Synergistic influence of cytokine gene polymorphisms over the risk of dementia: A multifactor dimensionality reduction analysis.

Objective: Evidence supports the important role of neuroinflammation in some types of dementia. This study aimed to evaluate the effect of epistasis of gene cytokines such as interleukin (IL)-α, IL-6, tumor necrosis factor (TNFα), and interferon-gamma (IFN-γ) on the susceptibility to the development of dementia. Materials and methods: In the study, 221 patients diagnosed with dementia and 710 controls were included. The multifactor-dimensionality reduction (MDR) analysis was performed to identify the epistasis between SNP located in genes of IL-α (rs1800587), IL-6 (rs1800796), TNFα (rs361525 and rs1800629), and IFNγ (rs2069705). The best risk prediction model was identified based on precision and cross-validation consistency. Results: Multifactor-dimensionality reduction analysis detected a significant model with the genes TNFα, IFNγ, IL1α, and IL6 (prediction success: 72%, p < 0.0001). When risk factors were analyzed with these polymorphisms, the model achieved a similar prediction for dementia as the genes-only model. Conclusion: These data indicate that gene-gene interactions form significant models to identify populations susceptible to dementia.

Development and validation of a questionnaire to evaluate satisfaction of the patient with diabetes at the primary care level.

Aims: To develop and validate a new instrument to measure satisfaction with integral care (doctor-nurse) of the patient with type 2 diabetes mellitus, considering expectations-experiences together for the primary level of care. Methods: The instrument was constructed with questions regarding integral care to measure the satisfaction of the diabetes patient and was classified into four domains. The validity of the content was done through a panel of experts, apparent validity through a focus group, the validity of the construct through analysis of the main components and confirmatory factorial analysis, instrument reliability with internal consistency, determined by Cronbach alpha and temporal stability (test-retest). Results: The reliability of the questionnaire was 0.942. The intraclass correlation coefficient was 0.849. Validity of the construct showed acceptable goodness-of-fit and factorial structure with four factors: communication, empathy, technical care, care continuity, and 24 items for each domain, giving a Kayser-Meyer-Olkin index above 0.80 and a total variance above 73. Conclusions: The instrument is reliable and is also valid in terms of up into construct and content to evaluate satisfaction. Practice Implications: In addition, these results allow to have elements for the design of strategies aimed at improving the relationship of health personnel with the patient.

Reduction of inappropriate prescriptions in older adults through the support of Asynchronous Geriatric Counseling Online (AGAlink): Implemented in primary care.

BACKGROUND/AIM: Medication prescription is a fundamental component in the care of the elderly. Several characteristics of aging and geriatric medicine affect prescriptions for these people and make the selection of drug therapy a difficult and complex process. The objective of this study is to develop a geriatric portal for asynchronous online counseling (AGAlink) for use by physicians specializing in family medicine to reduce medication problems among older adult patients in the first level of care. METHOD: A qualitative study was carried out in the first level of care at the Mexican Institute of Social Security (IMSS), 31 family doctors were interviewed to identify attitudes, preferences about the use of the AGAlink geriatric portal, as well as their recommendations for the implementation of this tool in their daily practice. For the analysis of the data obtained, a qualitative thematic content analysis was used. RESULTS: 90% of the physicians used the geriatric portal outside office hours without the need for the patient to be present. The perception of the physician towards the use of the AGAlink geriatric portal was favorable, provided relevant information and had several positive effects on the process of care for medical prescription. The barriers identified to accept the change in medication were not having the proposed therapeutic option, lack of any laboratory analysis, continuing to consider their experience for the prescription of the medication. CONCLUSIONS: The AGAlink geriatric portal was a tool that was well received by physicians who expressed a positive attitude, considered an investment of a short time that allowed them to update and learn about strategies to reduce the prescription problems presented among the elderly population. However, the main barrier was the use of technology, especially in the doctors with more seniority in the service.

