Paediatric Rheumatology Fails to Meet Current Benchmarks, a Call for Health Equity for Children Living with Juvenile Idiopathic Arthritis, Using Digital Health Technologies.

PURPOSE OF REVIEW: This critical review begins by presenting the history of Juvenile Idiopathic Arthritis (JIA) management. To move the conversation forward in addressing the current shortcomings that exist in the clinical management of children living with JIA, we argue that to date, the advancement of successful treatments for JIA has been historically slow. Factors implicated in this situation include a lack of rigorous research, JIA being considered a rare disease, and JIA's idiopathic and complex pathophysiology. RECENT FINDINGS: Despite the well-intended legislative changes to increase paediatric research, and the major advancements seen in molecular medicine over the last 30 years, globally, paediatric rheumatology services are still failing to meet the current benchmarks of best practice. Provoking questions on how the longstanding health care disparities of poor access and delayed treatment for children living with JIA can be improved, to improve healthcare outcomes. Globally, paediatric rheumatology services are failing to meet the current benchmarks of best practice. Raising awareness of the barriers hindering JIA management is the first step in reducing the current health inequalities experienced by children living with JIA. Action must be taken now, to train and well-equip the paediatric rheumatology interdisciplinary workforce. We propose, a resource-efficient way to improve the quality of care provided could be achieved by embedding digital health into clinical practice, to create an integrative care model between the children, general practice and the paediatric rheumatology team. To improve fragmented service delivery and the coordination of interdisciplinary care, across the healthcare system.

Effectiveness of eHealth and mHealth Interventions Supporting Children and Young People Living With Juvenile Idiopathic Arthritis: Systematic Review and Meta-analysis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) management aims to promote remission through timely, individualized, well-coordinated interdisciplinary care using a range of pharmacological, physical, psychological, and educational interventions. However, achieving this goal is workforce-intensive. Harnessing the burgeoning eHealth and mobile health (mHealth) interventions could be a resource-efficient way of supplementing JIA management. OBJECTIVE: This systematic review aims to identify the eHealth and mHealth interventions that have been proven to be effective in supporting health outcomes for children and young people (aged 1-18 years) living with JIA. METHODS: We systematically searched 15 databases (2018-2021). Studies were eligible if they considered children and young people (aged 1-18 years) diagnosed with JIA, an eHealth or mHealth intervention, any comparator, and health outcomes related to the used interventions. Independently, 2 reviewers screened the studies for inclusion and appraised the study quality using the Downs and Black (modified) checklist. Study outcomes were summarized using a narrative, descriptive method and, where possible, combined for a meta-analysis using a random-effects model. RESULTS: Of the 301 studies identified in the search strategy, 15 (5%) fair-to-good-quality studies met the inclusion criteria, which identified 10 interventions for JIA (age 4-18.6 years). Of these 10 interventions, 5 (50%) supported symptom monitoring by capturing real-time data using health applications, electronic diaries, or web-based portals to monitor pain or health-related quality of life (HRQoL). Within individual studies, a preference was demonstrated for real-time pain monitoring over recall pain assessments because of a peak-end effect, improved time efficiency (P=.002), and meeting children's and young people's HRQoL needs (P<.001) during pediatric rheumatology consultations. Furthermore, 20% (2/10) of interventions supported physical activity promotion using a web-based program or a wearable activity tracker. The web-based program exhibited a moderate effect, which increased endurance time, physical activity levels, and moderate to vigorous physical activity (standardized mean difference [SMD] 0.60, SD 0.02-1.18; I2=79%; P=.04). The final 30% (3/10) of interventions supported self-management development through web-based programs, or apps, facilitating a small effect, reducing pain intensity (SMD -0.14, 95% CI -0.43 to 0.15; I2=53%; P=.33), and increasing disease knowledge and self-efficacy (SMD 0.30, 95% CI 0.03-0.56; I2=74%; P=.03). These results were not statistically significant. No effect was seen regarding pain interference, HRQoL, anxiety, depression, pain coping, disease activity, functional ability, or treatment adherence. CONCLUSIONS: Evidence that supports the inclusion of eHealth and mHealth interventions in JIA management is increasing. However, this evidence needs to be considered cautiously because of the small sample size, wide CIs, and moderate to high statistical heterogeneity. More rigorous research is needed on the longitudinal effects of real-time monitoring, web-based pediatric rheumatologist-children and young people interactions, the comparison among different self-management programs, and the use of wearable technologies as an objective measurement for monitoring physical activity before any recommendations that inform current practice can be given.

