A perturbation-based balance training program for older adults: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Previous research investigating exercise as a means of falls prevention in older adults has shown mixed results. Lack of specificity of the intervention may be an important factor contributing to negative results. Change-in-support (CIS) balance reactions, which involve very rapid stepping or grasping movements of the limbs, play a critical role in preventing falls; hence, a training program that improves ability to execute effective CIS reactions could potentially have a profound effect in reducing risk of falling. This paper describes: 1) the development of a perturbation-based balance training program that targets specific previously-reported age-related impairments in CIS reactions, and 2) a study protocol to evaluate the efficacy of this new training program.</p> <p>Methods/Design</p> <p>The training program involves use of unpredictable, multi-directional moving-platform perturbations to evoke stepping and grasping reactions. Perturbation magnitude is gradually increased over the course of the 6-week program, and concurrent cognitive and movement tasks are included during later sessions. The program was developed in accordance with well-established principles of motor learning, such as individualisation, specificity, overload, adaptation-progression and variability. Specific goals are to reduce the frequency of multiple-step responses, reduce the frequency of collisions between the stepping foot and stance leg, and increase the speed of grasping reactions. A randomised control trial will be performed to evaluate the efficacy of the training program. A total of 30 community-dwelling older adults (age 64–80) with a recent history of instability or falling will be assigned to either the perturbation-based training or a control group (flexibility/relaxation training), using a stratified randomisation that controls for gender, age and baseline stepping/grasping performance. CIS reactions will be tested immediately before and after the six weeks of training, using platform perturbations as well as a distinctly different method of perturbation (waist pulls) in order to evaluate the generalisability of the training effects.</p> <p>Discussion</p> <p>This study will determine whether perturbation-based balance training can help to reverse specific age-related impairments in balance-recovery reactions. These results will help to guide the development of more effective falls prevention programs, which may ultimately lead to reduced health-care costs and enhanced mobility, independence and quality of life.</p

Immature and Maturation-Resistant Human Dendritic Cells Generated from Bone Marrow Require Two Stimulations to Induce T Cell Anergy In Vitro

Immature dendritic cells (DC) represent potential clinical tools for tolerogenic cellular immunotherapy in both transplantation and autoimmunity. A major drawback in vivo is their potential to mature during infections or inflammation, which would convert their tolerogenicity into immunogenicity. The generation of immature DC from human bone marrow (BM) by low doses of GM-CSF (lowGM) in the absence of IL-4 under GMP conditions create DC resistant to maturation, detected by surface marker expression and primary stimulation by allogeneic T cells. This resistence could not be observed for BM-derived DC generated with high doses of GM-CSF plus IL-4 (highGM/4), although both DC types induced primary allogeneic T cell anergy in vitro. The estabishment of the anergic state requires two subsequent stimulations by immature DC. Anergy induction was more profound with lowGM-DC due to their maturation resistance. Together, we show the generation of immature, maturation-resistant lowGM-DC for potential clinical use in transplant rejection and propose a two-step-model of T cell anergy induction by immature DC

Long term in-vivo studies of a photo-oxidized bovine osteochondral transplant in sheep

BACKGROUND: Articular cartilage has limited capacity to repair. Defects greater than 3 mm heal with formation of inferior fibrous cartilage. Therefore, many attempts have been made to find the ideal graft for larger cartilage lesions. Different grafts, such as untreated or cryopreserved osteochondral transplants, have been used with variable success. METHODS: Photo-oxidized osteochondral grafts were implanted in both femoral condyles of one ovine knee. Untreated xenogeneic and autogeneic grafts served as controls. Three groups of 8 sheep each were formed and they were sacrificed 6, 12 or 18 months after surgery. RESULTS: The macroscopic evaluation of the condyle and graft showed a well-maintained cartilage surface in most grafts at all time points. However, the host cartilage matrix deteriorated considerably in all xenogeneic, most autogeneic and fewer of the photo-oxidized grafts at 12 and 18 months, respectively. The blue colour of the photo-oxidized grafts resulting from the process of photo-oxidation was visible in all grafts at 6 months, had diminished at 12 months and had completely disappeared at 18 months after surgery. Histologically a loss of matrix staining was almost never noticed in untreated xenografts, transiently at 6 months in photo-oxidized grafts and increased at 12 and 18 months. Fusion between graft and host cartilage could be seen in photo-oxidized grafts at 12 and 18 months, but was never seen in autografts and xenografts. CONCLUSIONS: The photo-oxidation of osteochondral grafts and its use as transplant appears to have a beneficial effect on cartilage and bone remodelling. Osteochondral grafts pre-treated with photo-oxidation may be considered for articular cartilage replacement and therefore may delay artificial joint replacements in human patients

Monitoring of total positive end-expiratory pressure during mechanical ventilation by artificial neural networks

Ventilation treatment of acute lung injury (ALI) requires the application of positive airway pressure at the end of expiration (PEEPapp) to avoid lung collapse. However, the total pressure exerted on the alveolar walls (PEEPtot) is the sum of PEEPapp and intrinsic PEEP (PEEPi), a hidden component. To measure PEEPtot, ventilation must be discontinued with an end-expiratory hold maneuver (EEHM). We hypothesized that artificial neural networks (ANN) could estimate the PEEPtot from flow and pressure tracings during ongoing mechanical ventilation. Ten pigs were mechanically ventilated, and the time constant of their respiratory system (τRS) was measured. We shortened their expiratory time (TE) according to multiples of τRS, obtaining different respiratory patterns (Rpat). Pressure (PAW) and flow (V′AW) at the airway opening during ongoing mechanical ventilation were simultaneously recorded, with and without the addition of external resistance. The last breath of each Rpat included an EEHM, which was used to compute the reference PEEPtot. The entire protocol was repeated after the induction of ALI with i.v. injection of oleic acid, and 382 tracings were obtained. The ANN had to extract the PEEPtot, from the tracings without an EEHM. ANN agreement with reference PEEPtot was assessed with the Bland–Altman method. Bland Altman analysis of estimation error by ANN showed −0.40 ± 2.84 (expressed as bias ± precision) and ±5.58 as limits of agreement (data expressed as cmH2O). The ANNs estimated the PEEPtot well at different levels of PEEPapp under dynamic conditions, opening up new possibilities in monitoring PEEPi in critically ill patients who require ventilator treatment

5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR1 and 5-HTR2 receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR3, 5-HTR4 and 5-HTR7 receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field