1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Psychological and Family Factors Associated with Suicidal Ideation in Pre-Adolescents

To assess the psychological and family factors associated with suicidal ideation in preadolescent children, we studied a sample of 361 students, average age 9 years old. Twogroups were formed, on the basis of the presence (n = 34) or absence (n = 44) of suicidal ideation. Suicidal ideation was assessed with the Children’s Depression Inventory and the Children’s Depression Rating Scale-Revised. Depression, hopelessness, self-esteem, and perceived family environment were compared in both the suicidal ideation and the control groups. Students with suicidal ideation generally presented greater depressive symptoms and hopelessness, and lower self-esteem and family expressiveness, although there weredifferences both between sexes, and when the variable depression was controlled. Identifying these risk factors in pre-adolescents may have an impact on prevention of suicidal behavior at higher risk ages

Chemotaxonomy of three genera of the annonaceae family using self-organizing maps and 13C NMR data of diterpenes

The Annonaceae family is distributed throughout Neotropical regions of the world. In Brazil, it covers nearly all natural formations particularly Annona, Xylopia and Polyalthia and is characterized chemically by the production of sources of terpenoids (mainly diterpenes), alkaloids, steroids, polyphenols and, flavonoids. Studies from 13C NMR data of diterpenes related with their botanical occurrence were used to generate self-organizing maps (SOM). Results corroborate those in the literature obtained from morphological and molecular data for three genera and the model can be used to project other diterpenes. Therefore, the model produced can predict which genera are likely to contain a compound.

New hosts of Oidiopsis haplophylli in the solanaceae family in Brazil

A powdery mildew disease was observed on leaves of Solanum gilo, S. melongena, S. tuberosum S. chacoense, Nicotiana rustica and N. tabacum in Brasília (Federal District), Brazil. Symptoms were mainly characterized by adaxial yellow areas in the leaves corresponding to white fungal colonies on the abaxial surface. Profuse sporulation was often observed. Light microscopy of the fungal colonies revealed the presence of conidiophores emerging through stomata with some having two or three branches. Ellipsoidal, subhyaline conidia were predominantly born singly and terminally on the conidiophore. All morphometrical characteristics agreed with those of Oidiopsis haplophylli (Syn. O. sicula). The teleomorph (Leveillula taurica) was not observed. Inoculation tests indicated that O. haplophylli isolates obtained from S. gilo, S. melongena, S. tuberosum, S. chacoense, Nicotiana rustica and N. tabacum were also pathogenic to sweet pepper (Capsicum annuum) and tomato (Lycopersicon esculentum). This is apparently the first report of these Solanaceae species as hosts of O. haplophylli in Brazil. This disease may become important in these crops, especially in greenhouses, and in hot and dry areas where drip irrigation is employed.

Changing family institution challenges family policy making in Estonia

Artikkeli perustuu Edistyksen Päivillä Turussa 11.10.2008 pidettyyn esitelmään.

The family school : the impact of a group training programme on overactive hard-to-manage preschool children and their parents

