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Medication non-adherence is a prevalent healthcare problem with poor health outcomes and added healthcare costs. MedScrab, a gamification-based mHealth app, is the first attempt to deliver crucial life-saving medication information to patients and increase their medication adherence. The paper presents the development of MedScrab and a two-phase mixed-method usability evaluation of MedScrab. Phase I qualitatively evaluated MedScrab using a think-aloud protocol for its usability. With 51 participants, qualitative data analysis of Phase I revealed two themes: positive functionality of the app and four areas of improvement. The improvement recommendations were incorporated into MedScrab's design. Phase I also validated a widely used mHealth App Usability Questionnaire (MAUQ). Quantitative data analysis of Phase I reduced the original 18-item MAUQ scale to a 15-item scale with two factors: ease of use (4 items) and usefulness and satisfaction (11 items). Phase II surveyed 83 participants from Amazon's Mechanical Turk using a modified MAUQ. The modified MAUQ scale showed strong internal consistency (Cronbach alpha = 0.959) and high factor loadings (between 0.623 and 0.987). The study design of the usability evaluation can serve as a methodological guide for designing, evaluating, and improving mHealth apps.The usability study showed that MedScrab was perceived as ease of use (6.24 out of 7) with high usefulness and satisfaction (5.72 out of 7). The quantitative data analysis results support the use of the modified MAUQ as a valid instrument to measure the usability of the MedScrab. However, the instrument should be used with adaptation based on the app's characteristics.
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Aplicaciones Móviles , Telemedicina , Humanos , Gamificación , Proyectos de Investigación , Telemedicina/métodos , Cumplimiento de la MedicaciónRESUMEN
BACKGROUND: Little progress has been made in translating nutrigenomics knowledge into clinical counseling in the past decade. Currently, clinicians are overwhelmed by nutrigenomics information without the proper scientific guidelines on patient counseling. METHODS: In this study, we conducted a scoping review of the primary literature to assess the current evidence of nutrigenomics counseling. A literature search using PRISMA guidelines identified the current challenges and opportunities facing nutrigenomics counseling in clinical practice. RESULTS: We identified four main themes: inadequate training, lack of awareness, underdeveloped nutrigenomics counseling skills, and unreliable evidence-based practice information. Many clinicians did not have the necessary knowledge to perform nutrigenomic counseling and were unaware of the available scientific information source. Moreover, there are no guidelines in the scientific community to counsel patients on nutrigenomics testing. CONCLUSION: Opportunities exist for government and non-government entities to create an evidence-based information platform using clinical guidelines to integrate nutrigenomics knowledge from bench to bedside successfully.
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Asesoramiento Genético , Nutrigenómica , HumanosRESUMEN
Aim: To develop and assess an augmented reality tool for pharmacogenomics (PGx) education based on artificial intelligence. Materials & methods: A HoloLens application was developed using feedback from three clinical PGx-trained pharmacists. 15 Participants independently reviewed the application and assessed usability using the system usability scale (SUS). Results & conclusion: Eighteen different frames were developed. Each video module was 2-3 min for the education. The application included textual information and 3D structures of PGx concepts. The mean SUS score for 15 participants (11 pharmacy students and four pharmacists) was 83, with a standard deviation of 6.6. Results suggest that PGxKnow has the potential to bridge the gap in PGx education, further widespread utilization of PGx and boost its impact on precision medicine.
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Realidad Aumentada , Farmacogenética , Inteligencia Artificial , Humanos , Farmacogenética/educaciónRESUMEN
The aim of this study was to assess the validity of a mobile application-based self-report questionnaire in the assessment of suicidality. We developed a program for the administration of self-report components of the Suicide Ideation and Behavior Assessment Tool (SIBAT). We invited university students and trainees enrolled in a study of addictions to complete this component of the SIBAT using the program on their mobile devices or personal computer. 196 participants completed all required modules of the SIBAT, with 97 using their mobile device and 99 using their personal computer. Rates of completed questionnaires between the two groups were compared, as were the responses to the items and the total scores. There was a significant difference between proportions of scale completion in both groups, with a greater number of participants who used a personal computer to complete the scale not responding to all questions compared to participants who used a mobile device to complete the scale. Data collected via mobile device showed good concurrent validity with data collected via personal computer. A trend toward greater disclosure of suicidality was observed in the mobile device group however, replication of these findings using larger sample sizes is needed.
