Potential relationship between cytomegalovirus and immunosenescence: Evidence from observational studies.

Immunosenescence (IS) occurs as a natural outcome of ageing and may be described as a decline in immune system flexibility and adaptability to sufficiently respond to new, foreign antigens. Potential factors that may precipitate IS include persistent herpesvirus infections, such as cytomegalovirus (CMV). Here, we conducted a review of the literature evaluating the potential association between CMV and IS. Twenty-seven epidemiologic studies that included direct comparisons between CMV-seropositive and CMV-seronegative immunocompetent individuals were analysed. The majority of these studies (n = 20) were conducted in European populations. The strength of evidence supporting a relationship between CMV, and various IS-associated immunologic endpoints was assessed. T-cell population restructuring was the most prominently studied endpoint, described in 21 studies, most of which reported a relationship between CMV and reduced CD4:CD8 T-cell ratio or modified CD8+ T-cell levels. Telomere length (n = 4) and inflammageing (n = 3) were less frequently described in the primary literature, and the association of these endpoints with CMV and IS was less pronounced. An emergent trend from our review is the potential effect modification of the CMV-IS relationship with both sex and age, indicating the importance of considering various effector variables when evaluating associations between CMV and IS. Our analysis revealed plausible mechanisms that may underlie the larger epidemiologic trends seen in the literature that support the indirect effect of CMV on IS. Future studies are needed to clarify CMV-associated and IS-associated immunologic endpoints, as well as in more diverse global and immunocompromised populations.

Dementia, infections and vaccines: 30 years of controversy.

This paper reports the proceedings of a virtual meeting convened by the European Interdisciplinary Council on Ageing (EICA), to discuss the involvement of infectious disorders in the pathogenesis of dementia and neurological disorders leading to dementia. We recap how our view of the infectious etiology of dementia has changed over the last 30 years in light of emerging evidence, and we present evidence in support of the implication of infection in dementia, notably Alzheimer's disease (AD). The bacteria and viruses thought to be responsible for neuroinflammation and neurological damage are reviewed. We then review the genetic basis for neuroinflammation and dementia, highlighting the genes that are currently the focus of investigation as potential targets for therapy. Next, we describe the antimicrobial hypothesis of dementia, notably the intriguing possibility that amyloid beta may itself possess antimicrobial properties. We further describe the clinical relevance of the gut-brain axis in dementia, the mechanisms by which infection can move from the intestine to the brain, and recent findings regarding dysbiosis patterns in patients with AD. We review the involvement of specific pathogens in neurological disorders, i.e. SARS-CoV-2, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1), and influenza. Finally, we look at the role of vaccination to prevent dementia. In conclusion, there is a large body of evidence supporting the involvement of various infectious pathogens in the pathogenesis of dementia, but large-scale studies with long-term follow-up are needed to elucidate the role that infection may play, especially before subclinical or clinical disease is present.

Longevity, Centenarians and Modified Cellular Proteodynamics.

We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people-nonagenarians to (semi)supercentenarians-maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity. We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance. We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.

Infectious diseases and cognition: do we have to worry?

OBJECTIVES: Age-related physiological changes, particularly immune system decline, may contribute to greater vulnerability to infectious diseases in older individuals. A growing body of evidence shows that both, acute, and chronic infections may be accompanied by cognitive disturbances as part of their manifestations. Given the importance of cognition in aging trajectories, the objective of this article was to review current knowledge on cognitive outcomes of infectious diseases in older adults, and to emphasize the importance of considering cognition as a domain of interest in its own rights in these diseases. METHODS: A MEDLINE/PubMed database search was conducted to identify articles reporting cognitive impairment associated with various severe acute infections and specific chronic infectious conditions such as human immune deficiency virus, the herpes virus family, hepatitis C virus, Lyme borreliosis, Helicobacter pylori, periodontitis, and emerging pathogens like SARS-CoV-2, as well as potentially preventive strategies like vaccination. RESULTS/ CONCLUSIONS: Taken together, the studies examined in the present review emphasize that numerous acute and chronic infectious diseases share mechanisms that, when added to specific risk factors frequently found in older persons, contribute to considerably increase the risk of cognitive outcomes such as cognitive decline and dementia. This review may help to appreciate the role that infectious diseases play in cognitive trajectories and thus promote further investigation on the topic.

Cardiometabolic and Vascular Disease Factors and Mild Cognitive Impairment and Dementia.