Influence of COMT polymorphism in cognitive performance on dementia in community-dwelling elderly Mexican (SADEM study).

There is an inconsistent finding about the relationship of catechol-O-methyltransferase (COMT) with dementia susceptibility, as well as with cognitive impairment. To substantiate this, we examined COMT genotype effects in certain cognitive domains in dementia. To evaluate the effects of COMT Val158Met on cognitive performance, we used The Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) and the Syndrome Kurz Test (SKT). The results show COMT Val/Met, Val/Val genotype polymorphisms had a significant effect on cognition performance (OR = 1.75 (95 %CI 1.22-2.54) and (OR = 2.76 (95 %CI 1.78-4.26), p < 0.001), and with adjustment for all cognitive test scores together, Val/Val (OR = 4.98 (95 % CI 1.47-16.86) and Val/Met (OR = 3.62 (95 % CI 1.37-9.56) had effect. Our study allows us to understand the role of COMT in cognitive performance in dementia, as well as interaction with other known risk factors for this pathology. This data might help in developing new therapeutic targets for cognitive impairment, main symptom of dementia. Other risk genotypes or haplotypes should be evaluated to determine the association with cognitive decline in dementia.

Relationship Between Genetic Variants of ACAT1 and APOE with the Susceptibility to Dementia (SADEM Study).

One of the hypotheses that have emerged to explain the origin of dementia relates the disease with altered lipid metabolism, particularly cholesterol. To maintain cholesterol homeostasis, the ACAT1 enzyme has an important function to regulate the production of Aß. Moreover, APOE is the main cholesterol carrier in the brain, and it has been reported as a risk factor for this disease. This study evaluates the relationship between ACAT1 and APOE genetic variants with susceptibility for the development of Alzheimer's disease and other dementias. We examined four ACAT1 polymorphisms (rs2247071, rs2862616, rs3753526, rs1044925) and two in the APOE gene (rs7412, rs429358) in a group of 204 controls and 196 cases of dementia. Our results show one protective haplotype: CGCA (OR = 0.34, 95% CI = 0.23-0.46; p < 0.001) and one risk haplotype: CGGA (OR = 1.87, 95% CI = 1.34-2.60; p < 0.001) for the development of dementia. Subjects identified as APOE-ε4 allele carriers had a higher risk of developing dementia compared with non-carriers, OR = 13.33 (95% CI = 3.14-56.31). The results support the hypothesis that the ACAT1 gene, together with the APOE gene, plays an important role in susceptibility to the development of dementia and shows genetic characteristics of the Mexican population that can be used to identify the population at risk.

Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide.

Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets-GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.

Adaptation of Lorke's method to determine and compare ED50 values: the cases of two anticonvulsants drugs.

INTRODUCTION: We determined the median effective dose (ED50) values for the anticonvulsants phenobarbital and sodium valproate using a modification of Lorke's method. This modification allowed appropriate statistical analysis and the use of a smaller number of mice per compound tested. METHODS: The anticonvulsant activities of phenobarbital and sodium valproate were evaluated in male CD1 mice by maximal electroshock (MES) and intraperitoneal administration of pentylenetetrazole (PTZ). The anticonvulsant ED50 values were obtained through modifications of Lorke's method that involved changes in the selection of the three first doses in the initial test and the fourth dose in the second test. Furthermore, a test was added to evaluate the ED50 calculated by the modified Lorke's method, allowing statistical analysis of the data and determination of the confidence limits for ED50. RESULTS: The ED50 for phenobarbital against MES- and PTZ-induced seizures was 16.3mg/kg and 12.7mg/kg, respectively. The sodium valproate values were 261.2mg/kg and 159.7mg/kg, respectively. DISCUSSION: These results are similar to those found using the traditional methods of finding ED50, suggesting that the modifications made to Lorke's method generate equal results using fewer mice while increasing confidence in the statistical analysis. This adaptation of Lorke's method can be used to determine median letal dose (LD50) or ED50 for compounds with other pharmacological activities.