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Aplicaciones Móviles , Suicidio , Estudios de Factibilidad , Humanos , Autoinforme , Ideación Suicida , Encuestas y CuestionariosRESUMEN
Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients' caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.
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This study aimed to assess the internal consistency of self-report components of the Suicide Ideation and Behavior Assessment Tool (SIBAT) and validate it with relevant elements of the Mini International Neuropsychiatric Interview (MINI). The SIBAT is a newly developed instrument for the evaluation of suicidality. In this study, we invited university students and trainees participating in a study of addictions to complete the self-report component of the SIBAT as an add-on study. We evaluated the internal consistency of the self-report component of the SIBAT and validated it against the suicidality component of the MINI. Data were analysed using both complete case analysis and multiple imputation. SIBAT data were collected for 394 participants, 314 of whom had also completed the MINI. The internal consistency of modules 2, 3, and 5 of the SIBAT was high. Each item from module 5 had a statistically significant association with the corresponding item from the MINI. The sum of scores from modules 2 and 3 had a moderate correlation with the assessment of suicide risk determined by the MINI, and a strong correlation with the total score of SIBAT module 5. The completion median time of modules 2, 3 and 5 was 14.3 min.
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Intento de Suicidio , Suicidio , Humanos , Escalas de Valoración Psiquiátrica , Psicometría , Reproducibilidad de los Resultados , Autoinforme , Ideación SuicidaRESUMEN
BACKGROUND: Medication Guides consisting of crucial interactions and side effects are extensive and complex. Due to the exhaustive information, patients do not retain the necessary medication information, which can result in hospitalizations and medication nonadherence. A gap exists in understanding patients' cognition of managing complex medication information. However, advancements in technology and artificial intelligence (AI) allow us to understand patient cognitive processes to design an app to better provide important medication information to patients. OBJECTIVE: Our objective is to improve the design of an innovative AI- and human factor-based interface that supports patients' medication information comprehension that could potentially improve medication adherence. METHODS: This study has three aims. Aim 1 has three phases: (1) an observational study to understand patient perception of fear and biases regarding medication information, (2) an eye-tracking study to understand the attention locus for medication information, and (3) a psychological refractory period (PRP) paradigm study to understand functionalities. Observational data will be collected, such as audio and video recordings, gaze mapping, and time from PRP. A total of 50 patients, aged 18-65 years, who started at least one new medication, for which we developed visualization information, and who have a cognitive status of 34 during cognitive screening using the TICS-M test and health literacy level will be included in this aim of the study. In Aim 2, we will iteratively design and evaluate an AI-powered medication information visualization interface as a smartphone app with the knowledge gained from each component of Aim 1. The interface will be assessed through two usability surveys. A total of 300 patients, aged 18-65 years, with diabetes, cardiovascular diseases, or mental health disorders, will be recruited for the surveys. Data from the surveys will be analyzed through exploratory factor analysis. In Aim 3, in order to test the prototype, there will be a two-arm study design. This aim will include 900 patients, aged 18-65 years, with internet access, without any cognitive impairment, and with at least two medications. Patients will be sequentially randomized. Three surveys will be used to assess the primary outcome of medication information comprehension and the secondary outcome of medication adherence at 12 weeks. RESULTS: Preliminary data collection will be conducted in 2021, and results are expected to be published in 2022. CONCLUSIONS: This study will lead the future of AI-based, innovative, digital interface design and aid in improving medication comprehension, which may improve medication adherence. The results from this study will also open up future research opportunities in understanding how patients manage complex medication information and will inform the format and design for innovative, AI-powered digital interfaces for Medication Guides. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21659.