INTRODUCTION: There is empirical evidence that cardiovascular risk factors and vascular pathology contribute to cognitive impairment and dementia. METHODS: We profiled cardiometabolic and vascular disease (CMVD) and CMVD burden in community-living older adults in the Singapore Longitudinal Ageing Study cohort and examined the association of CMVD risk markers with the prevalence and incidence of mild cognitive impairment (MCI) and dementia from a median 3.8 years of follow-up. RESULTS: Prevalent MCI and dementia, compared with normal cognition, was associated with higher proportions of persons with any CMVD, hypertension, diabetes, coronary heart disease, atrial fibrillation, or stroke. Diabetes, stroke, and the number of CMVD risk markers remained significantly associated with dementia or MCI after adjusting for age, sex, formal education level, APOE-ε4 genotype, and level of physical, social, or productive activities, with odds ratios ranging from 1.3 to 5.7. Among cognitively normal participants who were followed up, any CMVD risk factor, dyslipidemia, diabetes, or heart failure at baseline predicted incident MCI or its progression to dementia after adjusting for potential confounders. CONCLUSION: Older adults with higher burden of CMVD, driven especially by diabetes, are likely to increase the risk of prevalent and incident MCI and dementia.

The integration of inflammaging in age-related diseases.

Aging is characterized by a morpho-functional adaptation, variably affecting major physiological systems, depending on a complex interaction between genetic, environmental and stochastic factors. This dynamic interaction drives an age-related remodelling of a number of pathways/systems, providing the chance to reach the extreme limit of human life in healthy state which is reflected in the ever-increasing number of centenarians. This conceptualization implies that aging process per se and the development of the most common age-related diseases (ARD) are somewhat separate but must share somehow common set of basic biological mechanisms. One of the features that characterize both processes is the development and progression of an inflammatory state named inflammaging. Notably, inflammaging is characterized by a peculiar presentation, being a chronic, systemic, low grade and therefore for a long time subclinical, inflammatory process. For these reasons, even if the rate of progression of inflammaging is currently recognized as the main force driving aging and one of the main risk factors for clinical morbidity and mortality in the elderly, current knowledge on the causal agents are still incomplete and the "clinical evaluation" of inflammaging has not yet been standardized. Even if a number of biomarkers of inflammaging have been identified, their analysis is not recommended as part of the routine evaluation of elderly patients. This review will aim to describe the concept of inflammaging within several other concepts such as the definition of aging per se and how we integrate it in the context of ARD.

Frailty in older people living with HIV: current status and clinical management.

This paper will update care providers on the clinical and scientific aspects of frailty which affects an increasing proportion of older people living with HIV (PLWH). The successful use of combination antiretroviral therapy has improved long-term survival in PLWH. This has increased the proportion of PLWH older than 50 to more than 50% of the HIV population. Concurrently, there has been an increase in the premature development of age-related comorbidities as well as geriatric syndromes, especially frailty, which affects an important minority of older PLWH. As the number of frail older PLWH increases, this will have an important impact on their health care delivery. Frailty negatively affects a PLWH's clinical status, and increases their risk of adverse outcomes, impacting quality of life and health-span. The biologic constructs underlying the development of frailty integrate interrelated pathways which are affected by the process of aging and those factors which accelerate aging. The negative impact of sarcopenia in maintaining musculoskeletal integrity and thereby functional status may represent a bidirectional interaction with frailty in PLWH. Furthermore, there is a growing body of literature that frailty states may be transitional. The recognition and management of related risk factors will help to mitigate the development of frailty. The application of interdisciplinary geriatric management principles to the care of older PLWH allows reliable screening and care practices for frailty. Insight into frailty, increasingly recognized as an important marker of biologic age, will help to understand the diversity of clinical status occurring in PLWH, which therefore represents a fundamentally new and important aspect to be evaluated in their health care.

Effects of Sex and Physical Activity Level on Serum Biomarker-Based Physiological Dysregulation: The Impact to Predict Frailty and Mortality in the Quebec NuAge Cohort.