Validation of an Electronic Visual Analog Scale mHealth Tool for Acute Pain Assessment: Prospective Cross-Sectional Study.

BACKGROUND: Accurate measurement of pain is required to improve its management and in research. The visual analog scale (VAS) on paper format has been shown to be an accurate, valid, reliable, and reproducible way to measure pain intensity. However, some limitations should be considered, some of which can be implemented with the introduction of an electronic VAS version, suitable to be used both in a tablet and a smartphone. OBJECTIVE: This study aimed to validate a new method of recording pain level by comparing the traditional paper VAS with the pain level module on the newly designed Interactive Clinics app. METHODS: A prospective observational cross-sectional study was designed. The sample consisted of 102 participants aged 18 to 65 years. A Force Dial FDK 20 algometer (Wagner Instruments) was employed to induce mild pressure symptoms on the participants' thumbs. Pain was measured using a paper VAS (10 cm line) and the app. RESULTS: Intermethod reliability estimated by ICC(3,1) was 0.86 with a 95% confidence interval of 0.81 to 0.90, indicating good reliability. Intramethod reliability estimated by ICCa(3,1) was 0.86 with a 95% confidence interval of 0.81 to 0.90, also indicating good reliability. Bland-Altman analysis showed a difference of 0.175 (0.49), and limits of agreement ranged from -0.79 to 1.14. CONCLUSIONS: The pain level module on the app is highly reliable and interchangeable with the paper VAS version. This tool could potentially help clinicians and researchers precisely assess pain in a simple, economic way with the use of a ubiquitous technology.

Comparison of a Mobile Health Electronic Visual Analog Scale App With a Traditional Paper Visual Analog Scale for Pain Evaluation: Cross-Sectional Observational Study.

BACKGROUND: Accurate quantification of pain in a clinical setting is vital. The use of an electronic pain scale enables data to be collected, analyzed, and utilized much faster compared with traditional paper-based scales. The advancement of smart technology in pediatric and adult pain evaluation may offer opportunities to introduce easy-to-use and reliable pain assessment methods within different clinical settings. If promptly introduced within different pediatric and adult pain clinic services, validated and easily accessible mobile health pain apps may lead to early pain detection, promoting improvement in patient's quality of life and leading to potentially less time off from school or work. OBJECTIVE: This cross-sectional observational study aimed to investigate the interchangeability of an electronic visual analog scale (eVAS) app with a traditional paper visual analog scale (pVAS) among Australian children, adolescents, and adults for pain evaluation. METHODS: Healthy participants (age range 10-75 years) were recruited from a sporting club and a secondary school in Melbourne (Australia). The data collection process involved application of pressure (8.5 kg/cm2) from a Wagner Force Dial FDK 20 to the midpoint of the thumb. The pressure was applied twice with a 5-minute interval. At each pressure application, participants were asked to randomly record their pain perception using the "eVAS" accessible via the "Interactive Clinics" app and the traditional pVAS. Statistical analysis was conducted to determine intermethod and intramethod reliabilities. RESULTS: Overall, 109 healthy participants were recruited. Adults (mean age 42.43 years, SD 14.50 years) had excellent reliability, with an intraclass correlation coefficient (ICC) of 0.94 (95% CI 0.91-0.96). Children and adolescents (mean age 13.91 years, SD 2.89 years) had moderate-to-good intermethod and intramethod reliabilities, with an ICC of 0.80 (95% CI 0.70-0.87) and average ICC of 0.80 (95% CI 0.69-0.87), respectively. CONCLUSIONS: The eVAS app appears to be interchangeable compared with the traditional pVAS among children, adolescents, and adults. This pain evaluation method may offer new opportunities to introduce user-friendly and validated pain assessment apps for patients, clinicians, and allied health professionals.