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Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in H2O2-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in H2O2-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.
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Exosomas , Células Madre Mesenquimatosas , Animales , Antioxidantes/metabolismo , Exosomas/metabolismo , Peróxido de Hidrógeno/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. METHODS: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. DISCUSSION: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. TRIAL REGISTRATION NUMBER: NCT03903068, pre-results.
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Depresión/etiología , Depresión/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/complicaciones , Estimulación Transcraneal de Corriente Directa , Adolescente , Adulto , Anciano , Ondas Encefálicas , Depresión/fisiopatología , Método Doble Ciego , Humanos , Persona de Mediana Edad , Seguridad del Paciente , Selección de Paciente , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/psicología , Accidente Cerebrovascular/terapia , Estimulación Transcraneal de Corriente Directa/métodos , Adulto JovenRESUMEN
Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
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Astrocitos/inmunología , Exosomas/metabolismo , Inflamación/inmunología , Células Madre Mesenquimatosas/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoquímica , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
It has been generally accepted that inflammatory responses induced by status epilepticus (SE) in the brain are associated with microglial activation. One important regulator of microglial activation is high mobility group box-1 (HMGB1) protein. HMGB1 exerts its influence on microglia via various pathways including Toll-like receptor (TLR) subtypes 2 and 4. To explore the HMGB1 role in the SE-induced microglial activation and the involvement of TLRs we conducted in vivo and ex vivo experiments using the HMGB1 antagonist BoxA. Blood-brain barrier (BBB) permeability, brain water content, hippocampal neuroinflammation and neuronal apoptosis were measured 24â¯h after the pilocarpine induction of status epilepticus (SE) in Sprague-Dawley rats treated with BoxA. In ex vivo experiments, post-SE microglia cells were isolated from the hippocampal CA1 area and subjected to lipopolysaccharide (LPS) stimulation followed by inflammatory cytokine IL-1ß and IL-6 by qPCR and HMGB1, TLR2, TLR3 by Western blotting. A significant down-regulation of IL-1ß, IL-6 and TNF-α but not HMGB1 was found in BoxA-treated compared to untreated animals. These changes were associated with decreased BBB permeability, reduced hippocampal neuronal apoptosis and reduction in hippocampal microglial activation. We conclude that BoxA-induced suppression of HMGB1-mediated neuroinflammatory responses is associated with TLR-2 and 4 down-regulation and should be explored as a potential therapeutic target.
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Proteína HMGB1/metabolismo , Estado Epiléptico/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Citocinas/metabolismo , Proteína HMGB1/antagonistas & inhibidores , Hipocampo/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Microglía/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/metabolismoRESUMEN
This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.
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Toma de Decisiones Clínicas , Sistema Enzimático del Citocromo P-450/genética , Interacciones Farmacológicas , Prescripciones de Medicamentos/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Pruebas de Farmacogenómica/normas , Variantes Farmacogenómicas , Interacciones Farmacológicas/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/enzimología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , HumanosRESUMEN
A 56-year old Chinese female was referred to an academic medical center with atypical, treatment-resistant depression that continued for approximately 3 years after her sister's death. Comprehensive evaluation including neurocognitive testing, EEG, spinal tap, HIV testing and brain MRI revealed behavioral variant of fronto-temporal dementia (bvFTD) with significant frontal and temporal lobe atrophy.This patient's unusual clinical presentation emphasizes the overlap between depression and bvFTD, and underlines the importance of prompt, accurate diagnosis to minimize often-ineffective pharmacological interventions and caregiver burnout.
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Lóbulo Frontal/patología , Demencia Frontotemporal/diagnóstico por imagen , Lóbulo Temporal/patología , Antidepresivos/uso terapéutico , Atrofia , China , Electroencefalografía , Femenino , Demencia Frontotemporal/patología , Humanos , Imagen por Resonancia Magnética , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Trastornos del Humor , Pruebas Neuropsicológicas , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition - a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term "MRI-defined vascular depression". DISCUSSION: This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal-subcortical-limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed. CONCLUSION: The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.