BACKGROUND: Age-related changes in biological processes such as physiological dysregulation (the progressive loss of homeostatic capacity) vary considerably among older adults and may influence health profiles in late life. These differences could be related, at least in part, to the impact of intrinsic and extrinsic factors such as sex and physical activity level (PAL). OBJECTIVES: The objectives of this study were (1) to assess the magnitude and rate of changes in physiologi-cal dysregulation in men and women according to PAL and (2) to determine whether/how sex and PAL mediate the apparent influence of physiological dysregulation on health outcomes (frailty and mortality). METHODS: We used data on 1,754 community-dwelling older adults (age = 74.4 ± 4.2 years; women = 52.4%) of the Quebec NuAge cohort study. Physiological dysregulation was calculated based on Mahalanobis distance of 31 biomarkers regrouped into 5 systems: oxygen transport, liver/kidney function, leukopoiesis, micronutrients, and lipids. RESULTS: As expected, mean physiological dysregulation significantly increased with age while PAL decreased. For the same age and PAL, men showed higher levels of physiological dysregulation globally in 3 systems: oxygen transport, liver/kidney function, and leukopoiesis. Men also showed faster global physiological dysregulation in the liver/kidney and leukopoiesis systems. Overall, high PAL was associated with lower level and slower rate of change of physiological dysregulation. Finally, while mortality and frailty risk significantly increased with physiological dysregulation, there was no evidence for differences in these effects between sexes and PAL. CONCLUSION: Our results showed that both sex and PAL have a significant effect on physiological dysregulation levels and rates of change. Also, although a higher PAL was associated with lower level and slower rate of change of physiological dysregulation, there was no evidence that PAL attenuates the effect of physiological dysregulation on subsequent declines in health at the end of life. Substantial work remains to understand how modifiable behaviors impact the relationship between physiological dysregulation, frailty, and mortality in men and women.

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. OBJECTIVES: AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. RESULTS: We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. CONCLUSION: Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.

INTRODUCTION: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

Revisiting the hypothesis of syndromic frailty: a cross-sectional study of the structural validity of the frailty phenotype.

BACKGROUND: Fried's Phenotype Model of Frailty (PMF) postulates that frailty is a syndrome. Features of a syndrome are a heterogeneous population that can be split into at least two classes, those presenting and those not presenting the syndrome. Syndromes are characterized by a specific mixture of signs and symptoms which increase in prevalence, from less to more severe classes. So far, the null hypothesis of homogeneity - signs and symptoms of frailty cannot identify at least two classes - has been tested using Latent Class Analysis (LCA) on the five dichotomized components of PMF (unintentional weight loss, exhaustion, weakness, slowness, and low physical activity). The aim of this study is to investigate further the construct validity of frailty as a syndrome using the extension offered by Factor Mixture Models (FMM). METHODS: LCA on dichotomized scores and FMM on continuous scores were conducted to test homogeneity on the five PMF components in a sample of 1643 community-dwelling older adults living in Québec, Canada (FRéLE). RESULTS: With dichotomized LCA, three frailty classes were found: robust, prefrail and frail, and the hypothesis of homogeneity was rejected. However, in FMM, frailty was better represented as a continuous variable than as latent heterogeneous classes. Thus, the PMF measurement model of frailty did not meet the features of a syndrome in this study. CONCLUSION: Using the FRéLE cohort, the PMF measurement model validity is questioned. Valid measurement of a syndrome depends on an understanding of its etiological factors and pathophysiological processes, and on a modelling of how the measured components are linked to these processes. Without these features, assessing frailty in a clinical setting may not improve patient health. Research on frailty should address these issues before promoting its use in clinical settings.

Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE-/- mice.

Nanostructured lipid carriers (NLC) might represent an interesting approach for the identification and targeting of rupture-prone atherosclerotic plaques. In this study, we evaluated the biodistribution, targeting ability and safety of 64Cu-fonctionalized NLC in atherosclerotic mice. 64Cu-chelating-NLC (51.8±3.1 nm diameter) with low dispersity index (0.066±0.016) were produced by high pressure homogenization at tens-of-grams scale. 24 h after injection of 64Cu-chelated particles in ApoE-/- mice, focal regions of the aorta showed accumulation of particles on autoradiography that colocalized with Oil Red O lipid mapping. Signal intensity was significantly greater in aortas isolated from ApoE-/- mice compared to wild type (WT) control (8.95 [7.58, 10.16]×108 vs 4.59 [3.11, 5.03]×108 QL/mm2, P < 0.05). Moreover, NLC seemed safe in relevant biocompatibility studies. NLC could constitute an interesting platform with high clinical translation potential for targeted delivery and imaging purposes in atherosclerosis.

Effect of e-Cigarettes Plus Counseling vs Counseling Alone on Smoking Cessation: A Randomized Clinical Trial.