A neurocognitive approach for recovering upper extremity movement following subacute stroke: a randomized controlled pilot study.

[Purpose] This study aims to describe a protocol based on neurocognitive therapeutic exercises and determine its feasibility and usefulness for upper extremity functionality when compared with a conventional protocol. [Subjects and Methods] Eight subacute stroke patients were randomly assigned to a conventional (control group) or neurocognitive (experimental group) treatment protocol. Both lasted 30 minutes, 3 times a week for 10 weeks and assessments were blinded. Outcome measures included: Motor Evaluation Scale for Upper Extremity in Stroke Patients, Motricity Index, Revised Nottingham Sensory Assessment and Kinesthetic and Visual Imagery Questionnaire. Descriptive measures and nonparametric statistical tests were used for analysis. [Results] The results indicate a more favorable clinical progression in the neurocognitive group regarding upper extremity functional capacity with achievement of the minimal detectable change. The functionality results are related with improvements on muscle strength and sensory discrimination (tactile and kinesthetic). [Conclusion] Despite not showing significant group differences between pre and post-treatment, the neurocognitive approach could be a safe and useful strategy for recovering upper extremity movement following stroke, especially regarding affected hands, with better and longer lasting results. Although this work shows this protocol's feasibility with the panel of scales proposed, larger studies are required to demonstrate its effectiveness.

Development and Delivery of an Integrated Digital Health Care Approach for Children With Juvenile Idiopathic Arthritis: Usability Study.

Background: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder with no cure. Most children are prescribed several medications aimed at controlling disease activity, managing symptoms, and reducing pain. Physical activity is also encouraged to retain musculoskeletal function. The primary determinants of treatment success are maintaining long-term adherence, ongoing monitoring by a pediatric rheumatologist, and involvement of an interdisciplinary team. To support these goals, a new digital intervention was developed, InteractiveClinics, which aimed to prompt children to take their medications, report pain levels, and increase their physical activity. Objective: This study aims to evaluate the usability of InteractiveClinics among children with JIA. Methods: As part of this pediatric cross-sectional study, 12 children were asked to wear a smartwatch for 2 weeks, which was synchronized to the InteractiveClinics phone app and web-based platform. Personalized notifications were sent daily to the watch and phone, to prompt and record medication adherence and pain level assessment. Physical activity was automatically recorded by the watch. At the end of the study, all children and parents completed a postintervention survey. Written comments were also encouraged to gain further feedback. Descriptive statistics were used to summarize the survey results, and all qualitative data underwent thematic analysis. Results: Twelve children aged 10 to 18 years (mean 14.2, SD 3.1 years; female: n=8, 66.7%) and 1 parent for each child (n=12; female: n=8, 66.7%) were enrolled in the study. Based on the highest and lowest agreement areas of the survey, most children and parents liked the smartwatch and web-based platform; they found it easy to learn and simple to use. They were also satisfied with the pain and physical activity module. However, usability and acceptability barriers that hindered uptake were identified in the phone app and medication module. Children required a unique in-app experience, and their suggestive improvements included more personalization within the app; simplification by removing all links not relevant to antirheumatic medications; flexibility in response times; improved conferment through gamification; additional comment fields for the input of more data, such as medication side effects or pain-related symptoms; more detailed graphical illustrations of the physical activity module, including a breakdown of metrics; and importantly, interconnections between modules, because medication adherence, pain levels, and physical activity can each influence the other. They were, overall, improving usefulness for children and parents. Conclusions: The usability of InteractiveClinics was positive. Children and parents liked the watch and web-based platform and were satisfied with the pain and physical activity module. However, children wanted a unique in-app experience through more personalization, simplification, flexibility, conferment, comment fields, graphical illustrations, a breakdown of metrics, and interconnections. Certainly, inclusions are needed to promote user adoption and advancement of new validated digital health interventions in pediatric rheumatology, to support the delivery of integrated care.

