Excesso de peso pré-gestacional e ácidos graxos poli-insaturados no leite humano: modelo teórico de causalidade / Pre-gestational overweight and polyunsaturated fatty acids in human milk: theoretical causality model

Resumo Inúmeros estudos têm se detido na avaliação da associação entre o excesso de peso pré-gestacional e os ácidos graxos poli-insaturados no leite humano. Todavia, diante da complexidade de fatores de risco potencialmente confundidores, é recomendável a utilização de ferramentas gráficas para identificar possíveis vieses. O objetivo deste artigo é propor um modelo teórico de causalidade utilizando o gráfico acíclico direcionado entre o excesso de peso pré-gestacional e os ácidos graxos poli-insaturados no leite humano. Foi realizada ampla revisão da literatura para identificar as variáveis com relações causais com a exposição e/ou desfecho. A escolha das variáveis para ajuste seguiu o algoritmo gráfico que compreende seis critérios para a seleção de um conjunto mínimo de variáveis potencialmente confundidoras. Condições socioeconômicas, intervalo interpartal, idade materna e padrão de consumo alimentar foram as variáveis ajustadas a fim de se estimar o efeito total do excesso de peso pré-gestacional sobre o conteúdo dos ácidos graxos poli-insaturados no leite humano. O conjunto mínimo de variáveis encontrado pelo presente estudo pode ser utilizado na análise de outros estudos que avaliem essa associação.

Abstract A number of studies have focused on the evaluation of the relationship between pre-pregnancy overweight and polyunsaturated fatty acids content in human milk. However, given the complexity of potentially confounding risk factors, the use of graphical tools is recommended to identify possible biases. This article aims to propose a theoretical model of causality using the directed acyclic graph between pre-pregnancy overweight and polyunsaturated fatty acids content in human milk. Methods: An extensive literature review was performed to identify variables with causal relationships with exposure and/or outcome. The choice of variables for adjustment followed the graphic algorithm that comprises six criteria for selecting a minimum set of potentially confounding variables. Socioeconomic conditions, interpartum interval, maternal age and food consumption pattern were the variables that would have to be adjusted in order to estimate the total effect of pre-pregnancy overweight on polyunsaturated fatty acids content in human milk. The minimum set of variables found in the present study can be used in the analysis of other studies that evaluate this association.

A questão da causalidade em Epidemiologia / The issue of causality in Epidemiology

Resumo Este ensaio trata da questão da causalidade em epidemiologia a partir da década de 1970, cujo marco inicial aqui adotado foi a publicação de The causal thinking in health sciences, por M. Susser, até os dias de hoje, buscando elencar os vários movimentos filosóficos, teóricos e metodológicos que ao longo destes 50 anos buscaram refletir sobre o problema da causalidade na disciplina, tendo em vista o predomínio das pesquisas observacionais no campo. Partindo da contribuição seminal de Susser, foram discutidos vários movimentos, bem como as críticas a eles, tais como a proposta da adoção de lógica popperiana na década de 1980, a crítica aos modelos multicausais e a teoria ecossocial proposta por N. Krieger na década de 1990, as críticas à epidemiologia social também da década de 1990, a influência de J. Pearl e a adoção dos gráficos acíclicos direcionados como nova metodologia na questão da causalidade. A chamada revolução metodológica no início deste século e as críticas de filósofos e epidemiologistas a esta abordagem reducionista também foram revisadas, bem como as alternativas propostas nos últimos 10 anos, incluindo a perspectiva inferencialista, a triangulação de métodos e a defesa da epidemiologia social e de seus modelos de determinação.

Abstract This essay deals with the issue of causality in epidemiology from the 1970s onwards, whose starting point adopted here was the publication of The Causal Thinking in Health Sciences by M. Susser, up to the present day, seeking to list the various philosophical, theoretical and methods that throughout these 50 years have sought to reflect on the problem of causality in the discipline, in view of the predominance of observational research in the field. Starting from Susser's seminal contribution, several movements were discussed as well as their criticisms, such as the proposal to adopt Popperian logic on the 1980s, the criticism of multicausal models and the ecosocial theory proposed by N. Krieger in the 1990s, criticism of social epidemiology also in the 1990s, the influence of J.Pearl and the adoption of directed acyclic graphs as a new tool in the issue of causality. The so-called methodological revolution at the beginning of this century and the criticism of philosophers and epidemiologists to this reductionist approach were also reviewed, as well as the alternatives proposed in the last 10 years, including the inferentialist perspective, the triangulation of methods and the defense of social epidemiology and their determination models.