Importance: Electronic cigarettes (e-cigarettes) for smoking cessation remain controversial. Objective: To evaluate e-cigarettes with individual counseling for smoking cessation. Design, Setting, and Participants: A randomized clinical trial enrolled adults motivated to quit smoking from November 2016 to September 2019 at 17 Canadian sites (801 individuals screened; 274 ineligible and 151 declined). Manufacturing delays resulted in early termination (376/486 participants, 77% of target). Outcomes through 24 weeks (March 2020) are reported. Interventions: Randomization to nicotine e-cigarettes (n = 128), nonnicotine e-cigarettes (n = 127), or no e-cigarettes (n = 121) for 12 weeks. All groups received individual counseling. Main Outcomes and Measures: The primary end point was point prevalence abstinence (7-day recall, biochemically validated using expired carbon monoxide) at 12 weeks, changed from 52 weeks following early termination. Participants missing data were assumed to be smoking. The 7 secondary end points, examined at multiple follow-ups, were point prevalence abstinence at other follow-ups, continuous abstinence, daily cigarette consumption change, serious adverse events, adverse events, dropouts due to adverse effects, and treatment adherence. Results: Among 376 randomized participants (mean age, 52 years; 178 women [47%]), 299 (80%) and 278 (74%) self-reported smoking status at 12 and 24 weeks, respectively. Point prevalence abstinence was significantly greater for nicotine e-cigarettes plus counseling vs counseling alone at 12 weeks (21.9% vs 9.1%; risk difference [RD], 12.8 [95% CI, 4.0 to 21.6]) but not 24 weeks (17.2% vs 9.9%; RD, 7.3 [95% CI, -1.2 to 15.7]). Point prevalence abstinence for nonnicotine e-cigarettes plus counseling was not significantly different from counseling alone at 12 weeks (17.3% vs 9.1%; RD, 8.2 [95% CI, -0.1 to 16.6]), but was significantly greater at 24 weeks (20.5% vs 9.9%; RD, 10.6 [95% CI, 1.8 to 19.4]). Adverse events were common (nicotine e-cigarette with counseling: 120 [94%]; nonnicotine e-cigarette with counseling: 118 [93%]; counseling only: 88 [73%]), with the most common being cough (64%) and dry mouth (53%). Conclusions and Relevance: Among adults motivated to quit smoking, nicotine e-cigarettes plus counseling vs counseling alone significantly increased point prevalence abstinence at 12 weeks. However, the difference was no longer significant at 24 weeks, and trial interpretation is limited by early termination and inconsistent findings for nicotine and nonnicotine e-cigarettes, suggesting further research is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02417467.

Thermodynamical Extension of a Symplectic Numerical Scheme with Half Space and Time Shifts Demonstrated on Rheological Waves in Solids.

On the example of the Poynting-Thomson-Zener rheological model for solids, which exhibits both dissipation and wave propagation, with nonlinear dispersion relation, we introduce and investigate a finite difference numerical scheme. Our goal is to demonstrate its properties and to ease the computations in later applications for continuum thermodynamical problems. The key element is the positioning of the discretized quantities with shifts by half space and time steps with respect to each other. The arrangement is chosen according to the spacetime properties of the quantities and of the equations governing them. Numerical stability, dissipative error, and dispersive error are analyzed in detail. With the best settings found, the scheme is capable of making precise and fast predictions. Finally, the proposed scheme is compared to a commercial finite element software, COMSOL, which demonstrates essential differences even on the simplest-elastic-level of modeling.

Four Spacetime Dimensional Simulation of Rheological Waves in Solids and the Merits of Thermodynamics.

The recent results attained from a thermodynamically conceived numerical scheme applied on wave propagation in viscoelastic/rheological solids are generalized here, both in the sense that the scheme is extended to four spacetime dimensions and in the aspect of the virtues of a thermodynamical approach. Regarding the scheme, the arrangement of which quantity is represented where in discretized spacetime, including the question of appropriately realizing the boundary conditions, is nontrivial. In parallel, placing the problem in the thermodynamical framework proves to be beneficial in regards to monitoring and controlling numerical artefacts-instability, dissipation error, and dispersion error. This, in addition to the observed preciseness, speed, and resource-friendliness, makes the thermodynamically extended symplectic approach that is presented here advantageous above commercial finite element software solutions.

Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease?

