Novel genetically encoded fluorescent probes enable real-time detection of potassium in vitro and in vivo

Changes in intra-and extracellular potassium ion (K+) concentrations control many important cellular processes and related biological functions. However, our current understanding of the spatiotemporal patterns of physiological and pathological K+ changes is severely limited by the lack of practicable detection methods. We developed K+-sensitive genetically encoded, Forster resonance energy transfer-(FRET) based probes, called GEPIIs, which enable quantitative real-time imaging of K+ dynamics. GEPIIs as purified biosensors are suitable to directly and precisely quantify K+ levels in different body fluids and cell growth media. GEPIIs expressed in cells enable time-lapse and real-time recordings of global and local intracellular K+ signals. Hitherto unknown Ca2+-triggered, organelle-specific K+ changes were detected in pancreatic beta cells. Recombinant GEPIIs also enabled visualization of extracellular K+ fluctuations in vivo with 2-photon microscopy. Therefore, GEPIIs are relevant for diverse K+ assays and open new avenues for live-cell K+ imaging

Planning at the Roots: Low-income and Communities of Color in Portland, Oregon

In an effort to highlight community-planning efforts in low-income populations and communities of color, a group of Masters of Urban and Regional Planning students conducted interviews with community leaders and wrote this chapter of cases to be incorporated into ONI’s Community Involvement Handbook. These cases are meant to provide inspiration and understanding about the strengths and differences between planning approaches used in diverse communities working outside of the neighborhood association structure. This chapter may also help to inform opportunities for neighborhood associations and other organizations to better collaborate with diverse community groups

Effects of working memory training in patients with Parkinson's disease without cognitive impairment: A randomized controlled trial

Objective: To determine the feasibility and evaluate effects of a computerized working memory (WM) training (WMT) in patients with Parkinson's Disease (PD) on cognitive and clinical outcomes. Methods: 76 patients with PD without cognitive impairment were randomized to either the WMT group (n = 37), who participated in a 5-week adaptive WMT, or a passive waiting-list control group (CG, n = 39). Patients underwent clinical and neuropsychological examination at baseline, after training, and at 3-months follow-up, with verbal WM and non-verbal WM as primary outcomes. Outcome assessors were blinded for group allocation. Results: All WMT participants completed the training successfully and reported high levels of motivation for and satisfaction with the training. Repeated-measures, linear mixed-effects models revealed positive training effects for the WMT group compared to the CG in verbal working memory with a small relative effect size 0.39 [95%CI 0.05; 0.76] for the 3-months follow-up only. No other reliable training effects in cognitive and clinical variables were found for either point of time. Conclusions: In this randomized controlled trial, WMT was feasible and yielded some evidence for 3-months follow-up training gains in patients with PD. WMT might be an effective intervention to prevent cognitive decline in this patient group, however, more longitudinal studies with longer follow-up periods and more sensitive assessment tools will have to proof this concept

Predicting Working Memory Training Responsiveness in Parkinson's Disease: Both System Hardware and Room for Improvement Are Needed

Background. Patients with Parkinson's disease (PD) are highly vulnerable to develop cognitive dysfunctions, and the mitigating potential of early cognitive training (CT) is increasingly recognized. Predictors of CT responsiveness, which could help to tailor interventions individually, have rarely been studied in PD. This study aimed to examine individual characteristics of patients with PD associated with responsiveness to targeted working memory training (WMT). Methods. Data of 75 patients with PD (age: 63.99 +/- 9.74 years, 93% Hoehn & Yahr stage 2) without cognitive dysfunctions from a randomized controlled trial were analyzed using structural equation modeling. Latent change score models with and without covariates were estimated and compared between the WMT group (n = 37), who participated in a 5-week adaptive WMT, and a waiting list control group (n = 38). Results. Latent change score models yielded adequate model fit (chi(2)-test p > .05, SRMR = .95). For the near-transfer working memory composite, lower baseline performance, younger age, higher education, and higher fluid intelligence were found to significantly predict higher latent change scores in the WMT group, but not in the control group. For the far-transfer executive function composite, higher self-efficacy expectancy tended to significantly predict larger latent change scores. Conclusions. The identified associations between individual characteristics and WMT responsiveness indicate that there has to be room for improvement (e.g., lower baseline performance) and also sufficient hardware (e.g., younger age, higher intelligence) to benefit in training-related cognitive plasticity. Our findings are discussed within the compensation versus magnification account. They need to be replicated by methodological high-quality research applying advanced statistical methods with larger samples

Working memory training increases neural efficiency in Parkinson’s disease: a randomized controlled trial

Impairment of working memory and executive functions is already frequently observed in early stages of Parkinson’s disease. Improvements in working memory performance in this cohort could potentially be achieved via working memory training. However, the specific neural mechanisms underlying different working memory processes such as maintenance as opposed to manipulation are largely under-investigated in Parkinson’s disease. Moreover, the plasticity of these correlates as a function of working memory training is currently unknown in this population. Thus, the working memory subprocesses of maintenance and manipulation were assessed in 41 cognitively healthy patients with Parkinson’s disease using a newly developed working memory paradigm and functional MRI. Nineteen patients were randomized to a 5-week home-based digital working memory training intervention while the remaining patients entered a control, wait list condition. Working memory task-related activation patterns and context-dependent functional connectivity, as well as the change of these neural correlates as a function of training, were assessed. While both working memory processes activated an extended frontoparietal–cerebellar network, only the manipulation of items within working memory also recruited the anterior striatum. The intervention effect on the neural correlates was small, but decreased activation in areas relevant for working memory could be observed, with activation changes correlating with behavioural change. Moreover, training seemed to result in decreased functional connectivity when pure maintenance was required, and in a reorganization of functional connectivity when items had to be manipulated. In accordance with the neural efficacy hypothesis, training resulted in overall reduced activation and reorganized functional connectivity, with a differential effect on the different working memory processes under investigation. Now, larger trials including follow-up examinations are needed to further explore the long-term effects of such interventions on a neural level and to estimate the clinical relevance to potentially delay cognitive decline in cognitively healthy patients with Parkinson’s disease.Keywords: idiopathic Parkinson’s disease, home-based working memory training, functional magnetic resonance imaging, blood oxygen level dependent signal, functional connectivit