Violência familiar na infância, violência no namoro e saúde mental na adolescência / Family violence against children, dating violence and adolescent mental health

O objetivo geral desta tese foi conhecer as magnitudes e os padrões das violências no namoro na adolescência (VNA) e das violências familiares na infância (VFI), as repercussões da VFI nos diferentes padrões de VNA, bem como as relações entre os padrões de VFI e a saúde mental na adolescência. O objetivo geral suscitou três objetivos específicos, cada um explorado em um manuscrito. Os dados usados na tese derivaram da pesquisa "Estupro de vulnerável e outras violências contra adolescentes e jovens do sexo feminino", desenvolvida em 2017 e 2018 que contou com a participação de 721 estudantes de escolas públicas e privadas da IX Região Administrativa (RA) do Rio de Janeiro. Para identificar a VNA, a VFI e estimar a saúde mental, usou-se respectivamente as versões brasileiras do instrumento Conflict in Adolescent Dating Relationships Inventory (CADRI), do Childhood Trauma Questionnaire (CTQ) e do General Health Questionnaire (GHQ-12). As estratégias de análise de dados variaram em função dos diferentes objetivos/manuscritos. O manuscrito 1 estimou as magnitudes de exposição e perpetração das VNA entre os escolares da IX RA do município do Rio de Janeiro. A prevalência de vitimização variou de 16,7% (sexual) a 94,6% (emocional). A prevalência de perpetração variou entre 9,9% (sexual) e 94,6% (emocional). Os adolescentes que relataram serem vítimas de violência na infância, os que vivem em áreas violentas e os que consomem bebidas alcoólicas com maior frequência tiveram maior prevalência de VNA. Os manuscritos 2 e 3 utilizaram análises de classes latentes (ACL) para identificar os padrões de VNA (manuscrito 2) e o padrão de VFI (manuscrito 3) com base na agregação de indivíduos em classes, caracterizadas em função da probabilidade de endosso aos diferentes itens dos instrumentos CADRI e CTQ. Além da identificação destes padrões, buscou-se utilizar as classes estimadas em modelos causais aferindo os efeitos das dimensões de VFI para os padrões de VNA (manuscrito 2) e das classes de VFI para a saúde mental dos adolescentes (manuscrito 3). No manuscrito 2, identificou-se três classes latentes de VNA entre meninas e meninos. O abuso sexual na infância aumentou a chance de pertencer à classe mais grave de vitimização de VNA entre as meninas (OR = 5,72; IC 95% = 2,51-13,06). Os abusos emocionais (OR=5,97; IC 95% = 1,95-18,30) e físicos (OR=3,16; IC 95%=1,07-9,34) aumentaram as chances de classificar os meninos na classe mais grave de perpetração de VNA. A ACL do manuscrito 3 também identificou três classes de violência familiar na infância, tanto em meninas, como em meninos. Apesar de várias semelhanças entre as classes dos dois sexos, as meninas foram mais vítimas de abuso sexual e os meninos de punição corporal (castigo físico). Pertencer à classe mais grave de VFI aumentou os escores do GHQ-12 em 2 a 3 pontos quando comparados às classes mais brandas de violência. A partir destes resultados e com as discussões trazidas pelos três manuscritos, espera-se que esta tese tenha contribuído tanto com as discussões temáticas das violências, como apresentado alguns avanços metodológicos no campo da análise epidemiológica. Com relação aos primeiros aspectos, mais uma vez, evidenciou-se que a violência entre pais e filhos é um problema de saúde pública, por sua alta frequência e relações diretas e especificas com a violência no namoro de adolescentes; ampliou-se também os debates sobre a relação entre as violências e o gênero, na medida em que tanto as prevalências como os padrões de violência diferem entre meninos e meninas desde a infância; identificou-se padrões de violência que mostram que a vivência de diferentes tipos de abuso é a situação mais frequente entre crianças e adolescentes; percebeu-se que as repercussões das violências contra crianças na saúde mental de adolescentes dependem do padrão de coocorrência das diferentes formas de vitimização infantil. Com relação aos avanços metodológicos, a tese é inovadora por propor, pela primeira vez no Brasil, a utilização de ACL para caracterizar as violências contra crianças e em relacionamentos amorosos de adolescentes. Ademais, a tese avança ao articular a identificação de padrões de violência via análise de classes latentes com seus fatores de risco e consequências, ampliando as possibilidades de inferência dos modelos.

