Cell therapy in dilated cardiomyopathy: from animal models to clinical trials

Dilated cardiomyopathy can be the end-stage form and common denominator of several cardiac disorders of known cause, such as hypertensive, ischemic, diabetic and Chagasic diseases. However, some individuals have clinical findings, such as an increase in ventricular chamber size and impaired contractility (classical manifestations of dilated cardiomyopathy) even in the absence of a diagnosed primary disease. In these patients, dilated cardiomyopathy is classified as idiopathic since its etiology is obscure. Nevertheless, regardless of all of the advances in medical, pharmacological and surgical procedures, the fate of patients with dilated cardiomyopathy (of idiopathic or of any other known cause) is linked to arrhythmic episodes, severe congestive heart failure and an increased risk of sudden cardiac death. In this review, we will summarize present data on the use of cell therapies in animal models of dilated cardiomyopathies and will discuss the few clinical trials that have been published so far involving patients affected by this disease. The animal models discussed here include those in which the cardiomyopathy is produced by genetic manipulation and those in which disease is induced by chemical or infectious agents. The specific model used clearly creates restrictions to translation of the proposed cell therapy to clinical practice, insofar as most of the clinical trials performed to date with cell therapy have used autologous cells. Thus, translation of genetic models of dilated cardiomyopathy may have to wait until the use of allogeneic cells becomes more widespread in clinical trials of cell therapies for cardiac diseases.

Quality of life in multiple sclerosis: translation in French Canadian of the MSQoL-54

Affiliation: Louise Lafortune: Faculté de médecine, Université de Montréal

Les enjeux de la translation des technologies : le cas des tests de pharmacogénétique au Québec

Problématique : L’arrivée des tests de pharmacogénétique a été annoncée dans les médias et la littérature scientifique telle une révolution, un tournant vers la médecine personnalisée. En réalité, cette révolution se fait toujours attendre. Plusieurs barrières législatives, scientifiques, professionnelles et éthiques sont décrites dans la littérature comme étant la cause du délai de la translation des tests de pharmacogénétique, du laboratoire vers la clinique. Cet optimisme quant à l’arrivée de la pharmacogénétique et ces barrières existent-elles au Québec? Quel est le contexte de translation des tests de pharmacogénétique au Québec? Actuellement, il n’existe aucune donnée sur ces questions. Il est pourtant essentiel de les évaluer. Alors que les attentes et les pressions pour l’intégration rapide de technologies génétiques sont de plus en plus élevées sur le système de santé québécois, l’absence de planification et de mécanisme de translation de ces technologies font craindre une translation et une utilisation inadéquates. Objectifs : Un premier objectif est d’éclairer et d’enrichir sur les conditions d’utilisation et de translation ainsi que sur les enjeux associés aux tests de pharmacogénétique dans le contexte québécois. Un deuxième objectif est de cerner ce qui est véhiculé sur la PGt dans différentes sources, dont les médias. Il ne s’agit pas d’évaluer si la pharmacogénétique devrait être intégrée dans la clinique, mais de mettre en perspective les espoirs véhiculés et la réalité du terrain. Ceci afin d’orienter la réflexion quant au développement de mécanismes de translation efficients et de politiques associées. Méthodologie : L’analyse des discours de plusieurs sources documentaires (n=167) du Québec et du Canada (1990-2005) et d’entretiens avec des experts québécois (n=19) a été effectuée. Quatre thèmes ont été analysés : 1) le positionnement et les perceptions envers la pharmacogénétique; 2) les avantages et les risques reliés à son utilisation; 3) les rôles et les tensions entre professionnels; 4) les barrières et les solutions de translation. Résultats : L’analyse des représentations véhiculées sur la pharmacogénétique dans les sources documentaires se cristallise autour de deux pôles. Les représentations optimistes qui révèlent une fascination envers la médecine personnalisée, créant des attentes (« Génohype ») en regard de l’arrivée de la pharmacogénétique dans la clinique. Les représentations pessimistes qui révèlent un scepticisme (« Génomythe ») envers l’arrivée de la pharmacogénétique et qui semblent imprégnés par l’historique des représentations médiatiques négatives de la génétique. Quant à l’analyse des entretiens, celle-ci a permis de mettre en lumière le contexte actuel du terrain d’accueil. En effet, selon les experts interviewés, ce contexte comporte des déficiences législatives et un dysfonctionnement organisationnel qui font en sorte que l’utilisation des tests de pharmacogénétique est limitée, fragmentée et non standardisée. S’ajoute à ceci, le manque de données probantes et de dialogue entre des acteurs mal ou peu informés, la résistance et la crainte de certains professionnels. Discussion : Plusieurs changements dans la réglementation des systèmes d’innovation ainsi que dans le contexte d’accueil seront nécessaires pour rendre accessibles les tests de pharmacogénétique dans la pratique clinique courante. Des mécanismes facilitateurs de la translation des technologies et des facteurs clés de réussite sont proposés. Enfin, quelques initiatives phares sont suggérées. Conclusion : Des efforts au niveau international, national, provincial et local sont indispensables afin de résoudre les nombreux obstacles de la translation des tests de pharmacogénétique au Québec et ainsi planifier l’avenir le plus efficacement et sûrement possible.

