Objective
Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the ...earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset.
Methods
By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2‐weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood–brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination.
Results
On average, BBB permeability increased 3.5‐fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood‐derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001).
Interpretation
This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood‐derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. Ann Neurol 2014;76:594–608
Many individuals who experience a stroke exhibit reduced modulation of their mediolateral foot placement, an important gait stabilization strategy. One factor that may contribute to this deficit is ...altered somatosensory processing, which can be probed by applying vibration to the involved muscles (e.g., the hip abductors). The purpose of this study was to investigate whether appropriately controlled hip abductor vibration can increase foot placement modulation among people with chronic stroke. 40 people with chronic stroke performed a series of treadmill walking trials without vibration and with vibration of either the hip abductors or lateral trunk (a control condition) that scaled with their real-time mediolateral motion. To assess participants’ vibration sensitivity, we also measured vibration detection threshold and lateral sway evoked by abductor vibration during quiet standing. As a group, foot placement modulation increased significantly with either hip or trunk vibration, compared to without vibration. However, these changes were quite variable across participants, and were not predicted by either vibration detection threshold or the lateral sway evoked by hip vibration during standing. Overall, we found that somatosensory stimulation had small, positive effects on post-stroke foot placement modulation. Unexpectedly, these effects were observed with both hip abductor and lateral trunk vibration, perhaps indicating that the trunk can also provide useful somatosensory feedback during walking. Future work is needed to determine whether repeated application of such somatosensory stimulation can produce sustained effects on this important gait stabilization strategy.
•The skin of R. sphenocephala metamorphs harbors a rich microbiome inhibiting Bd.•An antibiotic cocktail reduced culturable skin bacteria within 48h.•Metamorphs with reduced skin bacteria had heavier ...Bd burdens within two weeks.•Skin bacteria may be protective of metamorphs prior to development of AMP defenses.
An important concern for conservation biologists is the continuing loss of global biodiversity. This is especially true for amphibians, which are disappearing at an alarming rate. The emerging fungal pathogen, Batrachochytrium dendrobatidis (Bd), causes the skin disease chytridiomycosis and is a major contributor to amphibian population declines. Recent studies suggest that symbiotic skin bacteria provide some protection against Bd. Possible mitigation strategies include skin microbiome manipulation and bioaugmentation with potentially beneficial bacteria. Such approaches may employ a method to reduce resident bacteria on the skin to allow for new colonization. Using the southern leopard frog, Rana (Lithobates) sphenocephala, we show here that the skin of this species harbors a rich array of culturable bacterial species that inhibit Bd growth in␣vitro. Use of a potent antibiotic cocktail dramatically reduced culturable skin bacteria within 48h. Reduction of bacteria on post-metamorphic juvenile skin using this antibiotic cocktail resulted in an increased Bd skin burden within two weeks of Bd exposure and a higher Bd burden in those frogs that died. However, efforts to maintain a normal bacterial skin community using a semi-natural mesocosm-derived source of microbes failed to provide long term protection of these vulnerable frogs. Regardless of presence or absence of mesocosm-derived bacteria, Bd loads decreased over time in surviving frogs, suggesting the development of an adaptive immune defense. In this species, development of an antimicrobial peptide defense is delayed, and thus, the microbial community and adaptive immune defenses may provide protection at this critical period of development.
Many people with chronic stroke (PwCS) exhibit walking balance deficits linked to increased fall risk and decreased balance confidence. One potential contributor to these balance deficits is a ...decreased ability to modulate mediolateral stepping behavior based on pelvis motion. This behavior, hereby termed mediolateral step modulation, is thought to be an important balance strategy but can be disrupted in PwCS.
Are biomechanical metrics of mediolateral step modulation related to common clinical balance measures among PwCS?
In this cross-sectional study, 93 PwCS walked on a treadmill at their self-selected speed for 3-minutes. We quantified mediolateral step modulation for both paretic and non-paretic steps by calculating partial correlations between mediolateral pelvis displacement at the start of each step and step width (ρSW), mediolateral foot placement relative to the pelvis (ρFP), and final mediolateral location of the pelvis (ρPD) at the end of the step. We also assessed several common clinical balance measures (Functional Gait Assessment FGA, Activities-specific Balance Confidence scale ABC, self-reported fear of falling and fall history). We performed Spearman correlations to relate each biomechanical metric of step modulation to FGA and ABC scores. We performed Wilcoxon rank sum tests to compare each biomechanical metric between individuals with and without a fear of falling and a history of falls.
Only ρFP for paretic steps was significantly related to all four clinical balance measures; higher paretic ρFP values tended to be observed in participants with higher FGA scores, with higher ABC scores, without a fear of falling and without a history of falls. However, the strength of each of these relationships was only weak to moderate.