The main objective of this thesis was to know the magnitudes and patterns of dating violence in adolescence (DV) and family violence against children (VAC), the repercussions of on different DV patterns, and the relationship of VAC patterns to health mentality in adolescence. The general objective raised three specific goals. Each one was explored in one manuscript. The data used in the thesis were derived from the research "Rape of the vulnerable and other violence against female adolescents and young people", developed in 2017 and 2018, with 721 students from public and private schools in the IX Administrative Region (AR) of Rio de Janeiro. The Brazilian versions of the Conflict in Adolescent Dating Relationships Inventory (CADRI) instrument, the Childhood Trauma Questionnaire (CTQ) and the General Health Questionnaire (GHQ-12) were used to identify DV, VAC and to estimate mental health trends respectively. Data analysis strategies varied according to different objectives/manuscripts. Manuscript 1 estimated the magnitudes of exposure and perpetration of DV among students from the IX AR in Rio de Janeiro. The estimated victimization prevalence ranged from 16.7% (sexual) to 94.6% (emotional). The prevalence of perpetration ranged from 9.9% (sexual) to 94.6% (emotional). Adolescents who reported child abuse, those living in violent areas, and those who consumed alcohol more frequently had a higher prevalence of DV. Manuscripts 2 and 3 used latent classes analysis (LCA) to identify the DV patterns (manuscript 2) and the VAC pattern (manuscript 3) based on the aggregation of individuals into classes, characterized according to the probability of endorsement to the different items from the CADRI and CTQ instruments. In addition to identifying these patterns, we sought to use the estimated classes in causal models, assessing the effects of the VAC dimensions for the DV patterns (manuscript 2) and the VAC classes for adolescents' mental health (manuscript 3). In manuscript 2, three latent classes of DV were identified among girls and boys. Childhood sexual abuse increased the chance of belonging to the most severe class of DV victimization among girls (OR = 5.72; 95% CI = 2.51-13.06). Emotional (OR=5.97; 95% CI = 1.95-18.30) and physical (OR=3.16; 95% CI=1.07-9.34) abuse increased the chances of classifying boys in the most severe class of DV perpetration. The LCA of manuscript 3 also identified three classes of VAC, both in girls and boys. Despite several similarities between the classes of the two sexes, girls suffered more with sexual abuse and boys with corporal punishment (physical punishment). Belonging to the most severe class of VAC increased the GHQ-12 scores by 2 to 3 points compared to the milder classes of violence. Based on these results and with the discussions brought by the three manuscripts, it is expected that this thesis has contributed both to the thematic discussions of violence and presented some methodological advances in the field of epidemiological analysis. Regarding the first aspect, once again, it is evident that violence between parents and children is a public health problem due to its high frequency and direct and specific relationship with violence in adolescents' dating. Debates on the relationship between violence and gender have expanded, as both the prevalence and patterns of violence differ between boys and girls since childhood; patterns of violence were identified that indicate that experiencing different types of abuse is the most frequent situation among children and adolescents, and it was noticed that the repercussions of violence against children on the mental health of adolescents depend on the pattern of co-occurrence of different forms of child victimization. Regarding methodological advances, the thesis is innovative as it proposes the use of LCA to characterize VAC and DV for the first time in Brazil. Furthermore, the thesis advances by articulating the identification of patterns of violence via the analysis of latent classes with their risk factors and consequences, expanding the possibilities of inference from the models.

Detection bias:structural analysis of different study designs / 上海预防医学

Detection bias is an information bias.It was first proposed by Horwitz from the study investigating the association of the administration of estrogen after menopause with the occurrence of endometrial cancer, which still prevails in most epidemiological studies.We use the Directed Acyclic Graph to analyze the effect of a given exposure on a specific outcome with the association estimates between the measured exposure and outcome.Detection bias occurs when there is additional open paths irrelevant to the target path of interest which is originated from measured exposure to measured outcome.We further analyzed how the detection bias was formed under different study designs, including cohort study, randomized clinical trial and case-control study in order to further investigate its potential influence on the effect/association estimation.

