Miracle-dz/UniFAR-FTUs huggingface dataset:
Neurorehabilitation After Stroke.

Even with recent advances in reperfusion therapy, a majority of patients with stroke will experience life-changing deficits beyond the acute phase. Stroke care, therefore, does not end at the ICU, and neurorehabilitation is a crucial component on a long path toward recovery. Poststroke rehabilitation is ideally delivered in a multidisciplinary team that includes physicians, therapists, nurses, and other healthcare specialists, as well as the patients and their social network. The settings for rehabilitation vary substantially from acute stroke units or ICUs over specialized rehabilitation care centers to early supported discharge. Furthermore, there are great variations regarding the type of therapy, its duration, and intensity. The at times confusing heterogeneity of approaches in poststroke rehabilitation can, in part, be explained by ongoing changes of organizational and administrational factors, for example, the growing number or specialized inpatient and outpatient rehabilitation services, the integration of specialized rehabilitation teams earlier in the recovery and changes in reimbursement and funding policies. However, another important reason is that our understanding of mechanisms that underlie stroke recovery is still limited, and therapeutic approaches are mainly not evidence based, simply because evidence from large clinical trials is missing. In this regard, neurorehabilitation is a dynamically changing field that is increasingly expanding. Physicians, therapists, or nurses in training, therefore, have a unique opportunity to be an integral part of systematic change and to engage in research with fundamental impact on clinical practices. Here, we try to highlight new developments in neurorehabilitation after stroke. Each section starts with an important clinical question that stroke specialists will encounter and links them to recent compelling findings. For further reading, we will reference new consensus-based recommendations or underline how early career stroke specialists can make an impact.
The Learned Interpretation of Cognitive Fluency

The fluency of cognitive processes influences many judgments: Fluently processed statements are judged to be true, fluently processed instances are judged to be frequent, and fluently processed names are judged to be famous. According to a cue-learning approach, these effects of experienced fluency arise because the fluency cue is interpreted differentially in accordance with its learned validity. Two experiments tested this account by manipulating the fluency cue's validity. Fluency was manipulated by color contrast (Experiment 1) and by required mental rotation (Experiment 2). If low fluency was correlated with a required affirmative or “old” response (and high fluency with a negative or “new” response) in a training phase, participants showed a reversal of the classic pattern in the recognition phase: Low-fluency stimuli had a higher probability than high-fluency stimuli to be classified as old. Thus, the interpretation and therefore the impact of fluency depended on the cue's learned validity.
Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range 49–84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with “Naming Animals” (TUGdt NA) and “Months Backwards” (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman’s rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration.
Zinc L‐carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

Background and Aims: Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L‐carnosine, an anti‐ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG.
Mouse Glucocorticoid Receptor Phosphorylation Status Influences Multiple Functions of the Receptor Protein*

Although studies have shown that the mouse glucocorticoid receptor (mGR) contains eight phosphorylation sites (Bodwell, J. E., Ortí, E., Coull, J. M., Pappin, D. J. C., Smith, L. I., and Swift, F. (1991) J. Biol. Chem. 266, 7549-7555), the effect of phosphorylation on receptor function is unclear. We have examined the consequences of single or multiple phosphorylation site mutations on several properties of mGR including receptor expression, ligand-dependent nuclear translocation, hormone-mediated transactivation, ligand-dependent down-regulation of mGR, and receptor protein half-life. Mutations had little effect on receptor expression, subcellular distribution, ligand-dependent nuclear translocation, or on the ability to activate hormone-mediated transcription from a complex (murine mammary tumor virus) promoter. In contrast, the phosphorylation status of the mGR had a profound effect on the ability to transactivate a minimal promoter containing simple glucocorticoid response elements after hormone administration. Similarly, ligand-dependent down-regulation by glucocorticoids of both receptor mRNA and protein was abrogated in mutants containing three or more phosphorylation site alterations. Finally, we show that the phosphorylation status of mGR has a profound effect on the stability of the glucocorticoid receptor protein. Receptors containing seven or eight mutated sites have a markedly extended half-life and do not show the ligand-dependent destabilization seen with wild type receptor. These data show that receptor phosphorylation may play a crucial role in regulating receptor levels and hence control receptor functions.
Improvement of Pancreatic Islet Isolation Outcomes Using Glutamine Perfusion during Isolation Procedure

