Mild cognitive impairment (MCI) represents a transitional stage between healthy aging and dementia, and affects 10-15% of the population over the age of 65. The failure of drug trials in Alzheimer's ...disease (AD) treatment has shifted researchers' focus toward delaying progression from MCI to dementia, which would reduce the prevalence and costs of dementia profoundly. Diagnostic criteria for MCI increasingly emphasize the need for positive biomarkers to detect preclinical AD. The phenomenology of MCI comprises lower quality-of-life, greater symptoms of depression, and avoidant coping strategies including withdrawal from social engagement. Neurobiological features of MCI are hypoperfusion and hypometabolism in temporoparietal cortices, medial temporal lobe atrophy particularly in rhinal cortices, elevated tau and phosphorylated tau and decreased Aβ42 in cerebrospinal fluid, and brain Aβ42 deposition. Elevated tau can be identified in MCI, particularly in the entorhinal cortex, using positron emission tomography, and analysis of signal complexity using electroencephalography or magnetoencephalography holds promise as a biomarker. Assessment of MCI also relies on cognitive screening and neuropsychological assessment, but there is an urgent need for standardized cognitive tests to capitalize on recent discoveries in cognitive neuroscience that may lead to more sensitive measures of MCI. Cholinesterase inhibitors are frequently prescribed for MCI, despite the lack of evidence for their efficacy. Exercise and diet interventions hold promise for increasing reserve in MCI, and group psychoeducational programs teaching practical memory strategies appear effective. More work is needed to better understand the phenomenology and neurobiology of MCI, and how best to assess it and delay progression to dementia.
James Anderson critically reinterprets the history of southern black education from Reconstruction to the Great Depression. By placing black schooling within a political, cultural, and economic ...context, he offers fresh insights into black commitment to education, the peculiar significance of Tuskegee Institute, and the conflicting goals of various philanthropic groups, among other matters.Initially, ex-slaves attempted to create an educational system that would support and extend their emancipation, but their children were pushed into a system of industrial education that presupposed black political and economic subordination. This conception of education and social order--supported by northern industrial philanthropists, some black educators, and most southern school officials--conflicted with the aspirations of ex-slaves and their descendants, resulting at the turn of the century in a bitter national debate over the purposes of black education. Because blacks lacked economic and political power, white elites were able to control the structure and content of black elementary, secondary, normal, and college education during the first third of the twentieth century. Nonetheless, blacks persisted in their struggle to develop an educational system in accordance with their own needs and desires.
Astrocyte dysfunction in Alzheimer disease Acosta, Crystal; Anderson, Hope D.; Anderson, Christopher M.
Journal of neuroscience research,
December 2017, Letnik:
95, Številka:
12
Journal Article
The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels.
Though ...mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials.
In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.
Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008).
Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
In school and out of trouble? Anderson, D. Mark
The review of economics and statistics,
05/2014, Letnik:
96, Številka:
2
Journal Article
Recenzirano
This paper examines the relationship between the minimum high school dropout age and juvenile arrest rates by exploiting state-level variation in dropout age laws. County-level arrest data for the ...period 1980 to 2008 and difference-in-difference-in-difference-type empirical strategy are used to compare the arrest rates over time of various age groups within counties that differ by their state's minimum dropout age. The evidence suggests that minimum dropout age requirements have a significant and negative effect on property and violent crime arrest rates for individuals 16 to 18 years old. The results are consistent with an incapacitation effect of schooling.
Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic ...effects in patients with relapsed and refractory multiple myeloma.
In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 10
to 450 × 10
CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses).
Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10
nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion.
Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.).
Why did the wave of democracy that swept the former Soviet Union and Eastern Europe starting more than a decade ago develop in ways unexpected by observers who relied on existing theories of ...democracy? In Postcommunism and the Theory of Democracy, four distinguished scholars conduct the first major assessment of democratization theory in light of the experience of postcommunist states. Richard Anderson, Steven Fish, Stephen Hanson, and Philip Roeder not only apply theory to practice, but using a wealth of empirical evidence, draw together the elements of existing theory into new syntheses. The authors each highlight a development in postcommunist societies that reveals an anomaly or lacuna in existing theory. They explain why authoritarian leaders abandon authoritarianism, why democratization sometimes reverses course, how subjects become citizens by beginning to take sides in politics, how rulers become politicians by beginning to seek popular support, and not least, how democracy becomes consolidated. Rather than converging on a single approach, each author shows how either a rationalist, institutionalist, discursive, or Weberian approach sheds light on this transformation. They conclude that the experience of postcommunist democracy demands a rethinking of existing theory. To that end, they offer rich new insights to scholars, advanced students, policymakers, and anyone interested in postcommunist states or in comparative democratization.
Medicine is constantly looking for new and improved treatments for diseases, which need to have a high efficacy and be cost-effective, creating a large demand on scientific research to discover such ...new treatments. One important aspect of any treatment is the ability to be able to target only the illness and not cause harm to another healthy part of the body. For this reason, metallic nanoparticles have been and are currently being extensively researched for their possible medical uses, including medical imaging, antibacterial and antiviral applications. Superparamagnetic metal nanoparticles possess properties that allow them to be directed around the body with a magnetic field or directed to a magnetic implant, which opens up the potential to conjugate various bio-cargos to the nanoparticles that could then be directed for treatment in the body. Here we report on some of the current bio-medical applications of various metal nanoparticles, including single metal nanoparticles, functionalized metal nanoparticles, and core-shell metal nanoparticles using a core of Fe
3
O
4
as well as synthesis methods of these core-shell nanoparticles.
Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell‐autonomous in nature, including ...nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane‐associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome‐based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC‐derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC‐derived exosome‐based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC‐exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation.
Characterization of over 200 preclinical studies investigating the therapeutic effects of mesenchymal stem/stromal cell‐derived exosomes.
PDF