Detection bias:structural analysis of different study designs / 上海预防医学

Detection bias is an information bias.It was first proposed by Horwitz from the study investigating the association of the administration of estrogen after menopause with the occurrence of endometrial cancer, which still prevails in most epidemiological studies.We use the Directed Acyclic Graph to analyze the effect of a given exposure on a specific outcome with the association estimates between the measured exposure and outcome.Detection bias occurs when there is additional open paths irrelevant to the target path of interest which is originated from measured exposure to measured outcome.We further analyzed how the detection bias was formed under different study designs, including cohort study, randomized clinical trial and case-control study in order to further investigate its potential influence on the effect/association estimation.

Application of directed acyclic graphs in identification and control of selection bias in causal inference / 中华疾病控制杂志

In the etiology study of epidemiology, selection bias will lead to the fact that the research sample cannot represent the general population, the association between exposure and outcome among those selected for analysis differs from the association among those eligible, and the true causal association cannot be inferred. Directed acyclic graphs (DAGs) could visualize complex causality, introduce the Collider-stratification bias using simple graphics language, provide a simple and intuitive way to identify Selection bias, different types of selection bias are verified by the graphic structure of the Collider-stratification bias. In practical studies, there may be multiple biases at the same time, improper adjustment of the collider will lead to Collider-stratification bias, open a backdoor path, even change the size and direction of the confounding bias. In order to obtain an unbiased estimate of the exposure to the outcome, it is necessary to identify the collider and avoid the adjustment to prevent the occurrence of Collider-stratification bias by using DAGs.

A structural classification of strategies for confounding control in research design / 中华流行病学杂志

Confounding affects the causal relation among the population.Depending on whether the confounders are known,measurable or measured,they can be divided into four categories.Based on Directed Acyclic Graphs,the strategies for confounding control can be classified as (1) the broken-confounding-path method,which can be further divided into single and dual broken paths,corresponding to exposure complete intervention,restriction and stratification,(2) and the reserved-confounding-path method,which can be further divided into incomplete exposure intervention (in instrumental variable design and non-perfect random control test),mediator method and matching method.Among them,random control test,instrumental variable design or Mendelian randomized design,mediator method can meet the requirements for controlling all four types of confounders,while the restriction,stratification and matching methods are only applicable to known,measurable and measured confounders.Identifying the mechanisms of confounding control is a prerequisite for obtaining correct causal effect estimates,which will be helpful in research design.

Exposure-preceding-outcome regarding time sequence among cohort studies in real world / 中华流行病学杂志

One of the commonly accepted merits of cohort studies (CSs) refers to the exposure precedes outcome superior to other observational designs.We use Directed Acyclic Graphs to construct a causal graph among research populations under CSs.We notice that the substitution of research population in place of a susceptible one can be used for effect estimation.Its correctness depends on the outcome-free status of the substituted population and the performance of both screening and diagnosis regarding the outcomes under study at baseline.The temporal precedence of exposure over outcome occurs theoretically,despite the opposite happens in realities.Correct effect estimate is affected by both the suitability of population substitution and the validities of outcome identification and exclusion.

Causality in objective world: Directed Acyclic Graphs-based structural parsing / 中华流行病学杂志

The overall details of causality frames in the objective world remain obscure,which poses difficulty for causality research.Based on the temporality of cause and effect,the objective world is divided into three time zones and two time points,in which the causal relationships of the variables are parsed by using Directed Acyclic Graphs (DAGs).Causal DAGs of the world (or causal web) is composed of two parts.One is basic or core to the whole DAGs,formed by the combination of any one variable originating from each time unit mentioned above.Cause effect is affected by the confounding only.The other is an internal DAGs within each time unit representing a parent-child or ancestor-descendant relationship,which exhibits a structure similar to the confounding.This paper summarizes the construction of causality frames for objective world research (causal DAGs),and clarify a structural basis for the control of the confounding in effect estimate.

Dynamic path analysis on life course epidemiology / 中华流行病学杂志

In the studies of modem epidemiology,exposure in a short term cannot fully elaborate the mechanism of the development of diseases or health-related events.Thus,lights have been shed on to life course epidemiology,which studies the exposures in early life time and their effects related to the development of chronic diseases.When exploring the mechanism leading from one exposure to an outcome and its effects through other factors,due to the existence of time-variant effects,conventional statistic methods could not meet the needs of etiological analysis in life course epidemiology.This paper summarizes the dynamic path analysis model,including the model structure and significance,and its application in life course epidemiology.Meanwhile,the procedure of data processing and etiology analyzing were introduced.In conclusion,dynamic path analysis is a useful tool which can be used to better elucidate the mechanisms that underlie the etiology of chronic diseases.