Using Digital Health Technologies to Monitor Pain, Medication Adherence and Physical Activity in Young People with Juvenile Idiopathic Arthritis: A Feasibility Study.

Juvenile idiopathic arthritis can be influenced by pain, medication adherence, and physical activity. A new digital health intervention, InteractiveClinics, aims to monitor these modifiable risk factors. Twelve children, aged 10 to 18 years, received daily notifications on a smartwatch to record their pain levels and take their medications, using a customised mobile app synchronised to a secure web-based platform. Daily physical activity levels were automatically recorded by wearing a smartwatch. Using a quantitative descriptive research design, feasibility and user adoption were evaluated. The web-based data revealed the following: Pain: mean app usage: 68% (SD 30, range: 28.6% to 100%); pain score: 2.9 out of 10 (SD 1.8, range: 0.3 to 6.2 out of 10). Medication adherence: mean app usage: 20.7% (SD, range: 0% to 71.4%), recording 39% (71/182) of the expected daily and 37.5% (3/8) of the weekly medications. Pro-re-nata (PRN) medication monitoring: 33.3% (4/12), one to six additional medications (mean 3.5, SD 2.4) for 2-6 days. Physical activity: watch wearing behaviour: 69.7% (439/630), recording low levels of moderate-to-vigorous physical activity (mean: 11.8, SD: 13.5 min, range: 0-47 min). To conclude, remote monitoring of real-time data is feasible. However, further research is needed to increase adoption rates among children.

Cognitive Profile and Cardiovascular Risk Factors in Older Adults with Mild Cognitive Impairment.

The prevalence of cardiovascular risk factors (CVRFs) in the older adults population and their specific impact on their cognitive profiles still requires further research. For this purpose, a cross-sectional study was carried out to describe the presence of CVRFs and their association with cognitive performance in a sample of older adults (65-85 years old) with Mild Cognitive Impairment (MCI). Participants (n = 185) were divided into three groups concerning their cardiovascular risk level determined by the presence of different CVRFs, including Type 2 Diabetes (T2D), dyslipidemia, hypertension, and obesity. The primary outcome measures were the participant's scores in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sociodemographic, clinical, and psychosocial data were collected. Non-parametrical statistical analyses and effect sizes were calculated. Findings revealed that a greater presence of CVRFs was not associated with a worse overall cognitive performance. High-risk patients were more likely to have significantly worse performance in the attentional domain compared to medium-risk (p = 0.029, r = 0.42) and compared to low-risk (p = 0.041, r = 0.35), specifically in the digits repetition subtest (p = 0.042). T2D alone was the CVRF associated with cognitive differences (p = 0.037, r = 0.32), possibly mediated by the duration of the condition. Consequently, a higher presence of CVRFs did not lead to a worse overall cognitive performance. However, high-risk individuals were more likely to experience cognitive impairment, particularly in the attentional domain. T2D played a significant role in these cognitive profile differences, possibly influenced by its duration.

The Clinical Impact of Flash Glucose Monitoring-a Digital Health App and Smartwatch Technology in Patients With Type 2 Diabetes: Scoping Review.

BACKGROUND: Type 2 diabetes has a growing prevalence and confers significant cost burden to the health care system, raising the urgent need for cost-effective and easily accessible solutions. The management of type 2 diabetes requires significant commitment from the patient, caregivers, and the treating team to optimize clinical outcomes and prevent complications. Technology and its implications for the management of type 2 diabetes is a nascent area of research. The impact of some of the more recent technological innovations in this space, such as continuous glucose monitoring, flash glucose monitoring, web-based applications, as well as smartphone- and smart watch-based interactive apps has received limited attention in the research literature. OBJECTIVE: This scoping review aims to explore the literature available on type 2 diabetes, flash glucose monitoring, and digital health technology to improve diabetic clinical outcomes and inform future research in this area. METHODS: A scoping review was undertaken by searching Ovid MEDLINE and CINAHL databases. A second search using all identified keywords and index terms was performed on Ovid MEDLINE (January 1966 to July 2021), EMBASE (January 1980 to July 2021), Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, latest issue), CINAHL (from 1982), IEEE Xplore, ACM Digital Libraries, and Web of Science databases. RESULTS: There were very few studies that have explored the use of mobile health and flash glucose monitoring in type 2 diabetes. These studies have explored somewhat disparate and limited areas of research, and there is a distinct lack of methodological rigor in this area of research. The 3 studies that met the inclusion criteria have addressed aspects of the proposed research question. CONCLUSIONS: This scoping review has highlighted the lack of research in this area, raising the opportunity for further research in this area, focusing on the clinical impact and feasibility of the use of multiple technologies, including flash glucose monitoring in the management of patients with type 2 diabetes.