Föräldraskap upplevs som en utmanande uppgift i dag och det påstås att föräldrar oftare än förr skulle var i behov av råd och stöd beträffande barnuppfostran. Denna uppgift kan ytterligare försvåras om det i familjen finns ett hyperaktivt okoncentrerat barn att uppfostra. Detta arbete undersökte effekterna av ett kortvarigt gruppbaserat interventionsprogram benämnt Familjeskolan POP (Preschool Overactivity Programme). Familjeskolan är avsedd för familjer med barn i lekåldern, som visar beteendesvårigheter såsom ADHD (Attention Deficit Hyperactivity Disorder), ODD (Oppositional Deficit Disorder) eller CD (Conduct Disorder). Målet för Familjeskolan är att öka föräldrarnas kunskaper och självförtroende då de har ett krävande svårhanterligt barn att uppfostra. Familjeskolan strävar också till att reducera barns icke-önskvärda beteenden genom att öka deras sociala färdigheter och koncentrationsförmåga. Familjeskolan verkställdes i Helsingfors vid ADHD- centrets lokaliteter. 45 mödrar och deras barn från huvudstadsregionen deltog i denna undersökning. Av dessa deltog 33 i Familjeskola-programmet medan de 12 övriga bildade den s.k. kontrollgruppen. Undersökningsresultaten tyder på förbättringar beträffande både moderns och faderns föräldrakunskaper efter Familjeskola-interventionen. Det är att lägga märke till att enbart mödrar deltog i interventionsprogrammet. Efter programmet klarade mödrar enligt egen utsaga vardagen bättre. Speciellt hade de blivit bättre på att hantera barnens beteendesvårigheter och hyperaktivt okoncentrerat beteende. Resultaten påvisade också att programmet var effektivast för de mödrar som före Familjeskolan upplevde sig besitta ringa föräldrakunskaper. Mödrarna rapporterade en signifikant minskning i barnens totala beteendesvårigheter. Efter interventionen ansåg mödrarna att deras barn var mindre olydiga, hyperaktiva samt att deras beteendesvårigheter var lindrigare. Enligt dagvårdspersonalen hade barnens totala beteendesvårigheter och problem med koncentration och hyperaktivitet också minskat. Motsvarande förbättringar uppnåddes inte i kontrollgruppen. Resultaten från uppföljningsintervjun, visade också att barnens beteendeförändringar var bestående både hemma och i daghemmet. Både föräldrar och dagvårdspersonalen rapporterade en signifikant minskning i barnens totala svårigheter jämfört med innan familjerna påbörjade interventionen. Föräldrarna rapporterade en marginell minskning i barnens ADHD-liknande beteende, beteendesvårigheter och i svårigheter med kamrater, dagvårdspersonalen däremot rapporterade en signifikant minskning i barnens beteendesvårigheter, hyperaktivt/okoncentrerat beteende samt i svårigheter med kamrater mellan innan familjerna påbörjade interventionen och uppföljningen ett år efter. Resultaten av denna undersökning stödjer hypotesen att kortvariga gruppbaserade interventionsprogram kan åstadkomma permanenta förbättringar i föräldrakunskaper och barns beteende. Detta gäller främst hyperaktivitet, koncentrationssvårigheter och trotsighet.

Outcomes of cervical human papillomavirus (HPV) infections among mothers in the Finnish Family HPV Study

To understand the natural history of cervical human papillomavirus (HPV)-infections, more information is needed on their genotype-specific prevalence, acquisition, clearance, persistence and progression. This thesis is part of the prospective Finnish Family HPV study. 329 pregnant women (mean age 25.5 years) were recruited during the third trimester of pregnancy and were followed up for 6 years. The outcomes of cervical HPV infections were evaluated among all the mothers participating in the study. Generalized estimating equation (GEE)-models and Poisson regression were used to estimate the risk factors of type-specific acquisition, clearance, persistence and progression of Species 7 and 9 HPV-genotypes. Independent protective factors against incident infections were higher number of life-time sexual partners, initiation of oral contraceptive use after age 20 years and becoming pregnant during FU. Older age and negative oral HR-HPV DNA status at baseline were associated with increased clearance, whereas higher number of current sexual partners decreased the probability of clearance. Early onset of smoking, practicing oral sex and older age increased the risk of type-specific persistence, while key predictors of CIN/SIL were persistent HR-HPV, abnormal Pap smear and new sexual partners. HPV16, together with multiple-type infections were the most frequent incident genotypes, most likely to remain persistent and least likely to clear. Collectively, LR-HPV types showed shorter incidence and clearance times than HR-HPV types. In multivariate models, different predictors were associated with these main viral outcomes, and there is some tentative evidence to suggest that oral mucosa might play a role in controlling some of these outcomes.

Heritability at family mean level

Based on a polygenic system of a diploid species, without epistasis, and a population in Hardy-Weinberg equilibrium, without inbreeding and under linkage equilibrium, it can be shown that: (1) the narrow sense heritability at half-sib family level is equal to the square of the correlation coefficient between family mean and the additive genetic value of its common parent; (2) the narrow sense heritability at full-sib family level is equal to the square of the correlation coefficient between family mean and the mean of the additive genetic values of its parents; (3) the narrow sense heritability at Sn family level is exactly equal to the square of the correlation coefficient between family mean and the additive genetic value of its parent only in absence of dominance or when allele frequencies are equal; and (4) the broad sense heritability at full-sib or Sn family level can be used to analyze selection efficiency, since the progeny genotypic mean is, in general, a good indicator of parents, or Sn-1 plant superiority with respect to the frequency of favorable genes.