A structural classification of strategies for confounding control in research design / 中华流行病学杂志

Confounding affects the causal relation among the population.Depending on whether the confounders are known,measurable or measured,they can be divided into four categories.Based on Directed Acyclic Graphs,the strategies for confounding control can be classified as (1) the broken-confounding-path method,which can be further divided into single and dual broken paths,corresponding to exposure complete intervention,restriction and stratification,(2) and the reserved-confounding-path method,which can be further divided into incomplete exposure intervention (in instrumental variable design and non-perfect random control test),mediator method and matching method.Among them,random control test,instrumental variable design or Mendelian randomized design,mediator method can meet the requirements for controlling all four types of confounders,while the restriction,stratification and matching methods are only applicable to known,measurable and measured confounders.Identifying the mechanisms of confounding control is a prerequisite for obtaining correct causal effect estimates,which will be helpful in research design.

Exposure-preceding-outcome regarding time sequence among cohort studies in real world / 中华流行病学杂志

One of the commonly accepted merits of cohort studies (CSs) refers to the exposure precedes outcome superior to other observational designs.We use Directed Acyclic Graphs to construct a causal graph among research populations under CSs.We notice that the substitution of research population in place of a susceptible one can be used for effect estimation.Its correctness depends on the outcome-free status of the substituted population and the performance of both screening and diagnosis regarding the outcomes under study at baseline.The temporal precedence of exposure over outcome occurs theoretically,despite the opposite happens in realities.Correct effect estimate is affected by both the suitability of population substitution and the validities of outcome identification and exclusion.

Causality in objective world: Directed Acyclic Graphs-based structural parsing / 中华流行病学杂志

The overall details of causality frames in the objective world remain obscure,which poses difficulty for causality research.Based on the temporality of cause and effect,the objective world is divided into three time zones and two time points,in which the causal relationships of the variables are parsed by using Directed Acyclic Graphs (DAGs).Causal DAGs of the world (or causal web) is composed of two parts.One is basic or core to the whole DAGs,formed by the combination of any one variable originating from each time unit mentioned above.Cause effect is affected by the confounding only.The other is an internal DAGs within each time unit representing a parent-child or ancestor-descendant relationship,which exhibits a structure similar to the confounding.This paper summarizes the construction of causality frames for objective world research (causal DAGs),and clarify a structural basis for the control of the confounding in effect estimate.

Dynamic path analysis on life course epidemiology / 中华流行病学杂志

In the studies of modem epidemiology,exposure in a short term cannot fully elaborate the mechanism of the development of diseases or health-related events.Thus,lights have been shed on to life course epidemiology,which studies the exposures in early life time and their effects related to the development of chronic diseases.When exploring the mechanism leading from one exposure to an outcome and its effects through other factors,due to the existence of time-variant effects,conventional statistic methods could not meet the needs of etiological analysis in life course epidemiology.This paper summarizes the dynamic path analysis model,including the model structure and significance,and its application in life course epidemiology.Meanwhile,the procedure of data processing and etiology analyzing were introduced.In conclusion,dynamic path analysis is a useful tool which can be used to better elucidate the mechanisms that underlie the etiology of chronic diseases.

Application of directed acyclic graphs in evidence-based medicine / 中国医师杂志

Evidence-based medicine (EBM) is a kind of clinic practice where clinicians use the best and the latest available evidence to diagnose and treat patients, and both evidence providers and users need to identify and control different kinds of biases in medical research.Directed acyclic graphsis is a tool to explore the causal relationship.The possible biases in the study can be revealed in a simple graphical language.The use of directed acyclic graphs could avoid the occurrence of bias and improve the quality of medical research and better guide clinical practice.