Cognitive Performance and Learning Parameters Predict Response to Working Memory Training in Parkinson's Disease

Background: Working memory (WM) training (WMT) is a popular intervention approach against cognitive decline in patients with Parkinson's disease (PD). However, heterogeneity in WM responsiveness suggests that WMT may not be equally efficient for all patients. Objective: The present study aims to evaluate a multivariate model to predict post-intervention verbal WM in patients with PD using a supervised machine learning approach. We test the predictive potential of novel learning parameters derived from the WMT and compare their predictiveness to other more commonly used domains including demographic, clinical, and cognitive data. Methods: 37 patients with PD (age: 64.09 +/- 8.56, 48.6% female, 94.7% Hoehn & Yahr stage 2) participated in a 5-week WMT. Four random forest regression models including 1) cognitive variables only, 2) learning parameters only, 3) both cognitive and learning variables, and 4) the entire set of variables (with additional demographic and clinical data, 'all' model), were built to predict immediate and 3-month-follow-up WM. Result: The 'all' model predicted verbalWMwith the lowest root mean square error (RMSE) compared to the other models, at both immediate (RMSE = 0.184; 95%-CI=[0.184;0.185]) and 3-month follow-up (RMSE = 0.216; 95%-CI=[0.215;0.217]). Cognitive baseline parameters were among the most important predictors in the `all' model. The model combining cognitive and learning parameters significantly outperformed the model solely based on cognitive variables. Conclusion: Commonly assessed demographic, clinical, and cognitive variables provide robust prediction of response to WMT. Nonetheless, inclusion of training-inherent learning parameters further boosts precision of prediction models which in turn may augment training benefits following cognitive interventions in patients with PD

Antalgie dans les services médico-chirurgicaux adultes. Recommandations pratiques du réseau douleur des Hôpitaux Universitaires de Genève

Guidelines for pain management in the medical and surgical departments of the Geneva University Hospitals (GUH) have been systematically developed using a multidisciplinary approach. These guidelines are aimed towards improving healthcare quality. We point to the ways the pain network of the GUH has elected to deal with the ever-increasing progression of concepts regarding pain management. This is of importance at a time when the risks related to the patients' transitions between the different departments, to the specificities of the clinical practices, and to the need for personalized care have never been so high

Effects of Home-Based Working Memory Training on Visuo-Spatial Working Memory in Parkinson's Disease: A Randomized Controlled Trial

Background: Cognitive impairment is a very frequent and severe nonmotor symptom of Parkinson's disease (PD). Early intervention in this at-risk group for cognitive decline may be crucial for long-term preservation of cognitive functions. Computerized working memory training (WMT) has been proven beneficial in non-PD patient populations, but such evidence is still needed for patients with PD. Objective: This study aimed to evaluate the effect of WMT on visuo-spatial working memory (WM) in cognitively unimpaired patients with PD. Methods: A single-blind randomized controlled trial encompassing 76 patients with PD but no cognitive impairment according to level II diagnostic criteria was conducted. Thirty-seven patients engaged in home-based adaptive WMT 5 times per week for a period of 5 weeks, whereas the remaining patients were in the waiting list arm of the study (control group [CG]). Working memory performance was evaluated using a computerized task before and after intervention and at 14-week follow-up, allowing to quantify the precision of WM on a continuous scale, ie, to test not only if an item was remembered but also how well the location of this item was retained. Results: Coincidently, the WMT group showed slightly worse WM performance compared with the CG at baseline, which was ameliorated after WMT. This training-induced effect remained stable until follow-up. Conclusion: Patients showing relatively low WM performance, despite not formally diagnosable as Parkinson's disease with mild cognitive impairment (PD-MCI), seem to benefit from home-based WMT. Thus, WMT could potentially be implemented in future trials as a time- and cost-efficient route to counteract subtle cognitive changes in early disease stages

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein β (S100β), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00–1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1β, and S100β levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies

Block of voltage-operated sodium channels by 2,6-dimethylphenol, a structural analogue of lidocaine's aromatic tail

1. The structural features that determine the state-dependent interaction of local anaesthetics with voltage-operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6-dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine. 2. The effects of 2,6-dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole-cell voltage-clamp experiments. 3. 2,6-Dimethylphenol was effective in blocking whole-cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC(50) at −70 mV holding potential was 150 and 187 μM for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at −70 mV with respect to −150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant K(d) from the inactivated state was 25 μM and 28 μM in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine. 4. Our results show that the blockade induced by 2,6-dimethylphenol retains voltage-dependency, a typical feature of lidocaine-like local anaesthetics. This is consistent with the hypothesis that the ‘aromatic tail' determines the state-dependent interaction of local anaesthetics with the sodium channel