Emerging Tools to Capture Self-Reported Acute and Chronic Pain Outcome in Children and Adolescents: A Literature Review.

The advancement of digital health provides strategic and cost-effective opportunities for the progression of health care in children and adolescents. It is important for clinicians to be aware of the potential of emerging pain outcome measures and employ evidence-based tools capable of reliably tracking acute and chronic pain over time. The main emerging pain outcome measures for children and adolescents were examined. Overall, seven main texts and their corresponding digital health technologies were included in this study. The main findings indicated that the use of emerging digital health is able to reduce recall bias and can improve the real time paediatric data capture of acute and chronic symptoms. This literature review highlights new developments in pain management in children and adolescents and emphasizes the need for further research to be conducted on the use of emerging technologies in pain management. This may include larger scale, multicentre studies to further assess validity and reliability of these tools across various demographics. The privacy and security of mHealth data must also be carefully evaluated when choosing health applications that can be introduced into daily clinical settings.

Usability of eHealth and Mobile Health Interventions by Young People Living With Juvenile Idiopathic Arthritis: Systematic Review.

BACKGROUND: Considering the changing landscape of internet use and rising ownership of digital technology by young people, new methods could be considered to improve the current model of juvenile idiopathic arthritis (JIA) management. OBJECTIVE: This systematic review aims to evaluate the usability of eHealth and mobile health (mHealth) interventions currently available for young people living with JIA. METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used to oversee this review. We systematically searched 15 databases for 252 potential studies; 2 authors independently screened all quantitative studies reporting the use of eHealth and mHealth interventions for young people (aged 1-18 years) diagnosed with JIA. Studies were excluded if they did not report outcome measures or were reviews, commentaries, or qualitative studies. Study methodological quality was scored using the Down and Black (modified) checklist. A narrative descriptive methodology was used to quantify the data because of heterogeneity across the studies. RESULTS: A total of 11 studies were included in this review, reporting 7 eHealth and mHealth interventions for young people (aged 4-18 years) living with JIA, targeting health issues such as pain, health-related quality of life, physical activity, and chronic disease self-management. The usability of the interventions was facilitated through training and ongoing support. The engagement was promoted by a combination of persuasive influences, and barriers preventing adherence were removed through personal reminders and flexible program schedules to cater to JIA and non-JIA illnesses or other commonly seen activities in childhood. The feedback obtained was that most young people and their parents liked the interventions. CONCLUSIONS: The results of this review need to be considered cautiously because of the lack of rigorous testing and heterogeneity, which limits the detailed descriptions of data synthesis. Further research is needed to consider gender differences, associated costs, and the effectiveness of the interventions on health outcomes to better support young people living with JIA.

Exploring the Effectiveness of Smart Technologies in the Management of Type 2 Diabetes Mellitus.

The global epidemic of diabetes, with increasing prevalence of type 2 diabetes (T2D), is placing a huge burden on health care management and financial systems. Unless new strategic solutions are developed, the increasing prevalence of T2D will result in a significant rise in morbidity, health care costs, and complications associated with diabetes. The introduction of smart devices in diabetes management may provide meaningful improvements in clinical outcomes, patient engagement, as well as potential cost reductions for the health care system. Future research may be capable of providing new smart and interactive solutions to the growing multidisciplinary diabetes team and, most important, to reduce the morbidity associated with T2D.