Transferência de embriões em éguas receptoras anovulatórias / Embryo transfer in anovulatory recipient mares / Transferencia de embriones en yeguas receptoras anovulatorias

Resumo: Este artigo discute os principais aspectos do uso de protocolos hormonais baseados na aplicação de estrógeno seguido de progestágenos em receptoras anovulatórias o acíclicas, seja em anestro ou transição nos protocolos de transferência de embriões. A maioria das éguas apresentam comportamento poliéstrico estacional, com o que manifestam estro e ciclos ovulatórios nos períodos de maior luminosidade diária. O ciclo reprodutivo anual das éguas é caracterizado pela presença de quatro fases definidas pela dinâmica folicular: de anestro, de transição de primavera, ovulatória e de transição de outono. Durante as fases de transição e anestro, a incidência das ovulações diminui ou é nula, ou que dificulta a sincronização das ovulações entre doadoras e receptoras durante a preparação para a transferência de embriões. Alguns estudos mostram que as receptoras anovulatórias/acíclicas mantidas com protocolos com base em esteroides apresentam mudanças uterinas similares às que acontecem nas éguas gestantes. Contudo, não há pesquisas suficientes que permitam esclarecer o melhor protocolo de esteroides, no que se refere à dose, tempos de tratamento e vias de administração.

Abstract: This article discusses the main aspects of using hormonal protocols based on the application of estrogen followed by progestogen in anovulatory or acyclic recipients, either in anestrous or transition in embryo transfer protocols. Most mares demonstrate seasonally polyestrous behavior, by which they manifest estrus and ovulatory cycles during periods of higher daily luminosity. The annual reproductive cycle of mares is characterized by the presence of four phases defined by follicular dynamics: anestrous, spring transition, ovulatory, and autumn transition. During the phases of transition and anestrous, the incidence of ovulations decreases or is zero, making it difficult to synchronize ovulations between donors and recipients in preparation for embryo transfer. Some studies have shown that anovulatory/acyclic recipient mares managed with steroid-based protocols have similar uterine changes to those observed in pregnant mares. However, there is no sufficient research to allow to clarify the best steroid protocol with respect to dose, treatment times, and routes of administration.

Resumen: Este artículo discute los principales aspectos del uso de protocolos hormonales basados en la aplicación de estrógeno seguido de progestágeno en receptoras anovulatorias o acíclicas, sea en anestro o transición en los protocolos de transferencia de embriones. La mayoría de las yeguas presentan comportamiento poliéstrico estacional, con lo que manifiestan estro y ciclos ovulatorios en los periodos de mayor luminosidad diaria. El ciclo reproductivo anual de las yeguas es caracterizado por la presencia de cuatro fases definidas por la dinámica folicular: de anestro, de transición de primavera, ovulatoria y de transición de otoño. Durante las fases de transición y anestro, la incidencia de las ovulaciones disminuye o es nula, lo que dificulta la sincronización de las ovulaciones entre donadoras y receptoras durante la preparación para la transferencia de embriones. Algunos estudios han mostrado que las receptoras anovulatorias/acíclicas mantenidas con protocolos con base en esteroides presentan cambios uterinos similares a los que pasan en las yeguas gestantes. Sin embargo, no hay investigaciones suficientes que permitan aclarar el mejor protocolo de esteroides, con respecto a dosis, tiempos de tratamiento y vías de administración.

Directed acyclic graphs: languages, rules and applications / 中华流行病学杂志

Nearly all scientific studies explore causality,which will be met by directed acyclic graphs (DAGs).This paper systematically introduces graphic language,basic and interference rules of DAGs,and their applications into identifying research questions,understanding and undertaking research designs,guiding data analysis,classifying biases,etc.DAGs play key roles in causality studies.

Directed acyclic graphs: languages, rules and applications / 中华流行病学杂志

Nearly all scientific studies explore causality,which will be met by directed acyclic graphs (DAGs).This paper systematically introduces graphic language,basic and interference rules of DAGs,and their applications into identifying research questions,understanding and undertaking research designs,guiding data analysis,classifying biases,etc.DAGs play key roles in causality studies.

Adenine: an important drug scaffold for the design of antiviral agents

Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template.

Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis

β-ionone (βI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of βI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with βI (16 mg/100 g body weight), GO (25 mg/100 g body weight), βI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the βI (91 ± 11 and 14 ± 3) and βI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of βI and GO (gas chromatography/mass spectrometry) were higher in the βI and GO groups, respectively, compared to the control and βI+GO groups. Therefore, GO, but not βI, represents a potential chemopreventive agent in colon carcrvpdate=20110329inogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.