Mild Parkinsonian Signs: A Systematic Review of Clinical, Imaging, and Pathological Associations

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. “Mild motor signs” appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required

Editorial: Immunogenicity of Proteins Used as Therapeutics

International audienc

Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

BACKGROUND: Insulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can also induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Whether low doses of AICAR can augment physiologic insulin action is unknown. In the present study we used the euglycemic hyperinsulinemic clamp to assess whether insulin action is augmented by low dose AICAR. METHODS: Anesthetized rats were studied during saline infusion or euglycemic insulin (3 mU/kg/min) clamp for 2 h in the absence or presence of AICAR for the last hour (5 mg bolus followed by 3.75 mg/kg/min). Muscle glucose uptake (R\u27g) was determined radioisotopically with (14)C-2-deoxyglucose and muscle microvascular perfusion by contrast-enhanced ultrasound with microbubbles. RESULTS: AICAR did not affect blood glucose, or lower leg R\u27g, although it significantly (p < 0.05) increased blood lactate levels and augmented muscle microvascular blood volume via a nitric oxide synthase dependent pathway. Insulin increased femoral blood flow, whole body glucose infusion rate (GIR), R\u27g, hindleg glucose uptake, and microvascular blood volume. Addition of AICAR during insulin infusion increased lactate production, further increased R\u27g in Type IIA (fast twitch oxidative) and IIB (fast twitch glycolytic) fiber containing muscles, and hindleg glucose uptake, but decreased R\u27g in the Type I (slow twitch oxidative) fiber muscle. AICAR also decreased GIR due to inhibition of insulin-mediated suppression of hepatic glucose output. AICAR augmented insulin-mediated microvascular perfusion. CONCLUSIONS: AICAR, at levels that have no direct effect on muscle glucose uptake, augments insulin-mediated microvascular blood flow and glucose uptake in white fiber type muscles. Agents targeted to endothelial AMPK activation are promising insulin sensitizers, however, the decrease in GIR and the propensity to increase blood lactate cautions against AICAR as an acute insulin sensitizer

Retirement and cognition: A life course view

This study examines the relationship between retirement and cognitive aging. We build on previous research by exploring how different specifications of retirement that reflect diverse pathways out of the labor market, including reason for leaving the pre-retirement job and duration spent in retirement, impact three domains of cognitive functioning. We further assess how earlylife factors, including adolescent cognition, and mid-life work experiences, condition these relationships. To do so, we draw on longitudinal data from the Wisconsin Longitudinal Study, a cohort study of Wisconsin high school graduates collected prospectively starting in 1957 until most recently in 2011 when individuals were aged 71. Results indicate that retirement, on average, is associated with improved abstract reasoning, but not with verbal memory or verbal fluency. Yet, when accounting for the reason individuals left their pre-retirement job, those who had retired for health reasons had both lower verbal memory and verbal fluency scores and those who had retired voluntarily or for family reasons had improved abstract memory scores. Together, the results suggest that retirement has an inconsistent effect on cognitive aging across cognitive domains and that the conditions surrounding the retirement decision are important to understanding cognitive functioning at older ages

Partner Bereavement and Detection of Dementia: A UK-Based Cohort Study Using Routine Health Data

BACKGROUND: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. // OBJECTIVE: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. // METHODS: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a partnership. Multivariate cox regression was performed. // RESULTS: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20-1.71) and first six months (HR 1.24, 95% CI 1.09-1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89-0.98). // CONCLUSIONS: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals

Clustering and Alignment of Polymorphic Sequences for HLA-DRB1 Genotyping

Located on Chromosome 6p21, classical human leukocyte antigen genes are highly polymorphic. HLA alleles associate with a variety of phenotypes, such as narcolepsy, autoimmunity, as well as immunologic response to infectious disease. Moreover, high resolution genotyping of these loci is critical to achieving long-term survival of allogeneic transplants. Development of methods to obtain high resolution analysis of HLA genotypes will lead to improved understanding of how select alleles contribute to human health and disease risk. Genomic DNAs were obtained from a cohort of n = 383 subjects recruited as part of an Ulcerative Colitis study and analyzed for HLA-DRB1. HLA genotypes were determined using sequence specific oligonucleotide probes and by next-generation sequencing using the Roche/454 GSFLX instrument. The Clustering and Alignment of Polymorphic Sequences (CAPSeq) software application was developed to analyze next-generation sequencing data. The application generates HLA sequence specific 6-digit genotype information from next-generation sequencing data using MUMmer to align sequences and the R package diffusionMap to classify sequences into their respective allelic groups. The incorporation of Bootstrap Aggregating, Bagging to aid in sorting of sequences into allele classes resulted in improved genotyping accuracy. Using Bagging iterations equal to 60, the genotyping results obtained using CAPSeq when compared with sequence specific oligonucleotide probe characterized 4-digit genotypes exhibited high rates of concordance, matching at 759 out of 766 (99.1%) alleles. © 2013 Ringquist et al

Synergistic Antibacterial Effects of Metallic Nanoparticle Combinations

© The Author(s) 2019.Metallic nanoparticles have unique antimicrobial properties that make them suitable for use within medical and pharmaceutical devices to prevent the spread of infection in healthcare. The use of nanoparticles in healthcare is on the increase with silver being used in many devices. However, not all metallic nanoparticles can target and kill all disease-causing bacteria. To overcome this, a combination of several different metallic nanoparticles were used in this study to compare effects of multiple metallic nanoparticles when in combination than when used singly, as single elemental nanoparticles (SENPs), against two common hospital acquired pathogens (Staphylococcus aureus and Pseudomonas. aeruginosa). Flow cytometry LIVE/DEAD assay was used to determine rates of cell death within a bacterial population when exposed to the nanoparticles. Results were analysed using linear models to compare effectiveness of three different metallic nanoparticles, tungsten carbide (WC), silver (Ag) and copper (Cu), in combination and separately. Results show that when the nanoparticles are placed in combination (NPCs), antimicrobial effects significantly increase than when compared with SENPs (P < 0.01). This study demonstrates that certain metallic nanoparticles can be used in combination to improve the antimicrobial efficiency in destroying morphologically distinct pathogens within the healthcare and pharmaceutical industry.Peer reviewe

Design of an Alternative Coolant Inlet Flow Configuaration for the Modular Helium Reactor

The coolant outlet temperature for the Modular Helium Reactor (MHR) was increased to improve the overall efficiency of nuclear hydrogen production using either thermochemical or high temperature electrolysis (HTE) processes. The inlet temperature was also increased to keep about the same _T across the reactor core. Thermal hydraulic analyses of the current MHR design were performed with these updated temperatures to determine the impact of these highter temperatures on pressure drops, coolant flow rates and temperature profiles within the vessel and core regions. Due to these increased operating temperatures, the overall efficiency of hydrogen production processes increases but the steady state reactor vessel temperature is found to be well above the ASME code limits for current vessel materials. Using the RELAP5-3D/ATHENA computer code, an alternative configuration for the MHR coolant inlet flow path was evaluated in an attempt to reduce the reactor vessel temperatures. The coolant inlet flow was shifted from channel boxes located in the annular region between the reactor core barrel and the inner wall of the reactor vessel to a flow path through the outer permanent reflector. Considering the available thickness of graphite in the permanent outer reflector, the total flow area, the number of coolant holes and the coolant-hole diameter were varied to optimize the pressure drop, the coolant inlet velocity and the percentage of graphite removed from the core. The resulting thermal hydraulic analyses of the optimized design showed that peak vessel and fuel temperatures were within acceptable limits for both steady-state and transient operating conditions