A Web-Based Platform for People With Memory Problems and Their Caregivers (CAREGIVERSPRO-MMD): Mixed-Methods Evaluation of Usability.

BACKGROUND: The increasing number of people with dementia (PwD) drives research exploring Web-based support interventions to provide effective care for larger populations. In this concept, a Web-based platform (CAREGIVERSPRO-MMD, 620911) was designed to (1) improve the quality of life for PwD, (2) reduce caregiver burden, (3) reduce the financial costs for care, and (4) reduce administration time for health and social care professionals. OBJECTIVE: The objective of this study was to evaluate the usability and usefulness of CAREGIVERSPRO-MMD platform for PwD or mild cognitive impairment (MCI), informal caregivers, and health and social care professionals with respect to a wider strategy followed by the project to enhance the user-centered approach. A secondary aim of the study was to collect recommendations to improve the platform before the future pilot study. METHODS: A mixed methods design was employed for recruiting PwD or MCI (N=24), informal caregivers (N=24), and professionals (N=10). Participants were asked to rate their satisfaction, the perceived usefulness, and ease of use of each function of the platform. Qualitative questions about the improvement of the platform were asked when participants provided low scores for a function. Testing occurred at baseline and 1 week after participants used the platform. The dropout rate from baseline to the follow-up was approximately 10% (6/58). RESULTS: After 1 week of platform use, the system was useful for 90% (20.75/23) of the caregivers and for 89% (5.36/6) of the professionals. When users responded to more than 1 question per platform function, the mean of satisfied users per function was calculated. These user groups also provided positive evaluations for the ease of use (caregivers: 82%, 18.75/23; professionals: 97%, 5.82/6) and their satisfaction with the platform (caregivers: 79%, 18.08/23; professionals: 73%, 4.36/6). Ratings from PwD were lower than the other groups for usefulness (57%, 13/23), ease of use (41%, 9.4/23), and overall satisfaction (47%, 11/23) with the platform (P<.05). Qualitative comments related to both improvements for functionality and the platform interface. CONCLUSIONS: Although caregivers and professionals were overall satisfied with the platform, further adaptations were recommended by PwD. This reiterates the importance of the involvement of end users in the development of Web-based interventions. Recommendations from users in this paper apply for the interface and functionality of a wider range of Web-based support interventions.

Harnessing interactive technologies to improve health outcomes in juvenile idiopathic arthritis.

BACKGROUND: Children and adolescents with Juvenile Idiopathic Arthritis (JIA) typically have reduced physical activity level and impaired aerobic and anaerobic exercise capacity when compared to their non-JIA counterparts. Low intensity exercise regimens appear to be safe in children with JIA and may results in improvements in overall physical function. Poor adherence to paediatric rheumatology treatment may lead to negative clinical outcomes and possibly increased disease activity. This includes symptoms such as pain, fatigue, quality of life, longer term outcomes including joint damage, as well as increase of healthcare associated costs. Low adherence to medications such as methotrexate and biological-drugs remains a significant issue for paediatric rheumatologists, with alarming reports that less than half of the children with JIA are compliant to drug-therapy. MAIN BODY: The recent advances in interactive technology resulting in a variety of wearable user-friendly smart devices may become a key solution to address important questions in JIA clinical management. Fully understanding the impact that arthritis and treatment complications have upon individual children and their families has long been a challenge for clinicians. Modern interactive technologies can be customised and accessed directly in the hands or wrists of children with JIA. These secured networks could be accessible 'live' at anytime and anywhere by the child, parents and clinicians. Multidisciplinary teams in paediatric rheumatology may benefit from adopting these technologies to better understand domains such as patient biological parameters, symptoms progression, adherence to drug-therapy, quality of life, and participation in physical activities. Most importantly the use of smart devices technologies may also facilitate more timely clinical decisions, improve self-management and parents awareness in the progression of their child's disease. Paediatric rheumatology research could also benefit from the use of these smart devices, as they would allow real-time access to meaningful data to thoroughly understand the disease-patterns of JIA, such as pain and physical activity outcomes. Data collection that typically occurs once every 1 or 3 months in the clinical setting could instead be gathered every week, day, minute or virtually live online. Arguably, few limitations in wearing such interactive technologies still exist and require further developments. CONCLUSION: Finally, by embracing and adapting these new and now highly accessible interactive technologies, clinical management and research in paediatric rheumatology may be greatly advanced.