During procurement, isolation, and transplantation, islets are exposed to high levels of oxidative stress triggering a variety of signaling pathways that can ultimately lead to cell death. Glutamine is an important cellular fuel and an essential precursor for the antioxidant glutathione. The aim of this study was to examine the role of intraductal glutamine administration in facilitating recovery of isolated rat islets from pancreases subjected to a clinically relevant period of warm ischemia. Islets were isolated in Sprague-Dawley (SD) rats (n= 18 per group). Pancreata in groups 1 and 2 were procured immediately while groups 3 and 4 were subjected to 30-min warm ischemia. Groups 2 and 4 were treated intraductally with 5 mM glutamine prior to pancreatectomy. Exposure to 30-min warm ischemia significantly reduced islet yield [groups 1 & 2 (nonischemia): 503 ± 29 islets/rat vs. groups 3 & 4 (ischemia): 247 ± 26 islets/rat; p < 0.05]. Intraductal glutamine treatment significantly improved islet yield when pancreata were subjected to 30-min warm ischemia [144 ± 16 islets/rat without glutamine (group 3) vs. 343 ± 36 islets/rat with glutamine (group 4), p < 0.05]. Glutamine also significantly improved islet viability (values were 50 ± 4% in group 4 vs. 27 ± 3% in group 3, p < 0.05). Similarly, glutathione (reduced) levels were significantly elevated in both glutamine-treated groups; however, this increase was greatest in tissues exposed to ischemia (2.76 ± 0.04 nmol/mg protein in group 4 vs. 1.66 ± 0.04 nmol/mg protein in group 3, p < 0.05). Intraductal glutamine administration considerably improves the islet yield, viability, and augments endogenous glutathione levels in pancreata procured after a clinically relevant period of ischemia. Intraductal administration of glutamine at the time of digestive enzyme delivery into the harvested pancreas may represent a simple yet effective tool to improve islet yields in clinical isolations.
Role of spinal mu opioid receptors in the development of morphine tolerance and dependence.

We previously demonstrated that the spinal cord is a primary site for the development of morphine-induced tolerance and dependence. In the current investigation, we have determined the significance of mu opioid receptors in the spinal cord in tolerance and dependence induced by systemically administered morphine. Rats surgically implanted with intrathecal (i.t.) catheters were injected i.t. with various doses of beta-funaltrexamine (beta-FNA), a specific irreversible mu opioid receptor antagonist. beta-FNA (i.t.) dose-dependently antagonized morphine-induced analgesia (i.p.) with approximately one-half the potency of beta-chlornaltrexamine, a nonselective irreversible opioid receptor antagonist. Rats injected with saline i.t. 24 h before implanting morphine pellets developed a significant degree of tolerance and dependence 72 h after morphine administration. Tolerance did not develop in similarly treated animals that received i.t. injections of 4.5 nmol beta-FNA. Signs of naloxone-precipitated withdrawal were also significantly antagonized in all instances, except weight loss, in animals pretreated with beta-FNA (i.t.). We conclude that i.t. injections of beta-FNA significantly antagonized the development of tolerance and dependence induced by systemically administered morphine. Therefore, our results indicate that mu opioid receptors within the spinal cord, and probably throughout the central nervous system, play a primary role in morphine-induced tolerance and dependence.
Daily Physical Activity, Functional Capacity and Quality of Life in Patients with COPD