HIV infection in the combination antiretroviral therapy (cART) era has become a chronic disease with a life expectancy almost identical to those free from this infection. Concomitantly, chronic diseases such as neurodegenerative diseases have emerged as serious clinical problems. HIV-induced cognitive changes, although clinically very diverse are collectively called HIV-associated neurocognitive disorder (HAND). HAND, which until the introduction of cART manifested clinically as a subcortical disorder, is now considered primarily cognitive disorder, which makes it similar to diseases like Alzheimer's (AD) and Parkinson's disease (PD). The pathogenesis involves either the direct effects of the virus or the effect of viral proteins such as Tat, Ggp120, and Nef. These proteins are either capable of destroying neurons directly by inducing neurotoxic mediators or by initiating neuroinflammation by microglia and astrocytes. Recently, it has become recognized that HIV infection is associated with increased production of the beta-amyloid peptide (Aß) which is a characteristic of AD. Moreover, amyloid plaques have also been demonstrated in the brains of patients suffering from HAND. Thus, the question arises whether this production of Aß indicates that HAND may lead to AD or it is a form of AD or this increase in Aß production is only a bystander effect. It has also been discovered that APP in HIV and its metabolic product Aß in AD manifest antiviral innate immune peptide characteristics. This review attempts to bring together studies linking amyloid precursor protein (APP) and Aß production in HIV infection and their possible impact on the course of HAND and AD. These data indicate that human defense mechanisms in HAND and AD are trying to contain microorganisms by antimicrobial peptides, however by employing different means. Future studies will, no doubt, uncover the relationship between HAND and AD and, hopefully, reveal novel treatment possibilities.

Human Inflammaging.

Human aging is a very complex process that occurs in an intricate biological and physiological setting. Many changes occur with aging and among the most important are changes in immune reactivity associated with cell differentiation stages and the phenomenon of inflammaging, understood as subclinical inflammatory readiness, manifested by elevated levels of proinflammatory factors. It was stated for a long time that this tandem occurs in parallel or eventually sequentially. However, recent evidence points to the fact that, as both originate from chronic antigen stimulation, they mutually drive each other. In this context, inflammaging is considered the basis of most age-related diseases (ARD). In this review concerning human inflammaging, we argue that inflammatory diseases develop during whole life as a diverted (excessive) normal immune reaction to specific stressors. Thus, inflammaging may not be the cause of these diseases; however, it can be the trigger of clinical manifestation of ARD. In this context, the best intervention should aim to regulate the balance between pro- and anti-inflammatory signals and the more appropriate reaction to chronic stimulations to avoid/delay the appearance of associated diseases.

Effect of a mixed-exercise program on physical capacity and sedentary behavior in older adults during cancer treatments.

BACKGROUND: Aging, cancer and its treatment all contribute to increase the risk of deconditioning and sedentary behaviors. Mixed exercise is recognized to counteract the effects of aging and deconditioning as well as improving physical capacity during cancer treatment in adults. AIMS: To determine the impact of a mixed exercise program (MXEP) to improve physical capacity and decrease sedentary behavior time (SBT) in older adults during cancer treatment. METHODS: Fourteen participants (68.8 ± 3.4 years) completed 12 weeks of a mixed exercise program (MEXP) (n = 6) or stretching (n = 8) while they were under cancer treatment. Five tests of the Senior Fitness Test (Chair Stand, 8-Foot Up & Go, Arm Curl, Sit & Reach, 6 min Walk Test), two maximal strength tests (leg press and handgrip) and a Global Physical Capacity Score (GPCS) were used to assess physical capacity. For the amount of SBT (min/day), we used question 1 of the Physical Activity Scale for the Elderly. RESULTS: Both groups presented significant pre- vs post-intervention differences for the Chair Stand, Arm Curl, 6 min Walk Tests and also GPCS. Nevertheless, this difference was significantly greater in the MEXP group only for the Chair Stand Test (4.3 ± 2.2 vs 1.0 ± 1.3 reps; p = 0.01) and the GPCS (4.0 ± 0.6 vs 1.5 ± 2.3 points; p = 0.047). A tend to display a greater decrease in SBT (- 295 ± 241 min/week vs - 11 ± 290 min/week; p = 0.079) was observed in favor of MEXP. CONCLUSION: A 12-week mixed exercise program led to significant improvements in physical capacity and may reduce SBT.

Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 µg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment.

INTRODUCTION: Unlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel. METHODS: Fifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later. RESULTS: Brain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention. DISCUSSION: A dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.