Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates ...in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-β resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with β1 adrenergic receptor antagonist. Conversely, β1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell β1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of β1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.
Summary
Metal‐based Golgi‐Cox (GC) staining is an established method used to visualise neurons with great morphological detail. Although GC stained samples are imaged routinely under transmitted ...light microscopy, this method is unable to yield information on the three‐dimensional structure of dendrites and neurons and thus help reveal the connective properties of the central nervous system. Although a few studies have attempted simultaneous visualisation of GC staining and antigen‐specific fluorescent labelling under a confocal reflection technique, the resolution of both confocal reflection and fluorescence modalities used to acquire GC reflection and fluorescently stained antibody signals are still limited by the diffraction limit of light at about 220 nm. Here, we report a confocal reflection super‐resolution technique (CRSR) to break this diffraction barrier, which is achieved by minimising the pinhole size from 1 airy unit (AU) to 0.1 AU. This is achieved by minimising or closing the confocal pinhole size and is possible in this reflection modality, unlike fluorescence, because it is not a photon limited technique. Utilising the lowest wavelength of light available in the system (405 nm), the CRSR technique results in ∼30% lateral and axial resolution improvement. We also show that the CRSR technique can be used in conjunction to visualise both GC and immunofluorescence targets to create precise and improved three‐dimensional visualisation and analysis. In addition, using these superresolution confocal reflection data sets from GC in CRSR mode significantly reduced the data overestimation, improving the accuracy of statistical analysis of dendritic spine density and average spine dimensions. Combining the 0.1 AU setting with deconvolution routines, the signal‐to‐noise ratio and resolution could further be improved an additional ∼20–25%, yielding CRSR images with resolutions up to 2‐fold over the diffraction limit both laterally and axially. The improved precision of both visualisation and quantification of subdiffraction limited dendritic spines using the CRSR technique may prove to be critical in investigations that concern changes in detailed neuron morphology under central nervous system disease conditions such as multiple sclerosis and Alzheimer's disease.
Lay Description
For over a century, Golgi‐Cox (GC) has been a leading staining technique in the field of neuroscience, used to visualise neurons with great morphological detail. GC stained brain or spinal cord samples are conventionally visualised under transmitted light techniques. This limits the view of Golgi‐staining to a two‐dimensional image. A recent report showed that Golgi staining can be visualised in three‐dimensions using the reflection modality of the confocal microscope. This visualisation also allows for the simultaneous acquisition of immunofluorescence signals. However, the reported resolution of Golgi staining confocal reflection is limited by the diffraction limit of light, which is around 220 nm. Here, we report a superresolution confocal reflection technique (CRSR) that achieves superresolution by minimising the pinhole size used in confocal microscopy. The CRSR technique results in ∼30% lateral and axial resolution improvement. Adding a deconvolution step in the final processing could improve the SNR and resolution even further up to 2‐fold improvement in resolution over the diffraction limit both laterally and axially. We hope that this improved visualisation will help in investigations that concern changes in detailed neuron morphology under central nervous system disease conditions such as multiple sclerosis and Alzheimer's disease.
To determine whether there is a significant correlation between the integrity of the foveal microstructures and the best-corrected visual acuity (BCVA) after pars plana vitrectomy for epiretinal ...membrane (ERM) removal.
This was a retrospective, interventional case series. Forty-six eyes of 45 patients with an ERM underwent vitrectomy. The foveal area was examined by spectral-domain-optical coherence tomography (SD-OCT) preoperatively and postoperatively. The correlation between the length of the photoreceptor cone outer segment tips (COST) line defect, the inner segment/outer segment junction (IS/OS) line defect, the external limiting membrane (ELM) line defect, and the BCVA was determined.
The length of the COST line defect was significantly correlated with the BCVA at postoperative 1, 3, 6, 9, and 12 months (P < 0.001 for all). Forward stepwise regression analyses showed that the postoperative BCVA was significantly correlated with the length of COST line defect (P < 0.001) but not with the IS/OS line and ELM line defects for up to 6 months. The preoperative length of the COST line defect was significantly correlated with the postoperative BCVA at 12 months (P = 0.005), but the lengths of the IS/OS line defect and ELM line defect were not. The factor that best predicted the postoperative BCVA was the length of the preoperative COST line defect (P = 0.04) but not the preoperative BCVA (P = 0.69).
The recovery of the foveal COST line defect is correlated with the BCVA after ERM surgery. The length of the preoperative COST line defect can predict the potential foveal function. (ClinicalTrials.gov number, NCT01549249.).
Side-effects of medications cause xerostomia. There have been cases where a medication has been discontinued owing to its severe side-effects. Therefore, the xerostomia must be treated to ensure that ...the primary disease is managed effectively. This study analyzed the actual status of patients with medication-induced xerostomia and investigates factors associated with its improvement.
This study assessed 490 patients diagnosed with medication-induced xerostomia who had an unstimulated salivary flow of ≤0.1 mL/min and received treatment for xerostomia at a xerostomia clinic. Patient age, sex, medical history, medications used, disease duration of xerostomia, and psychological disorders were recorded. The anticholinergic burden was assessed using the Anticholinergic Cognitive Burden scale. The unstimulated salivary flow was measured by the spitting method. According to their symptoms and diagnoses, the patients were introduced to oral lubricants, instructed on how to perform massage, and prescribed Japanese herbal medicines, and sialogogues. Factors associated with the subjective improvement of xerostomia and objective changes in the salivary flow rate were recorded at six months.