Abstract Introduction: In the therapy of chronic obstructive pulmonary disease (COPD), it is a major goal to improve health-related quality of life (HRQOL). Patients with COPD often suffer from exertional dyspnea and adopt a sedentary lifestyle, which could be associated with poorer HRQOL. The aim of this study was to investigate the independent association of objectively measured daily physical activity and functional capacity with HRQOL in patients with COPD. Methods: In this cross-sectional study conducted at the University Hospital Basel, Switzerland, 87 stable patients (58.6% male, mean age: 67.3 ± 9.6 yrs) with COPD in GOLD grades I (n = 23), II (n = 46), III (n = 12) and IV (n = 6) were investigated. To assess HRQOL, the COPD assessment test (CAT) was completed. Patients performed spirometry and 6-min walk test. Physical activity was measured by the SenseWear Mini Armband on 7 consecutive days. By performing a multiple linear regression analysis, independent predictors of CAT score were identified. Results: Age (β = −0.39, p = 0.001), average daily steps (β = −0.31, p = 0.033) and 6-min walk distance (β = −0.32, p = 0.019) were found to be independent predictors of CAT score, whereas physical activity duration above 3 METs (p = 0.498) and forced expiratory volume in 1 s in% of predicted (p = 0.364) showed no significant association. Conclusions: This study showed that average daily steps and functional capacity are independent determinants of HRQOL in patients with COPD. This emphasizes the importance to remain active and mobile, which is associated with better HRQOL.
Participatory design in interactive media design education for the solution of unfamiliar design problems: a case study on a disabling environment and an emerging technology

This paper investigates the effectiveness of participatory design study in rendering the students' capability of producing innovative design solutions to problems with uncertainties with which the students have no prior experience. At the project, the students were given a case to work on augmented reality technology with which they had no previous experience and design a tactical interface for sailing boats, a field they had no competence in. While the students were asked to develop proposals for this design problem with which they were inexperienced, a two-stage study was conducted to enable them to produce ideas on the topic. This paper discusses the impacts of such a participatory method in terms of design education. At the end of our study, it was observed that the students were positively influenced by the process in which they worked collaboratively with an expert user group.
A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family.

Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.
Differential immune system DNA methylation and cytokine regulation in post‐traumatic stress disorder

DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post‐traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site‐specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene‐specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress‐related illnesses. © 2011 Wiley‐Liss, Inc.
Review of Melatonin Supplementation for Sleep Disorders in Pediatric Special Populations

Objective To determine which pediatric populations, if any, benefit from exogenous melatonin supplementation. Methods PubMed was utilized for the purposes of this systematic review. The studies selected evaluated melatonin use in pediatric special populations and included randomized controlled trials, crossover studies, and meta-analyses. Each study’s objectives, measures of outcomes, and dosing strategies of melatonin were reviewed along with the results and author’s conclusions. Results Our analysis of the available data offers mixed results and recommendations with regard to the decision of whether to add supplementation of melatonin. Conclusion With further regulation of melatonin supplements, it may be plausible to hold larger, multicenter trials and come to a firm recommendation in the future. At this time, we believe that the benefit of exogenous melatonin supplementation outweighs the risks of adverse events and therefore would recommend its use in aiding patients in improving their sleep. Exogenous supplementation with melatonin should be used at the physician’s and patient’s discretion.
What is the biological reality of gene-environment interaction estimates? An assessment of bias in developmental models.