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Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/patología , Trastorno Depresivo/etiología , Trastorno Depresivo/patología , Anciano , Encéfalo/patología , Trastornos Cerebrovasculares/diagnóstico , Consenso , Trastorno Depresivo/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: To characterize prognostic and risk factors of central nervous system (CNS) metastases in patients with epithelial ovarian cancer (EOC). METHODS: A retrospective analysis of Xijing Hospital electronic medical records was conducted to identify patients with pathologically confirmed EOC and CNS metastases. In addition to patient demographics, tumor pathology, treatment regimens, and clinical outcomes, we compared putative cancer stem cell marker CD133 expression patterns in primary and metastatic lesions as well as in recurrent EOC with and without CNS metastases. RESULTS: Among 1366 patients with EOC, metastatic CNS lesions were present in 29 (2.1%) cases. CD133 expression in primary tumor was the only independent risk factor for CNS metastases; whilst the extent of surgical resection of primary EOC and platinum resistance were two independent factors significantly associated with time to CNS metastases. Absence of CD133 expression in primary tumors was significantly associated with high platinum sensitivity in both patient groups with and without CNS metastases. Platinum resistance and CD133 cluster formation in CNS metastases were associated with decreased survival, while multimodal therapy including stereotactic radiosurgery (SRS) for CNS metastases was associated with increased survival following the diagnosis of CNS metastases. CONCLUSIONS: These data suggest that there exist a positive association between CD133 expression in primary EOC, platinum resistance and the increased risk of CNS metastases, as well as a less favorable prognosis of EOC. The absence of CD133 clusters and use of multimodal therapy including SRS could improve the outcome of metastatic lesions. Further investigation is warranted to elucidate the true nature of the association between platinum sensitivity, CD133 expression, and the risk and prognosis of CNS metastases from EOC.
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Antígenos CD/análisis , Neoplasias del Sistema Nervioso Central/secundario , Resistencia a Antineoplásicos , Glicoproteínas/análisis , Neoplasias Glandulares y Epiteliales/química , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Péptidos/análisis , Compuestos de Platino/uso terapéutico , Antígeno AC133 , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario , Neoplasias del Sistema Nervioso Central/terapia , Terapia Combinada , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de TiempoRESUMEN
Treatment of hypertension reduces vascular dementia (VaD) risk but not all anti-hypertensive drugs (AHDs) are equally effective, suggesting drug-gene interactions. To understand this relationship, publicly accessible databases were searched for genes deregulated in VaD and their interactions with AHDs. Genes that were downregulated in association with VaD were MTHFR, SYK, AGT, and RPGRIP1L. Genes that were upregulated in VaD were MMP9 and VEGFA. TNFSF14, AR, and PHLDB2 were also associated with VaD, however, transcription or protein level changes could not be ascertained. Analysis of gene expression data suggests that AHDs differentially regulate VaD-associated genes. Information about AHD up- or downregulation of VaD-associated genes could be used as an empirical basis for the optimal selection of AHDs in clinical trials and, ultimately, for VaD prevention and treatment.
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Antihipertensivos/uso terapéutico , Genómica , Hipertensión , Enfermedades Vasculares , Animales , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Enfermedades Vasculares/etiología , Enfermedades Vasculares/genética , Enfermedades Vasculares/prevención & controlRESUMEN
Recent studies point to an association between the late-onset sporadic Parkinson's disease (PD) and single nucleotide polymorphisms (SNPs) rs1559085 and rs27852 in Ca(2+)-dependent protease calpain inhibitor calpastatin (CAST) gene. This finding is of interest since loss of CAST activity could result in over activated calpain, potentially leading to Ca(2+) dysregulation and loss of substantia nigra neurons in PD. We explored the association between CAST SNPs and late-onset sporadic PD in the Han Chinese population. The study included 615 evaluable patients (363 male, 252 female) with PD and 636 neurologically healthy controls (380 male, 256 female) matched for age, gender, ethnicity, and area of residence. PD cases were identified from the PD cohort of the Chinese National Consortium on Neurodegenerative Diseases (www.chinapd.cn). A total of 24 tag-SNPs were genotyped capturing 95% of the genetic variation across the CAST gene. There was no association found between any of the polymorphisms and PD in all models tested (co-dominant, dominant-effect and recessive-effect). Similarly, none of the common haplotypes was associated with a risk for PD. Our data do not support a significant association between the CAST gene polymorphisms and late onset sporadic PD in the Han Chinese population.