Xerostomia improved in 338 patients (75.3%). The improvement rate was significantly lower in patients with psychiatric disorders (63.6%) (P = 0.009). The improvement rate decreased as more anticholinergics were used (P = 0.018). However, xerostomia improved in approximately 60% of patients receiving three or more anticholinergics. The unstimulated salivary flow increased significantly more in patients who reported an improvement of xerostomia (0.033±0.053 mL/min) than in those who reported no improvement (0.013±0.02 mL/min) (P = 0.025).
Xerostomia treatment improved oral dryness in 75.3% of patients receiving xerogenic medications in this study. If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the quality of life of patients with xerogenic medications and may reduce the number of patients who discontinue medications.
Dysphagia Rehabilitation in Japan INOUE, Makoto
Journal of Nutritional Science and Vitaminology,
2015, Letnik:
61, Številka:
Supplement
Journal Article
Recenzirano
Odprti dostop
In Japan, one of the most common causes of death in elderly people is aspiration pneumonia. Maintenance of oral hygiene and feeding functions are important elements, especially in patients with ...dysphagia caused by stroke, neurological diseases, and after operations on the head and neck cancer, as well as in the elderly to prevent aspiration pneumonia. It should also be noted that not only oral health care and physical therapy related to feeding functions but also dental treatment is included in the clinical management during interventions whenever needed. On the other hand, for the patients and/or elderly in need of assistance in maintaining a safe diet, it is recommended that a specialized team comprising physicians, dentists, and speech therapists in functional rehabilitation observes meal conditions of the subjects and evaluates such factors as meal contents, posture during meals, usage of dishes and cutlery, meal times, status of consciousness, perception, and motivation. First, I will present the clinical interventions to those patients, which include oral health care, dental treatment, physical therapy and meal assistance, as well as team approaches in those circumstances. In addition, clinical and basic research results will be introduced, which are expected to foster the understanding of physiology in chewing and swallowing. These results are also expected to develop the clinical technology to maintain or recover the feeding functions.
The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune ...system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4⁺ T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to upregulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3⁻/⁻ and Asc⁻/⁻ mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.
Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand, TNF-related apoptosis-inducing ligand (TRAIL), and a combination of ...TRAIL and agents that increase the expression of DR5 is expected to be a novel anticancer therapy. In this report, we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of activating transcription factor 4 (ATF4)-CCAAT enhancer-binding protein (C/EBP) homologous protein, which were remarkably suppressed by reactive oxygen species scavengers. In the absence of ATF3, the induction of DR5 mRNA and protein was abrogated significantly, and this was associated with reduced cell death by cotreatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused a more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. Taken together, our results provide novel insights into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB treatment, and this may be a useful biomarker for TRAIL-based anticancer therapy.
Background: Death receptor 5 (DR5) triggers cell death upon binding to its ligand TRAIL.
Results: ATF3 promotes DR5 induction and apoptotic cell death upon zerumbone or celecoxib treatment in human p53-deficient colorectal cancer cells.
Conclusion: ATF3 is an essential transcription factor for p53-independent DR5 induction through the ROS-ER stress pathway.
Significance: ATF3 may be a useful biomarker for TRAIL-based anticancer therapy.
The velocity field of the M87 jet from milli-arcsecond (mas) to arcsecond scales is extensively investigated together with new radio images taken from European VLBI Network (EVN) observations. We ...detected proper motions of components located at between 160 mas from the core and the HST-1 complex for the first time. Newly derived velocity fields exhibit a systematic increase from sub- to superluminal speeds in the upstream of HST-1. If we assume that the observed velocities reflect the bulk flow, here we suggest that the M87 jet may be gradually accelerated through a distance of 10 super(6) times the Schwarzschild radius of the supermassive black hole. The acceleration zone is co-spatial with the jet parabolic region, which is interpreted as the collimation zone of the jet. The acceleration and collimation take place simultaneously, which we suggest is characteristic of magnetohydrodynamic flows. The distribution of the velocity field has a peak at HST-1, which is considered as the site of over-collimation, and shows a deceleration downstream of HST-1 where the jet is conical. Our interpretation of the velocity map in the M87 jet provides a hypothesis for active galactic nuclei which suggests that the acceleration and collimation zone of relativistic jets extends over the whole scale within the sphere of influence of the supermassive black hole.
After the first report of induced pluripotent stem cells (iPSCs), considerable efforts have been made to develop more efficient methods for generating iPSCs without foreign gene insertions. Here we ...show that Sendai virus vector, an RNA virus vector that carries no risk of integrating into the host genome, is a practical solution for the efficient generation of safer iPSCs. We improved the Sendai virus vectors by introducing temperature-sensitive mutations so that the vectors could be easily removed at nonpermissive temperatures. Using these vectors enabled the efficient production of viral/factor-free iPSCs from both human fibroblasts and CD34+ cord blood cells. Temperature-shift treatment was more effective in eliminating remaining viral vector-related genes. The resulting iPSCs expressed human embryonic stem cell markers and exhibited pluripotency. We suggest that generation of transgene-free iPSCs from cord blood cells should be an important step in providing allogeneic iPSC-derived therapy in the future.
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