Dietary Derived Propionate Regulates Pathogenic Fibroblast Function and Ameliorates Experimental Arthritis and Inflammatory Tissue Priming.

Short-chain fatty acids are gut-bacteria-derived metabolites that execute important regulatory functions on adaptive immune responses, yet their influence on inflammation driven by innate immunity remains understudied. Here, we show that propionate treatment in drinking water or upon local application into the joint reduced experimental arthritis and lowered inflammatory tissue priming mediated by synovial fibroblasts. On a cellular level, incubation of synovial fibroblasts with propionate or a physiological mixture of short-chain fatty acids interfered with production of inflammatory mediators and migration and induced immune-regulatory fibroblast senescence. Our study suggests that propionate mediates its alleviating effect on arthritis by direct abrogation of local arthritogenic fibroblast function.

Unbalancing the Attentional Priority Map via Gaze-Contingent Displays Induces Neglect-Like Visual Exploration.

Selective spatial attention is a crucial cognitive process that guides us to the behaviorally relevant objects in a complex visual world by using exploratory eye movements. The spatial location of objects, their (bottom-up) saliency and (top-down) relevance is assumed to be encoded in one "attentional priority map" in the brain, using different egocentric (eye-, head- and trunk-centered) spatial reference frames. In patients with hemispatial neglect, this map is supposed to be imbalanced, leading to a spatially biased exploration of the visual environment. As a proof of concept, we altered the visual saliency (and thereby attentional priority) of objects in a naturalistic scene along a left-right spatial gradient and investigated whether this can induce a bias in the exploratory eye movements of healthy humans (n = 28; all right-handed; mean age: 23 years, range 19-48). We developed a computerized mask, using high-end "gaze-contingent display (GCD)" technology, that immediately and continuously reduced the saliency of objects on the left-"left" with respect to the head (body-centered) and the current position on the retina (eye-centered). In both experimental conditions, task-free viewing and goal-driven visual search, this modification induced a mild but significant bias in visual exploration similar to hemispatial neglect. Accordingly, global eye movement parameters changed (reduced number and increased duration of fixations) and the spatial distribution of fixations indicated an attentional bias towards the right (rightward shift of first orienting, fixations favoring the scene's outmost right over left). Our results support the concept of an attentional priority map in the brain as an interface between perception and behavior and as one pathophysiological ground of hemispatial neglect.

The time course of ineffective sham-blinding during low-intensity (1 mA) transcranial direct current stimulation.

Studies using transcranial direct current stimulation (tDCS) typically compare an active protocol relative to a shorter sham (placebo) protocol. Both protocols are presumed to be perceptually identical on the scalp, and thus represent an effective method of delivering double-blinded experimental designs. However, participants often show above-chance accuracy when asked which condition involved active/sham retrospectively. We assessed the time course of sham-blinding during active and sham tDCS. We predicted that participants would be aware that the current is switched on for longer in the active versus sham protocol. Thirty-two adults were tested in a preregistered, double-blinded, within-subjects design. A forced-choice reaction time task was undertaken before, during and after active (10 min 1 mA) and sham (20 s 1 mA) tDCS. The anode was placed over the left primary motor cortex (C3) to target the right hand, and the cathode on the right forehead. Two probe questions were asked every 30 s: "Is the stimulation on?" and "How sure are you?". Distinct periods of non-overlapping confidence intervals were identified between conditions, totalling 5 min (57.1% of the total difference in stimulation time). These began immediately after sham ramp-down and lasted until the active protocol had ended. We therefore show a failure of placebo control during 1 mA tDCS. These results highlight the need to develop more effective methods of sham-blinding during transcranial electrical stimulation protocols, even when delivered at low-intensity current strengths.

Adaptive Cueing Treatment of Neglect in Stroke Patients Leads to Improvements in Activities of Daily Living: A Randomized Controlled, Crossover Trial.

BACKGROUND: Visuospatial neglect is a disabling syndrome with serious consequences for activities in daily life. This study investigated the effect of adaptive cueing during a reading task as a possible treatment for neglect by including (1) a task relevant for the patient's daily life, (2) a fading out procedure to stimulate independent orientation to the left by self-cueing, and (3) a clear definition of neglect severity for the adaptive treatment protocol. METHODS: A randomized controlled crossover design was used, including 26 patients from an early rehabilitation unit with left-sided visuospatial neglect after stroke or hemorrhage. They were examined twice at baseline (T1, T2), after 15 daily sessions in 1 condition (T3), and again after 15 daily sessions in the other condition (T4). The intervention condition included a daily reading task combined with endogenous and exogenous cues provided by a therapist, which were continuously reduced after a patient had reached a defined level of performance. The control condition consisted of a neuropsychological treatment of the same length, not targeting visuospatial attention. RESULTS: Significant improvements were shown after intervention on scores for reading (word and text reading), daily life activities (Catherine Bergego Scale), Line Bisection, and the Clock Drawing Task. CONCLUSION: This study shows that adaptive cueing in a reading task can improve neglect symptoms by using an intensive intervention lasting 3 weeks.

Distinct CD11b+-monocyte subsets accelerate endothelial cell recovery after acute and chronic endothelial cell damage.

BACKGROUND: Endothelial cell recovery requires replenishment of primary cells from the endothelial lineage. However, recent evidence suggests that cells of the innate immune system enhance endothelial regeneration. METHODS AND RESULTS: Focusing on mature CD11b+-monocytes, we analyzed the fate and the effect of transfused CD11b+-monocytes after endothelial injury in vivo. CD11b-diphtheria-toxin-receptor-mice--a mouse model in which administration of diphtheria toxin selectively eliminates endogenous monocytes and macrophages--were treated with WT-derived CD11b+-monocytes from age-matched mice. CD11b+-monocytes improved endothelium-dependent vasoreactivity after 7 days while transfusion of WT-derived CD11b--cells had no beneficial effect on endothelial function. In ApoE-/--CD11b-DTR-mice with a hypercholesterolemia-induced chronic endothelial injury transfusion of WT-derived CD11b+-monocytes stimulated by interferon-γ (IFNγ) decreased endothelial function, whereas interleukin-4-stimulated (IL4) monocytes had no detectable effect on vascular function. Bioluminescent imaging revealed restriction of transfused CD11b+-monocytes to the endothelial injury site in CD11b-DTR-mice depleted of endogenous monocytes. In vitro co-culture experiments revealed significantly enhanced regeneration properties of human endothelial outgrowth cells (EOCs) when cultured with preconditioned-media (PCM) or monocytes of IL4-stimulated-subsets compared to the effects of IFNγ-stimulated monocytes. CONCLUSION: CD11b+-monocytes play an important role in endothelial cell recovery after endothelial injury by homing to the site of vascular injury, enhancing reendothelialization and improving endothelial function. In vitro experiments suggest that IL4-stimulated monocytes enhance EOC regeneration properties most likely by paracrine induction of proliferation and cellular promotion of differentiation. These results underline novel insights in the biology of endothelial regeneration and provide additional information for the treatment of vascular dysfunction.