Assessment of PEG on Polymeric Particles Surface, a Key Step in Drug Carrier Translation

Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage-density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicates even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage-density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface.

Translation and usability of autism screening and diagnostic tools for autism spectrum conditions in India

There is a critical need for screening and diagnostic tools (SDT) for autism spectrum conditions (ASC) in regional languages in South Asia. To address this, we translated four widely used SDT (Social Communication Disorder Checklist, Autism Spectrum Quotient, Social Communication Questionnaire, and Autism Diagnostic Observation Schedule) into Bengali and Hindi, two main regional languages (∼ 360 million speakers), and tested their usability in children with and without ASC. We found a significant difference in scores between children with ASC (n = 45 in Bengali, n = 40 in Hindi) and typically developing children (n = 43 in Bengali, n = 42 in Hindi) on all SDTs. These results demonstrate that these SDTs are usable in South Asia, and constitute an important resource for epidemiology research and clinical diagnosis in the region.

Impact of socioeconomic and clinical factors on child oral health-related quality of life (COHRQoL)

Child oral health-related quality of life (COHRQoL) has been increasingly assessed; however, few studies appraised the influence of socioeconomic status on COHRQoL in developing countries. This study assessed the relationship of COHRQoL with socioeconomic backgrounds and clinical factors. This study followed a cross-sectional design, with a multistage random sample of 792 schoolchildren aged 12 years, representative of Santa Maria, a southern city in Brazil. Participants completed the Brazilian version of the Child Perceptions Questionnaire (CPQ(11-14)), their parents or guardians answered questions on socioeconomic status, and a dental examination provided information on the prevalence of caries, dental trauma and occlusion. The assessment of association used hierarchically adjusted Poisson regression models. Higher impacts on COHRQoL were observed for children presenting with untreated dental caries (RR 1.20; 95% CI 1.07-1.35) and maxillary overjet (RR 1.19; 95% CI 1.02-1.40). Socioeconomic factors also associated with COHRQoL; poorer scores were reported by children whose mothers have not completed primary education (RR 1.30; 95% CI 1.17-1.44) and those with lower household income (RR 1.13; 95% CI 1.02-1.26). Poor socioeconomic standings and poor dental status have a negative impact on COHRQoL; reducing health inequalities may demand dental programmes and policies targeting deprived population.