While the present results do not provide insight into causality, they justify future work investigating whether interventions designed to increase ρFP can improve clinical measures of post-stroke balance in parallel.
•Many people with chronic stroke have reduced walking balance and confidence.•Modulation of mediolateral foot placement may be an important balance strategy.•Paretic foot placement modulation was related to clinical balance measures.
Sleep disruption has received little attention in hematopoietic cell transplantation (HCT). The goal of this study was to describe severity, course, and predictors of sleep disruption following HCT. ...A secondary data analysis was conducted of the Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) 0902 study. Participants completed a modified version of the Pittsburgh Sleep Quality Index prior to transplant and 100 and 180 days posttransplant. Growth mixture models were used to characterize subgroups of patients based on baseline sleep disruption and change over time. A total of 570 patients (mean age 55 years, 42% female) were included in the current analyses. Patients could be grouped into four distinct classes based on sleep disruption: (1) clinically significant sleep disruption at baseline that did not improve over time (20%); (2) clinically significant sleep disruption at baseline that improved over time (22%); (3) sleep disruption that did not reach clinical significance at baseline and did not improve over time (45%); and (4) no sleep disruption at baseline or over time (13%). These data provide a more comprehensive understanding of sleep disruption that can be used to develop interventions to improve sleep in HCT recipients.
HIV pre-exposure prophylaxis (PrEP) may change serosorting patterns. We examined the influence of serosorting on the population-level HIV transmission impact of PrEP, and how impact could change if ...PrEP users stopped serosorting.
We developed a compartmental HIV transmission model parameterized with bio-behavioural and HIV surveillance data among MSM in Canada.
We separately fit the model with serosorting and without serosorting counterfactual; sero-proportionate mixing (random partner-selection proportional to availability by HIV status), and reproduced stable HIV epidemics with HIV-prevalence 10.3-24.8%, undiagnosed fraction 4.9-15.8% and treatment coverage 82.5-88.4%. We simulated PrEP-intervention reaching stable pre-specified coverage by year-one and compared absolute difference in relative HIV-incidence reduction 10 years post-intervention (PrEP-impact) between models with serosorting vs. sero-proportionate mixing; and counterfactual scenarios when PrEP users immediately stopped vs. continued serosorting. We examined sensitivity of results to PrEP-effectiveness (44-99%; reflecting varying dosing or adherence levels) and coverage (10-50%).
Models with serosorting predicted a larger PrEP-impact than models with sero-proportionate mixing under all PrEP-effectiveness and coverage assumptions median (interquartile range): 8.1% (5.5-11.6%). PrEP users' stopping serosorting reduced PrEP-impact compared with when PrEP users continued serosorting: reductions in PrEP-impact were minimal 2.1% (1.4-3.4%) under high PrEP-effectiveness (86-99%); however, could be considerable 10.9% (8.2-14.1%) under low PrEP effectiveness (44%) and high coverage (30-50%).
Models assuming sero-proportionate mixing may underestimate population-level HIV-incidence reductions due to PrEP. PrEP-mediated changes in serosorting could lead to programmatically important reductions in PrEP-impact under low PrEP-effectiveness. Our findings suggest the need to monitor sexual mixing patterns to inform PrEP implementation and evaluation.
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can ...include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.
Abstract
Using cross-sectional survey data (Engage, 2017–2018) from 1,137 men who have sex with men, ≥16 years old, in Montreal, we compared observed human immunodeficiency virus (HIV) ...seroconcordance in previous-6-months’ sexual partnerships with what would have been observed by chance if zero individuals serosorted. Of 5 recent partnerships where both individuals were HIV-negative, we compared observed concordance in preexposure prophylaxis (PrEP) use with the counterfactual if zero individuals selected partners based on PrEP use. We estimated the concordance by chance using a balancing-partnerships approach assuming proportionate mixing. HIV-positive respondents had a higher proportion of HIV-positive partners (66.4%, 95% confidence interval (CI): 64.0, 68.6) than by chance (23.9%, 95% CI: 23.1, 24.7). HIV-negative respondents (both on and not on PrEP) had higher proportions of HIV-negative partners (82.9% (95% CI: 81.1, 84.7) and 90.7% (95% CI: 89.6, 91.7), respectively) compared with by chance (76.1%, 95% CI: 75.3, 76.9); however, those on PrEP had a higher proportion of HIV-positive partners than those not on PrEP (17.1% (95% CI: 15.3, 18.9) vs. 9.3% (95% CI: 8.3, 10.4). Those on PrEP also had a higher proportion of partners on PrEP among their HIV-negative partners (50.6%, 95% CI: 42.5, 58.8) than by chance (28.5%, 95% CI: 27.5, 29.4). The relationship between PrEP and sexual-mixing patterns demonstrated by less population-level serosorting among those on PrEP and PrEP-matching warrants consideration during PrEP roll-out.
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