Customized passive-dynamic ankle-foot orthoses can improve walking economy and speed for many individuals post-stroke.

BACKGROUND: Passive-dynamic ankle-foot orthoses (PD-AFOs) are often prescribed to address plantar flexor weakness during gait, which is commonly observed after stroke. However, limited evidence is available to inform the prescription guidelines of PD-AFO bending stiffness. This study assessed the extent to which PD-AFOs customized to match an individual's level of plantar flexor weakness influence walking function, as compared to No AFO and their standard of care (SOC) AFO. METHODS: Mechanical cost-of-transport, self-selected walking speed, and key biomechanical variables were measured while individuals greater than six months post-stroke walked with No AFO, with their SOC AFO, and with a stiffness-customized PD-AFO. Outcomes were compared across these conditions using a repeated measures ANOVA or Friedman test (depending on normality) for group-level analysis and simulation modeling analysis for individual-level analysis. RESULTS: Twenty participants completed study activities. Mechanical cost-of-transport and self-selected walking speed improved with the stiffness-customized PD-AFOs compared to No AFO and SOC AFO. However, this did not result in a consistent improvement in other biomechanical variables toward typical values. In line with the heterogeneous nature of the post-stroke population, the response to the PD-AFO was highly variable. CONCLUSIONS: Stiffness-customized PD-AFOs can improve the mechanical cost-of-transport and self-selected walking speed in many individuals post-stroke, as compared to No AFO and participants' standard of care AFO. This work provides initial efficacy data for stiffness-customized PD-AFOs in individuals post-stroke and lays the foundation for future studies to enable consistently effective prescription of PD-AFOs for patients post-stroke in clinical practice. TRIAL REGISTRATION: NCT04619043.

Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood.

Adverse experiences in childhood are associated with altered hypothalamic-pituitary-adrenal (HPA) axis function and negative health outcomes throughout life. It is now commonly accepted that abuse and neglect can alter epigenetic regulation of HPA genes. Accumulated evidence suggests harsh parenting practices such as spanking are also strong predictors of negative health outcomes. We predicted harsh parenting at 2.5 years old would predict HPA gene DNA methylation similarly to abuse and neglect, and cortisol output at 8.5 years old. Saliva samples were collected three times a day across 3 days to estimate cortisol diurnal slopes. Methylation was quantified using the Illumina Infinium MethylationEPIC array BeadChip (850 K) with DNA collected from buccal cells. We used principal components analysis to compute a summary statistic for CpG sites across candidate genes. The first and second components were used as outcome variables in mixed linear regression analyses with harsh parenting as a predictor variable. We found harsh parenting significantly predicted methylation of several HPA axis genes, including novel gene associations with AVPRB1, CRHR1, CRHR2, and MC2R (FDR corrected p < 0.05). Further, we found NR3C1 methylation predicted a steeper diurnal cortisol slope. Our results extend the current literature by demonstrating harsh parenting may influence DNA methylation similarly to more extreme early life experiences such as abuse and neglect. Further, we show NR3C1 methylation is associated with diurnal HPA function. Elucidating the molecular consequences of harsh parenting on health can inform best parenting practices and provide potential treatment targets for common complex disorders.

Deformable foot orthoses redistribute power from the ankle to the distal foot during walking.

Recently, carbon fiber plates, or orthoses, have been incorporated into footwear to improve running performance, presumably through improved energy storage and return. However, few studies have explored the energetic effects these orthoses have on the distal foot, have utilized such orthoses in walking, and none have sought to specifically harness metatarsophalangeal joint deformation to store and return energy to the ankle-foot complex. To address these gaps, we developed and tested a deformable carbon fiber foot orthosis aiming to harness foot energetics and quantify the resulting effects on ankle energetics during walking in healthy adults. Eight subjects walked under three conditions: barefoot (BF), with minimalist shoes (SH), and with bilateral, deformable foot orthoses in the minimalist shoes (ORTH). Ankle and distal foot energetics, foot-to-floor and ankle angle, stance time, step length, and max center of pressure (COP) position were calculated. When walking with the orthoses, subjects showed 263.6% increase in positive distal foot work along with a 31.9% decrease in ankle work and little to no change in the overall ankle-foot complex work. Step length, stance time, and max anterior COP position significantly increased with orthosis use. No statistical or visual differences were found between BF and SH conditions indicating that our findings were due to the foot orthoses. These results suggest this foot orthosis redistributes power from the ankle to the distal foot for healthy adults, reducing the energetic demand on the ankle. These results lay the foundation for designing orthotics and footwear to improve ankle-foot energetics for clinical populations.

Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro.

The organic anion transporter Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.

DNA Methylation and Expression Profiles of Whole Blood in Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.

Early-Stage Diabetic Neuropathy Reduces Foot Strength and Intrinsic but Not Extrinsic Foot Muscle Size.

BACKGROUND: Tracking progression of diabetic peripheral polyneuropathy (DPN) is usually focused on sensory nerves and subjective testing methods. Recent studies have suggested that distal muscle atrophy may precede sensation loss. Methods to objectively measure distal muscle size and strength are needed to help understand how neuropathy affects muscle function. PURPOSE: To evaluate individual intrinsic and extrinsic foot muscle sizes and functional foot strength in participants with DPN. METHODS: Thirty individuals participated in this cross-sectional study (15 DPN and 15 matched controls). Sizes of 10 separate muscles of the lower leg and foot were measured using ultrasound imaging. Functional foot strength was also quantified using custom great toe and lateral toe flexion tests along with a doming test. Muscle size and strength metrics were compared between groups using ANOVAs and paired t-tests (α = 0.05). Correlations between strength and relevant muscle sizes were also evaluated. RESULTS: The sizes of all four intrinsic foot muscles were smaller in individuals with DPN (p ≤ 0.03), while only one (toe extensor) of the six extrinsic muscles was smaller (p ≤ 0.03), while only one (toe extensor) of the six extrinsic muscles was smaller (p ≤ 0.03), while only one (toe extensor) of the six extrinsic muscles was smaller (p ≤ 0.03), while only one (toe extensor) of the six extrinsic muscles was smaller (r ≤ 0.80) with several corresponding intrinsic muscle sizes. The doming strength test did not show any difference between groups and was moderately correlated with one muscle size (r ≤ 0.80) with several corresponding intrinsic muscle sizes. The doming strength test did not show any difference between groups and was moderately correlated with one muscle size (. CONCLUSION: Diabetic peripheral polyneuropathy affects intrinsic muscles before extrinsics. Ultrasound imaging of individual muscles and functional toe flexion tests can be used clinically to monitor DPN progression and foot function. Participants need to be trained in the doming test before a relationship can be established between this test and DPN foot function. Future studies should include muscle quality measurements to better understand characteristics of affected muscles.

Diabetic Gait Is Not Just Slow Gait: Gait Compensations in Diabetic Neuropathy.

BACKGROUND: Neuropathic complications from diabetes mellitus affect multiple nerve types and may manifest in gait. However, gait compensations are still poorly understood, as narrow analyses and lack of speed controls have contributed to conflicting or equivocal results. PURPOSE: To evaluate gait mechanics and energetics in diabetic peripheral polyneuropathy. METHODS: Instrumented gait analysis was performed on 14 participants with diabetic peripheral polyneuropathy and 14 matched controls, walking at 1.0 m/s. A full-body model with a multisegment foot was used to calculate inverse dynamics and analyze sagittal plane metrics and time series waveforms across stance phase. RESULTS: Alterations included increased hip and knee flexion in early stance followed by a prolonged hip extension moment in midstance. Late stance ankle dorsiflexion and power absorption were increased, and final push-off was delayed and truncated. CONCLUSION: A neuropathic diabetic gait shares important similarities to a mild crouch gait with weakness/dysfunction in the foot and ankle. This study highlights two main compensation mechanisms that have been overlooked in previous literature. First, increased triceps surae stretch in terminal stance may be used to increase proprioception and/or energy storage, while a prolonged hip extension moment in midstance compensates for a limited push-off. These result in an overall workload shift from distal to proximal joints. Clinical assessment, monitoring, and treatment of neuropathy may benefit by focusing on these specific functional alterations.