[The motor organization of cerebral cortex and the role of the mirror neuron system. Clinical impact for rehabilitation]. / Organización motora del córtex cerebral y el papel del sistema de las neuronas espejo. Repercusiones clínicas para la rehabilitación.

The basic characteristics of Penfield homunculus (somatotopy and unique representation) have been questioned. The existence of a defined anatomo-functional organization within different segments of the same region is controversial. The presence of multiple motor representations in the primary motor area and in the parietal lobe interconnected by parieto-frontal circuits, which are widely overlapped, form a complex organization. Both features support the recovery of functions after brain injury. Regarding the movement organization, it is possible to yield a relevant impact through the understanding of actions and intentions of others, which is mediated by the activation of mirror-neuron systems. The implementation of cognitive functions (observation, image of the action and imitation) from the acute treatment phase allows the activation of motor representations without having to perform the action and it plays an important role in learning motor patterns.

N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease.

Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.

Rational modelling of the voltage-dependent K+ channel inactivation by aminopyridines.

A functional model for the in vitro inactivation of voltage-dependent K(+) channels is developed. The model expresses the activity as a function of the aminopyridine pK(a), the interaction energy with the receptor, and a quotient of partition functions. Molecular quantum similarity theory is introduced in the model to express the activity as a function of the principal components of the similarity matrix for a series of agonists. To validate the model, a set of five active (protonated) aminopyridines is considered: 2-aminopyridine, 3-aminopyridine, 4-aminoquinoleine, 4-aminopyridine, and 3,4-diaminopyridine. A regression analysis of the model gives good results for the variation of the observed activity with the overlap similarity index when pyridinic rings are superposed. The results support the validity of the model, and the hypothesis of a ligand-receptor entropy variation depending mainly on the nature of the ligand. In addition, the results suggest that the pyridinic ring must play an active role in the interaction with the receptor site. This interaction with the protonated pyridinic nitrogen can involve a cation-pi interaction or a donor hydrogen bond. The amine groups, at different relative positions of the pyridinic nitrogen, can form one or more hydrogen bonds due to the C(4) symmetry of the inner part of the pore in the K(+) channel.

Molecular Quantum Similarity Measures from Fermi hole densities: modeling Hammett sigma constants.

A new approach, based on the use of fragment Quantum Self-Similarity Measures (MQS-SM) as descriptors of electronic substituent effect in aromatic series, was proposed. The novelty of this approach consists of the fact that the corresponding MQS-SM are not derived, as usual, from ordinary density functions (DF) but from the so-called domain averaged Fermi holes. This approach was applied to the study of substituent effects on the acidobasic dissociation constants in 6 series of para-substituted aromatic carboxylic acids. It has been shown that MQS-SM calculated for each particular set of acids correlate with the Hammett substituent constants. As a consequence, the corresponding similarity measures can be used as new efficient descriptors of the substituent effect, which hopefully could replace empirical sigma constants in QSAR models.

Topological quantum similarity indices based on fitted densities: theoretical background and QSPR application.

A novel methodology to derive adjacency matrices for 3-dimensional molecules is presented in this work. These matrices, which are derived from atomic quantum similarity calculations, allow redefining several adjacency matrix-based topological indices, such as Randic, Zagreb or Chi's. The present derivation is built upon a previous work, where a simpler class of density function was used to describe the atoms composing the molecule, and the present proposal suggests using fitted atomic densities from the Atomic Shell Approximation procedure, which has been proved to appropriately reproduce, in its application space, atomic ab initio densities. The construction of such matrices as well as the derived indices are presented, along with some QSPR, where these topological indices are used as molecular descriptors for heat of formation, inhibition, and toxicity with promising results.