Tradução e adaptação da escala de dependência de substâncias do Millon Clinical Multiaxial III para o Brasil

Millon describes the normal personality by means of adaptation styles that are effective in normal environments and personality disorders such as unadapted operating styles. To operacionalize his theoretical model, Millon has built several instruments, including the Millon Clinical Multiaxial Inventory III (MCMI-III), wich consists of a self report inventory composed by 175 true or false response items, containing four verification scales, and others scales wich evaluates 14 personality patterns and 10 clinical syndromes. The Substance Dependence scale (T) is placed along with Clinical Syndromes scales. This research is justified by the lack of a Brazilian instrument to assess personality psychopathological aspects, and aims to translate and semantically adapt the MCMI-III to the Brazilian context, checking validity elements of the Substance Dependence scale, and developing a computer application for assisting the evaluation of assessment results. To this intent, 2.588 individuals data was collected, male and female, aged between 18 and 85 years, characterized as belonging to a clinical or non-clinical group, who took part in the survey via the internet or in person. Respondents completed the MCMI-III, a socio-demographic questionnaire and a subgroup also answered to the Goldberg General Health Questionnaire (GHQ). Besides descriptive statistics, we performed the analysis using the Student t test, principal components analysis and internal consistency. Despite difficulties related to translating very specific English terms, the assessment by judges, experts on Millon´s theory, and the back translation, attested the adequacy of the Brazilian version. Factorial analysis indicated the grouping of translated T scale items into three factors (social activities prejudice, lack of impulse control, and oppositional behavior), by presenting a single item on a fourth factor (apparently related to seeking pleasurable stimuli). The Cronbach alpha for this set of items was 0,82, indicating an acceptable scale reliability. The data analysis resulted in distinction of scores between clinical and non-clinical groups and between men and women; the relationship between high scores on the scale T and the other scales; scores of drug users according to the declared used substance; and the relationship between high scores on T and the verification of disorder or risk on GHQ mental health factor, indicating the instrument´s adequate sensistivity in identifying psychopathologies and the relationship between the different disorders or psychopathological personality patterns. Although further studies are necessary to develop the scores transformation factors, the computerized correction tool was adequate.

Estudos de validade da escala de dependência alcoólica do millon clinical multiaxial inventory iii para o Brasil

This study has as main objectives to translate and to adapt the MCMI-III to brazilian Portuguese, as well as investigate and analyze the involved modifications in the Alcohol Dependence Scale concerning to the results obtained on the validity and on the process of adaptation to Brazil. The inventory was translated and, posteriorly, applied on people with different reading levels to certify that the items are understandable to public in general, from diverse places of the country, divided into clinical and non-clinical groups. Were evaluated 2855 subjects between the ages of 18 and 85 years old, male and female, resident and dwellers of Brazilian cities. The application methods were face-to-face and computerized. Results showed that the clinical group presented significant differences between the means in comparison to the non-clinical group. Through the application of the General Health Questionnaire were developed studies related to the achievement of convergent validity and its results pointed to the relation between the instrument scores and the MCMI-III. The Alcohol Dependence Scale analysis indicated that people who reported abusive use of alcohol had highest scores, indicating adequacy of the instrument on identifying manifestation of disorders and syndromes. Nevertheless, further studies are necessary to the establishment of normative patterns to the Brazilian sample

Translation, cultural adaptation to Brazil and validation of the venous leg ulcer quality of life questionnaire (VLU-QoL-Br)

Objetivo:traduzir o instrumento Venous legulcer quality of life questionnaire (VLU-QoL), adaptá-lo culturalmente para o português do Brasil e validá-lo com pacientes do Hospital das Clínicas da Faculdade de Medicina de Botucatu (FMB) da Universidade Estadual Paulista (Unesp). Métodos:o questionário foi traduzido por um tradutor profissional e por dois dermatologistas especialistas na área de úlceras venosas (UV), sendo reformulado em reunião com os três tradutores. O constructo (VLU-QoL-Br) foi submetido a pré-entrevista com 10 portadores de UV para a adaptação da linguagem. Posteriormente, foi aplicado em pacientes do HC-Unesp, e como teste-reteste para verificação de sua reprodutibilidade. Resultados:foram avaliados 82 pacientes, sendo 56 (68%) do sexo feminino. A idade média foi de 67,3 anos. O questionário foi traduzido, adaptado e aplicado aos pacientes. O constructo apresentou alta consistência interna (alfa= 0,94) e adequada correlação item-total. Quando avaliados os 32 retestes, observou-se correlação intraclasse para concordância de 0,78 (p < 0,01), indicando boa reprodutibilidade do constructo. A análise fatorial confirmatória corroborou as dimensões do questionário original: atividades, psicológico e sintomas. Escores do VLU-QoL-Br se associaram, independentemente, à área total das úlceras e a menor escolaridade dos sujeitos (p < 0,01). Conclusão:a tradução, a adaptação e a validação do questionário VLU-Qol-Br demonstrou boa performance psicométrica, permitindo seu uso clínico no Brasil. É importante avaliar seu desempenho em outras regiões e em diferentes amostras de indivíduos.

