Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, ...aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.
Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant A beta(42).
Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).
Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.
Objective:To identify the most frequent gender-specific suicide methods in Europe.Design:Proportions of seven predominant suicide methods utilised in 16 countries participating in the European ...Alliance Against Depression (EAAD) were reported in total and cross-nationally. Relative risk (RR) relating to suicide methods and gender was calculated. To group countries by pattern of suicide methods, hierarchical clustering was applied.Setting and participants:Data on suicide methods for 119 122 male and 41 338 female cases in 2000–4/5 from 16 EAAD countries, covering 52% of European population were obtained.Results:Hanging was the most prevalent suicide method among both males (54.3%) and females (35.6%). For males, hanging was followed by firearms (9.7%) and poisoning by drugs (8.6%); for females, by poisoning by drugs (24.7%) and jumping from a high place (14.5%). Only in Switzerland did hanging rank as second for males after firearms. Hanging ranked first among females in eight countries, poisoning by drugs in five and jumping from a high place in three. In all countries, males had a higher risk than females of using firearms and hanging and a lower risk of poisoning by drugs, drowning and jumping. Grouping showed that countries might be divided into five main groups among males; for females, grouping did not yield clear results.Conclusions:Research on suicide methods could lead to the development of gender-specific intervention strategies. Nevertheless, other approaches, such as better identification and treatment of mental disorders and the improvement of toxicological aid should be put in place.
Sound decision‐making relies on accurate prediction for tangible outcomes ranging from military conflict to disease outbreaks. To improve crowdsourced forecasting accuracy, we developed SAGE, a ...hybrid forecasting system that combines human and machine generated forecasts. The system provides a platform where users can interact with machine models and thus anchor their judgments on an objective benchmark. The system also aggregates human and machine forecasts weighting both for propinquity and based on assessed skill while adjusting for overconfidence. We present results from the Hybrid Forecasting Competition (HFC)—larger than comparable forecasting tournaments—including 1085 users forecasting 398 real‐world forecasting problems over 8 months. Our main result is that the hybrid system generated more accurate forecasts compared to a human‐only baseline, which had no machine generated predictions. We found that skilled forecasters who had access to machine‐generated forecasts outperformed those who only viewed historical data. We also demonstrated the inclusion of machine‐generated forecasts in our aggregation algorithms improved performance, both in terms of accuracy and scalability. This suggests that hybrid forecasting systems, which potentially require fewer human resources, can be a viable approach for maintaining a competitive level of accuracy over a larger number of forecasting questions.
Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound ...excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre- and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have receptors implicated in epilepsy and many of them are considered to participate in endogenous neuroprotective actions. Neuropeptide receptors, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic targets. Receptors of hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and receptors of some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin- releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Activation and inhibition of receptors by oral application of peptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration of peptides through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of agonists and antagonists within the central nervous system will also be discussed.
A variable number of tandem repeats (VNTR) polymorphism in exon 3 of the human dopamine D4 receptor gene (DRD4) has been associated with attention deficit hyperactivity disorder (ADHD). Rodents ...possess no analogous repeat sequence, whereas a similar tandem repeat polymorphism of the DRD4 gene was identified in dogs, horses and chimpanzees. Here, we present a genetic association study of the DRD4 VNTR and the activity-impulsivity dimension of the recently validated dog-ADHD Rating Scale. To avoid false positives arising from population stratification, a single breed of dogs (German shepherd) was studied. Two DRD4 alleles (referred to as 2 and 3a) were detected in this breed, and genotype frequencies were in Hardy-Weinberg equilibrium. For modelling distinct environmental conditions, 'pet' and 'police' German shepherds were characterized. Police German shepherds possessing at least one 3a allele showed significantly higher scores in the activity-impulsivity dimension of the dog-ADHD Rating Scale than dogs without this allele (P = 0.0180). This difference was not significant in pet German shepherds. To the best of our knowledge, this is the first report of an association between a candidate gene and a behaviour trait in dogs, and it reinforces the functional role of DRD4 exon 3 polymorphism.
Alzheimer's disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might ...prevent the onset of Alzheimer's disease. Since the early 1990s numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer's disease using meta-analyses of published studies.
A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer's disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers.
Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer's disease was 0.51 (95% Cl=0.40-0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% Cl=0.62-0.89) for 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% Cl=0.26-0.66) for the 3 studies reporting a duration of use of 2 or more years.
Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer's disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer's disease.
Vaclav Trnka from Křovice (1739-1791, in Latin: Wenzel Trnka Krzowitz) was a remarkable physician whose life serves as an example in the history of medicine by connecting major capital cities of ...Central Europe. In view of current geographical layout, he was born and brought up in the Czech Republic, graduated from University of Vienna in Austria, and was appointed Professor of the Anatomy at the newly established Faculty of Medicine of University of Nagyszombat, presently Trnava in Slovak Republic. When the University moved to Buda and later to Pest (today Budapest, Hungary), he was the first educator to introduce anatomy as a medical subject to be taught in a Hungarian medical school. He also was elected the Dean of Faculty of Medicine three times and in 1786-1787 he acted as Rector of then the Royal University of Pest. During his life, he published twenty-seven monographs dealing with different areas of clinical medicine, such as malaria (intermittent fever), diabetes, and rickets. Based on these monographs we can proclaim that Václav Trnka was a co-founder of modern infectology, diabetology and ophthalmology in Central Europe. Nowadays, artificial intelligence and bioinformatics are inseparable parts of modern health care system which help the transformation of big data into valuable knowledge. In the 18th century, Professor Trnka owned more than 3,000 scientific books and had natural, innate intelligence and wisdom which made him a real "medical polymath". As a musician, Trnka also composed sixty-one canons, two of them long wrongly considered as Mozart's work. Despite the fact that Trnka is considered to be the founder of Hungarian anatomy education and a major medical figure of the eighteenth century Central Europe, no internationally acclaimed biographical record of his life or work has so far been published in English. Therefore, we would like to reintroduce Václav Trnka both as an anatomist and medical polymath, and to give an overview of the early days of anatomy teaching in present-day Slovakia and Hungary (Fig. 1, Ref. 27). Keywords: Trnka from Křovice, anatomist, medical polymath, history of medicine.
Genetic polymorphisms in the human dopamine D4 receptor (DRD4) gene, especially the exon 3 variable number of tandem repeats (VNTR), have been related to several psychiatric disorders and personality ...traits. A homologous exon 3 VNTR has been described in dogs, and we previously showed an association between the DRD4 exon 3 polymorphism and activity/impulsivity trait in German shepherds. In this study, we present a detailed analysis of the intron 2 VNTR of the DRD4 gene. A short and a long form of the intronic variation were identified in 678 unrelated dogs from five breeds and in 22 wolves. For molecular analysis, the intron 2 region was cloned into a promoterless luciferase reporter vector that led to an elevation in transcriptional activity. Moreover, an allelic difference in promoter activity was detected, and a repressive effect of the long allele was observed. Behavioral analysis of 96 unrelated German shepherds showed a significant association between the social impulsivity endophenotype of the Greeting Test and both the exonic (P = 0.002) and the intronic (P = 0.003) VNTRs of the DRD4 gene. Moreover, an additive effect of the two polymorphisms was also shown (Spearman’s rho = 0.356, P = 0.0004). In conclusion, these results give further support to our previous findings that the DRD4 gene is associated with dog behavior. We also present molecular evidence for the functional role of the intron 2 VNTR in the canine DRD4 gene.
Various topological indices have been put forward in different studies, from biochemistry to pure mathematics. Among them, the Wiener index, the number of subtrees, and the Randić index have received ...great attention from mathematicians. In the study of extremal problems regarding these indices among trees, one interesting phenomenon is that they share the same extremal tree structures. Much effort was devoted to the study of the correlations between these various indices. In this note we provide a common characteristic (the ‘semi-regular’ property) of these extremal structures, with respect to the above mentioned indices, among trees with a given maximum degree. This observation leads to a more unified approach for characterizing these extremal structures. As an application/example, we illustrate the idea by studying the extremal trees, regarding the sum of distances between all pairs of leaves of a tree, a new index, which recently appeared in phylogenetic tree reconstruction, and the study of the neighborhood of trees.
Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported ...NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time.
Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling.
Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE epsilon4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more epsilon4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more epsilon4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an epsilon4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year; p = 0.02).
Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE epsilon4 alleles.
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