BACKGROUND Standard models used to test gene-environment interaction (G × E) hypotheses make the causal assumption that there are no unobserved variables that could be biasing the interaction estimate. Whether this assumption can be met in nonexperimental studies is unclear because the interactive biological pathways from genetic polymorphisms and environments to behavior, and the confounders that can be introduced along these pathways, are often not delineated. This is problematic in the context of studies focused on caregiver-child dyads, in which common genes and environments induce gene-environment correlation. To address the impact of sources of bias in G × E models specifically assessing the interaction between child genotype and caregiver behavior, we provide a causal framework that integrates biological and statistical concepts of G × E, and assess the magnitude of bias introduced by various confounding pathways in different causal circumstances. METHODS A simulation assessed the magnitude of bias introduced by four types of confounding pathways in different causal models. Unadjusted and adjusted statistical models were then applied to the simulated data to assess the efficacy of these procedures to capture unbiased G × E estimates. Finally, the simulation was run under null effects of the genotype to assess the impact of biasing sources on the false-positive rate. RESULTS Common environmental pathways between caregiver and child inflated G × E estimates and raised the false-positive rate. Evocative effects of the child also inflated G × E estimates. CONCLUSIONS Gene-environment interaction studies should be approached with consideration to the causal pathways at play and the confounding opportunities along these pathways to facilitate the inclusion of adequate statistical controls and correct inferences from study findings. Bridging biological and statistical concepts of G × E can significantly improve research design and the communication of how a G × E process fits into a broader developmental framework.
Tolerance to the Antinociceptive Effect of Morphine in the Absence of Short-Term Presynaptic Desensitization in Rat Periaqueductal Gray Neurons

Opioids activate the descending antinociceptive pathway from the ventrolateral periaqueductal gray (vlPAG) by both pre- and postsynaptic inhibition of tonically active GABAergic neurons (i.e., disinhibition). Previous research has shown that short-term desensitization of postsynaptic μ-opioid receptors (MOPrs) in the vlPAG is increased with the development of opioid tolerance. Given that pre- and postsynaptic MOPrs are coupled to different signaling mechanisms, the present study tested the hypothesis that short-term desensitization of presynaptic MOPrs also contributes to opioid tolerance. Twice-daily injections of morphine (5 mg/kg s.c.) for 2 days caused a rightward shift in the morphine dose-response curve on the hot plate test (D50 = 9.9 mg/kg) compared with saline-pretreated (5.3 mg/kg) male Sprague-Dawley rats. In vitro whole-cell patch-clamp recordings from vlPAG slices revealed that inhibition of evoked inhibitory postsynaptic currents (eIPSCs) by the MOPr-selective agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin was decreased in morphine-tolerant (EC50 = 708 nM) compared with saline-pretreated rats (EC50 = 163 nM). However, short-term desensitization of MOPr inhibition of eIPSCs was not observed in either saline- or morphine-pretreated rats. Reducing the number of available MOPrs with the irreversible opioid receptor antagonist, β-chlornaltrexamine decreased maximal MOPr inhibition with no evidence of desensitization, indicating that the lack of observed desensitization is not caused by receptor reserve. These results demonstrate that tolerance to the antinociceptive effect of morphine is associated with a decrease in presynaptic MOPr sensitivity or coupling to effectors, but this change is independent of short-term MOPr desensitization.
Signatures of sex: Sex differences in gene expression in the vertebrate brain

Women and men differ in disease prevalence, symptoms, and progression rates for many psychiatric and neurological disorders. As more preclinical studies include both sexes in experimental design, an increasing number of sex differences in physiology and behavior have been reported. In the brain, sex‐typical behaviors are thought to result from sex‐specific patterns of neural activity in response to the same sensory stimulus or context. These differential firing patterns likely arise as a consequence of underlying anatomic or molecular sex differences. Accordingly, gene expression in the brains of females and males has been extensively investigated, with the goal of identifying biological pathways that specify or modulate sex differences in brain function. However, there is surprisingly little consensus on sex‐biased genes across studies and only a handful of robust candidates have been pursued in the follow‐up experiments. Furthermore, it is not known how or when sex‐biased gene expression originates, as few studies have been performed in the developing brain. Here we integrate molecular genetic and neural circuit perspectives to provide a conceptual framework of how sex differences in gene expression can arise in the brain. We detail mechanisms of gene regulation by steroid hormones, highlight landmark studies in rodents and humans, identify emerging themes, and offer recommendations for future research.