Translation and cultural adaptation for Brazil of the Developing Nurses' Thinking model

OBJETIVOS:traduzir e adaptar culturalmente para a língua portuguesa do Brasil o modelo Developing Nurses' Thinking, utilizado como estratégia ao ensino do raciocínio clínico.MÉTODO:a tradução e adaptação cultural foi realizada por meio de tradução inicial, síntese das traduções, retrotradução, avaliação por comitê de especialistas e pré-teste com 33 estudantes de graduação em enfermagem.RESULTADOS:as etapas de tradução inicial, síntese das traduções e retrotradução foram realizadas a contento, havendo a necessidade de pequenos ajustes. Na avaliação pelo comitê de especialistas da versão traduzida, todos os itens obtiveram concordância superior a 80% na primeira rodada de avaliação e no pré-teste com os estudantes. O modelo mostrou-se adequado à sua finalidade.CONCLUSÃO:recomenda-se o uso do modelo como uma estratégia complementar ao ensino do raciocínio diagnóstico, visando a formação de enfermeiros mais conscientes sobre a tarefa diagnóstica e a importância da segurança do paciente.

Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration

Background: Rheumatic diseases in children are associated with significant morbidity and poor health-related quality of life (HRQOL). There is no health-related quality of life (HRQOL) scale available specifically for children with less common rheumatic diseases. These diseases share several features with systemic lupus erythematosus (SLE) such as their chronic episodic nature, multi-systemic involvement, and the need for immunosuppressive medications. HRQOL scale developed for pediatric SLE will likely be applicable to children with systemic inflammatory diseases.Findings: We adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY (c)) to Simple Measure of Impact of Illness in Youngsters (SMILY (c)-Illness) and had it reviewed by pediatric rheumatologists for its appropriateness and cultural suitability. We tested SMILY (c)-Illness in patients with inflammatory rheumatic diseases and then translated it into 28 languages. Nineteen children (79% female, n= 15) and 17 parents participated. The mean age was 12 +/- 4 years, with median disease duration of 21 months (1-172 months). We translated SMILY (c)-Illness into the following 28 languages: Danish, Dutch, French (France), English (UK), German (Germany), German (Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans, Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Xhosa.Conclusion: SMILY (c)-Illness is a brief, easy to administer and score HRQOL scale for children with systemic rheumatic diseases. It is suitable for use across different age groups and literacy levels. SMILY (c)-Illness with its available translations may be used as useful adjuncts to clinical practice and research.

TRANSLATION AND VALIDATION OF THE KNEE SOCIETY SCORE - KSS FOR BRAZILIAN PORTUGUESE

Objective: To translate, culturally adapt and validate the "Knee Society Score"(KSS) for the Portuguese language and determine its measurement properties, reproducibility and validity. Method: We analyzed 70 patients of both sexes, aged between 55 and 85 years, in a cross-sectional clinical trial, with diagnosis of primary osteoarthritis,undergoing total knee arthroplasty surgery. We assessed the patients with the English version of the KSS questionnaire and after 30 minutes with the Portuguese version of the KSS questionnaire, done by a different evaluator. All the patients were assessed preoperatively, and again at three, and six months postoperatively. Results: There was no statistical difference, using Cronbach's alpha index and the Bland-Altman graphical analysis, for the knees core during the preoperative period (p=1), and at three months (p=0.991) and six months postoperatively (p=0.985). There was no statistical difference for knee function score for all three periods (p=1.0). Conclusion: The Brazilian version of the Knee Society Score is easy to apply, as well providing as a valid and reliable instrument for measuring the knee score and function of Brazilian patients undergoing TKA. Level of Evidence: Level I - Diagnostic Studies Investigating a Diagnostic Test- Testing of previously developed diagnostic criteria on consecutive patients (with universally applied 'gold' reference standard).

