) in a GP setting with respect to the main healthcare indicators during the 12 months following initial evaluation. METHODS One hundred twenty-five consecutive patients aged 70 years and older were enrolled in a GP and followed up to one year. All patients underwent a CGA based on which the MPI was calculated and subdivided into three risk groups (MPI-1, 0-0.33 = low risk, MPI-2, 0.34-0.66 = moderate risk and MPI-3, 0.67-1, severe risk). Grade of Care (GC), hospitalization rate, mortality, nursing home admission, use of home care services, falls, number of general practitioner contacts (GPC), of geriatric resources (GR) and geriatric syndromes (GS) during the 12 months following initial evaluation were collected. RESULTS The MPI was significantly associated with number of GS (P < .001), GR (P < .001), GC (P < .001) as well as with the average number of GPC per year (mean 10.4, P = .046). Interestingly, the clinical judgement of the general practitioner, in this case knowing his patients for 16 years on average, was associated with adverse outcomes to a similar extent than the prediction offered by the MPI (GP/adverse outcomes and MPI/adverse outcomes P < .001). CONCLUSION The MPI is strongly associated with adverse outcomes in older GP patients and strongly predicts the number of GPC up to one year after initial evaluation. Considering the feasibility and the strong clinimetric properties of the MPI, its collection should be encouraged as early as possible to disclose risk conditions, implement tailored preventive strategies and improve cost-effectiveness of healthcare resources use

Políticas de Avaliação da Educação Superior Brasileira

O desenvolvimento do processo de avaliação da educação superior no país é recente, devido a sua concepção ter se consolidado em 2004 com a implantação da Lei do Sistema Nacional de Avaliação da Educação Superior (SINAES). A partir de 2008, ocorreram abordagens diferenciadas no desenvolvimento do Sistema sendo impostos indicadores com o objetivo de criarem rankings das melhores IES do país, utilizando somente o Exame Nacional de Desempenho dos Estudantes (ENADE). Neste sentido, apresenta-se um resgate histórico do processo de avaliação da educação superior do Brasil; a seguir, evidenciam-se os elementos que interferem no estabelecimento de diferentes políticas; por fim, discute-se a situação atual com a demonstração de possíveis encaminhamentos na busca da oferta de uma educação superior de melhor qualidade pelas IES do país