Preventive medication use among persons with limited life expectancy

Persons with limited life expectancy (LLE) – less than 1 year – are significant consumers of health care, are at increased risk of polypharmacy and adverse drug events, and have dynamic health statuses. Therefore, medication use among this population must be appropriate and regularly evaluated. The objective of this review is to assess the current state of knowledge and clinical practice presented in the literature regarding preventive medication use among persons with LLE. We searched Medline, Embase, and CINAHL using Medical Subject Headings. Broad searches were first conducted using the terms ‘terminal care or therapy’ or ‘advanced disease’ and ‘polypharmacy’ or ‘inappropriate medication’ or ‘preventive medicine’, followed by more specific searches using the terms ‘statins’ or ‘anti-hypertensives’ or ‘bisphosphonates’ or ‘laxatives’ and ‘terminal care’. Frameworks to assess appropriate versus inappropriate medications for persons with LLE, and the prevalence of potentially inappropriate medication use among this population, are presented. A considerable proportion of individuals with a known terminal condition continue to take chronic disease preventive medications until death despite questionable benefit. The addition of palliative preventive medications is advised. There is an indication that as death approaches the shift from a curative to palliative goal of care translates into a shift in medication use. This literature review is a first step towards improving medication use and decreasing polypharmacy in persons at the end of life. There is a need to develop consensus criteria to assess appropriate versus inappropriate medication use, specifically for individuals at the end of life

Lithium as a positive modulator of defective WNT pathway in Cornelia de Lange Syndrome models

The cohesin complex is a multimeric system, highly conserved in the course of cellular evolution from the most primitive life forms to human cells. Cohesins are essential Structural Maintenance of Chromosomes (SMC), protein-containing complexes that interact with chromatin and modulate chromatin organization and gene expression. Genetic variants that cause structural and/or functional alterations induce an array of congenital pathologies named "cohesinopathies". It is believed that such malformations arise from deregulation of pivotal developmental molecular pathways. Canonical WNT pathway has been shown to be perturbed in association with central nervous system malformation in Cornelia de Lange Syndrome (CdLS), one of the most characterized cohesinopathy. In this study, we validated the relevance of canonical WNT pathway and assess the effect of LiCl-dependent activation of WNT pathway in three CdLS experimental models: Lymphoblastoid cell lines from patients, murine Neural Stem Cells (NSCs) and Drosophila melanogaster. Methods Lymphoblastoid cells (immortalized lines from CdLS patients) of patients carrying mutations of NIPBL or HDAC8 genes and healthy donors were used in these studies. These cells were treated with LiCl 1mM, 2,5mM and 5mM, and vehicle and proliferation rate were measured. Proliferation and differentiation capabilities were also assessed in CdLS NSCs upon LiCl treatment. Flies were grown upon food added with a different concentration of LiCl. Drosophila brains were analyzed for morphological evaluation. Results and conclusions Preliminary data on lymphoblastoid cells showed no effects on cell death rate in healthy donor following LiCl treatment. And, although with a patient-specific response, LiCl appeared to induce an increase in proliferation, especially in cell lines that were slow-growing compared to controls. NSCs showed reduced NSCs proliferation rate and differentiating capabilities. The presence of lithium could reduce the detrimental effects in a significant way. Drosophila mutants for nipped-B gene, the ortholog of human NIPBL, display malformations in mushroom bodies (MB), a structure involved in olfactory learning and memory. Treating subsequent generation of flies with 100mM of LiCl, MB morphology was restored in the offspring. All these data further confirm the hypothesis that in \u201ccohesinophaties\u201d is present an impairment of WNT pathway that could, in part, explain the typical neurodevelopmental alterations of this syndrome. Moreover, these studies could pave the way for future therapeutic strategies

Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β

We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as \u201cwriter\u201d of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann\u2013Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein\u2013Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions

Experience with The ABC Foundation School of Medicine Undergraduate Meeting

OBJECTIVE: To quantify the number of studies that were presented during oral sessions, selected for awards and published from 2002 to 2007 at the Undergraduate Medical Congress of ABC at the ABC Foundation School of Medicine. METHODS: A retrospective systematic survey of papers selected for oral presentation and award at these undergraduate meeting from 2002 to 2007 was carried out by searching Medline and Lilacs databases and the annals of other medical meetings in order to ascertain which papers would eventually be published. RESULTS: From 2002 to 2007, 408 papers were selected for oral presentation and 71 (17.4%) received at least one award. The total number of papers published was 138 (33.8%), of which 33 (8.1%) were in Medline, 57 (14%) in Lilacs and 48 (11.7%) in the annals of other scientific meetings. Receiving an award by the scientific committee was an independent variable for publication (OR: 2.05 95% CI 1.22-3.46, p = 0.006) as well as for publication in Medline (OR: 2.62 95% CI 1.21 - 5.69, p = 0.01). CONCLUSION: The institutional scientific production of undergraduate medical students presented in Undergraduate Medical Meetings is relevant and should continue to be stimulated.OBJETIVO: Quantificar e descrever o número de trabalhos premiados e não premiados em apresentação oral no Congresso Médico Universitário do ABC no período de 2002 a 2007, que obtiveram posterior publicação em revistas científicas, a fim de avaliar se o trabalho premiado teria maior potencial para publicação. Mapear áreas por produtividade científica na instituição. MÉTODOS: Busca retrospectiva dos trabalhos inscritos no período de 2002 a 2007 que obtiveram publicação em periódicos indexados nas bases de dados Medline (Pubmed) e Lilacs ou em anais de congressos científicos de especialidades nacionais ou internacionais. RESULTADOS: Entre 2002 e 2007, foram inscritos 408 trabalhos e 71 foram premiados. O total de trabalhos publicados foi de 138 (33,8%), sendo 8,1% na base Medline, 14% na base Lilacs e 11,7% encontrados a partir da plataforma Lattes. Premiação pela banca examinadora foi variável independente para publicação (OR: 2,05 IC95% 1,22-3,46; p=0,006) assim como para publicação na base Medline (OR: 2,62 IC95% 1,21- 5,69; p=0,01). CONCLUSÃO: O papel de alunos de graduação na produção científica institucional refletido na produção de um Congresso Médico Universitário é relevante e deve continuar a ser estimulado

Orofacial manifestations in outpatients with anorexia nervosa and bulimia nervosa focusing on the vomiting behavior

Objective: This case-control study aims to evaluate the oral health status and orofacial problems in a group of outpatients with eating disorders (ED)—either anorexia nervosa (AN) or bulimia nervosa (BN)—further focusing on the influence of vomit. Materials and methods: Fifty-five women outpatients with AN or BN diagnosis were invited to participate, of which 33 agreed. ED outpatients and matched controls were submitted to a questionnaire and clinical oral examination. Results: Multivariate analysis identified a significantly higher incidence of teeth-related complications (i.e., tooth decay, dental erosion, and self-reported dentin hypersensitivity), periodontal disease, salivary alterations (i.e., hyposalivation and xerostomia), and oral mucosa-related complications in ED outpatients. Dental erosion, self-reported dentin hypersensitivity, hyposalivation, xerostomia, and angular cheilitis were found to be highly correlated with the vomiting behavior. Conclusions: ED outpatients were found to present a higher incidence of oral-related complications and an inferior oral health status, compared to gender- and age-matched controls. Alterations verified within outpatients were acknowledged to be quite similar to those previously reported within inpatients, in both of nature and severity, thus sustaining that the cranio-maxillofacial region is significantly affected by ED, even in the early/milder forms of the condition, as expectedly verified within outpatients.The work was supported by the Faculty of Dental Medicine, U. Porto

Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu2+ Coordination

coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species