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Proteínas de Unión al Calcio/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Edad de Inicio , Anciano , Estudios de Casos y Controles , China/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos GenéticosRESUMEN
Vascular dementia (VaD) is a common dementing illness. There are no pharmacological agents with a regulatory approval for its treatment or prevention. Review of published clinical trial reports indicates that early treatment of hypertension, a risk factor for stroke, reduces VaD risk and slows progression. However, unlike stroke, treatment of hyperlipidemia with statin class drugs or treatment of blood clotting abnormalities with acetylsalicylic acid do not appear to have an effect on VaD incidence or progression. Pharmacological agents for treatment of Alzheimer's dementia (AD) such as memantine or acetylcholinesterase inhibitors have small positive effects on cognition in VaD, which are likely due to their action on co-existing AD-related neuropathology. Drug development efforts using novel approaches such as patient stratification by their genotype are needed in order to address the increasing need for effective VaD therapeutics.
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Demencia Vascular/tratamiento farmacológico , Enfermedad de Alzheimer/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Aspirina/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Cognición/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Memantina/uso terapéutico , Accidente Cerebrovascular/prevención & controlRESUMEN
Several studies have indicated that three PITX3 single nucleotide polymorphisms (SNPs), rs2281983, rs4919621 and rs3758549, are likely to be associated with Parkinson's disease (PD) in Caucasians. Some studies also suggested an age-of-onset effect. We recently reported that allele and genotype frequencies did not differ between late-onset PD (LOPD) patients and controls for all three SNPs. To extend the analysis to early-onset PD (EOPD) patients, and to test whether an age-of-onset effect exists in Chinese, we genotyped these SNPs in 290 Chinese EOPD patients using a ligase detection reaction (LDR). For all three SNPs, allele and genotype frequencies did not differ between total PD patients and controls, between LOPD patients and controls, between EOPD patients and controls, or between LOPD and EOPD patients. Our results suggest that these PITX3 SNPs do not contribute to the risk of developing PD in EOPD or LOPD in Chinese.
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Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genética , Anciano , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Abnormalities of α-synuclein (α-syn) and NMDA receptors (NMDARs) are implicated in the pathogenesis of Parkinson's disease. However, how these proteins interact with each other has not been elucidated. Here, the effect of α-syn on NMDARs was investigated by examining the alterations of surface NMDAR NR1 subunits in MES23.5 dopaminergic cells transfected with the human α-syn gene as well as in cells treated with extracellularly added human α-syn. As demonstrated previously that α-syn can enter cells in a non-endocytic manner without being degraded by the cellular proteolytic systems, the extracellularly added α-syn entered the cytoplasm of MES23.5 cells in a concentration-dependent manner. Both the α-syn-transfected cells and α-syn-treated cells exhibited increased intracellular α-syn levels and reduced surface NR1 without altering the total NR1. The α-syn-induced surface NR1 reduction was accompanied by suppression of NMDA-elicited intracellular Ca(2+) elevation and reductions of NMDA-induced caspase 3 activation and cell death, which was abolished by hypotonic shock and K(+) depletion, a procedure that blocks clathrin-mediated endocytosis, and by suppression of RAB5B expression with anti-RAB5B oligonucleotides. The data obtained provide evidence for the first time that α-syn may promote clathrin-mediated NMDAR endocytosis.