Translation and Cross-cultural Adaptation of the Lower Extremity Functional Scale Into a Brazilian Portuguese Version and Validation on Patients With Knee Injuries

STUDY DESIGN: Clinical measurement. OBJECTIVE: To translate and culturally adapt the Lower Extremity Functional Scale (LEFS) into a Brazilian Portuguese version, and to test the construct and content validity and reliability of this version in patients with knee injuries. BACKGROUND: There is no Brazilian Portuguese version of an instrument to assess the function of the lower extremity after orthopaedic injury. METHODS: The translation of the original English version of the LEFS into a Brazilian Portuguese version was accomplished using standard guidelines and tested in 31 patients with knee injuries. Subsequently, 87 patients with a variety of knee disorders completed the Brazilian Portuguese LEES, the Medical Outcomes Study 36-Item Short-Form Health Survey, the Western Ontario and McMaster Universities Osteoarthritis Index, and the International Knee Documentation Committee Subjective Knee Evaluation Form and a visual analog scale for pain. All patients were retested within 2 days to determine reliability of these measures. Validation was assessed by determining the level of association between the Brazilian Portuguese LEFS and the other outcome measures. Reliability was documented by calculating internal consistency, test-retest reliability, and standard error of measurement. RESULTS: The Brazilian Portuguese LEES had a high level of association with the physical component of the Medical Outcomes Study 36-Item Short-Form Health Survey (r = 0.82), the Western Ontario and McMaster Universities Osteoarthritis Index (r = 0.87), the International Knee Documentation Committee Subjective Knee Evaluation Form (r = 0.82), and the pain visual analog scale (r = -0.60) (all, P<.05). The Brazilian Portuguese LEES had a low level of association with the mental component of the Medical Outcomes Study 36-Item Short-Form Health Survey (r = 0.38, P<.05). The internal consistency (Cronbach alpha = .952) and test-retest reliability (intraclass correlation coefficient = 0.957) of the Brazilian Portuguese version of the LEES were high. The standard error of measurement was low (3.6) and the agreement was considered high, demonstrated by the small differences between test and retest and the narrow limit of agreement, as observed in Bland-Altman and survival-agreement plots. CONCLUSION: The translation of the LEFS into a Brazilian Portuguese version was successful in preserving the semantic and measurement properties of the original version and was shown to be valid and reliable in a Brazilian population with knee injuries. J Ort hop Sports Phys Ther 2012;42(11):932-939, Epub 9 October 2012. doi:10.2519/jospt.2012.4101

Infantile Encephaloneuromyopathy and Defective Mitochondrial Translation Are Due to a Homozygous RMND1 Mutation

Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild-type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild-type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation.

S100A1 gene therapy for heart failure: a novel strategy on the verge of clinical trials

Representing the common endpoint of various cardiovascular disorders, heart failure (HF) shows a dramatically growing prevalence. As currently available therapeutic strategies are not capable of terminating the progress of the disease, HF is still associated with a poor clinical prognosis. Among the underlying molecular mechanisms, the loss of cardiomyocyte Ca(2+) cycling integrity plays a key role in the pathophysiological development and progression of the disease. The cardiomyocyte EF-hand Ca(2+) sensor protein S100A1 emerged as a regulator both of sarcoplasmic reticulum (SR), sarcomere and mitochondrial function implicating a significant role in cardiac physiology and dysfunction. In this review, we aim to recapitulate the translation of S100A1-based investigation from first clinical observations over basic research experiments back to a near-clinical setting on the verge of clinical trials today. We also address needs for further developments towards "second-generation" gene therapy and discuss the therapeutic potential of S100A1 gene therapy for HF as a promising novel strategy for future cardiologists. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".