Relations between communication and development of family farmers

This research investigates relations between communication and the development of family farmers from the Pontal do Paranapanema region (state of São Paulo), mainly in the municipality of Teodoro Sampaio. Family agriculture in this municipality is represented basically by beneficiaries the Agrarian Reform program. The main hypothesis is that communication contributes positively to the development of those family farmers. Thus, this study aimed to understand communication practices of these farmers and relate them with the development of their families. Quantitative and qualitative research methods were used. Development proxy is understood as the combination between the family living conditions and production. Among the main results, it was found that the effect of communication for "life and production conditions" increases as farmers at superior levels of "development" are analyzed; thus the main hypothesis should not be rejected for those farmers with higher development condition. For the others, communication did not have the same effect because many settled families are not focused on agricultural activities. The main suggestion is to improve ways for producers and professionals from public services related to them to access information.

A multicriteria model to assess tractors used in family agriculture

In recent years, public policy has been offering subsidized credit for machine purchase to family farmers. However, there is no methodological procedure to select a suitable tractor for these farmers' situation. In this way, we aimed to develop a selection model for smallholder farmers from Pelotas city region in the state of Rio Grande do Sul. Building a multicriteria model to aid decisions is divided into three main stages: structuring stage (identifying stakeholders, decisional context and model creation), evaluation stage (stakeholder preference quantification) and recommendation stage (choice selection). The Multicriteria method is able to identify and value the criteria used in tractor selection by regional family farmers. Six main evaluation areas were identified: operational cost (weight 0.20), purchase cost (weight 0.22), maintainability (weight 0.10), tractor capacity (weight 0.26), ergonomics (weight 0.14) and safety (weight 0.08). The best-rated tractor model (14.7 kW rated power) also was the one purchased by 53.3% of local families.

Identification of grain areas replaced by sugarcane and analysis of the relationship with family farming production in the state of Goiás

In Brazil, the State of Goiás is one of sugarcane expansion's frontiers to meet the growing demand for biofuels. The objective of this study was to identify the municipalities where there were replacement of annual crops (mainly grains) by sugarcane in the state of Goiás, as well as indicate correlations between the sugarcane expansion and the family farming production, in the period between 2005 and 2010. For this purpose, grains crop mask and sugarcane crop mask, obtained from satellite images, were intersected using geoprocessing techniques. It was also used IBGE data of sugarcane production and planted area, and data of family farming production linked with the National Food Acquisition Program (PAA), in relation to the number of cooperatives and family farmers. The crops masks and data tables of the National Food Acquisition Program were provided by National Food Supply Agency. There were 95 municipalities that had crops replacement, totaling 281,554 hectares of grains converted to sugarcane. We highlight the municipalities of Santa Isabel, Iaciara, Maurilândia, and Itapaci, where this change represented more than half of their agricultural areas. In relation to family farming, the sugarcane expansion in the state of Goiás has not affected their activities during the period studied.

Energetic sustainability of three arabica coffee growing systems used by family farming units in Espírito Santo state

Three growing systems of Arabica coffee were evaluated under the energy perspective, in the state of Espírito Santo in Brazil. The systems are conventional cultivation (CC), cultivation with good agricultural practices (CGP) and organic farming (OF). It was made a comparison of the energy flows within these three systems to show sustainable levels of each one based on production average data of several family-farming units. Therefore, we analyzed crop yield, total energy efficiency reverse (TEER), energy efficiency of ripe coffee (EERC) and non-renewable energy efficiency (NREE). OF system had values for TEER, EERC and NREE of 3.3 4.7 and 7.9 respectively. Yet CC showed values of 1.8, 1.9 and 1.6 for TEER, EERC and NREE respectively. Furthermore, CGP presented values for TEER, EERC and NREE of 0.7, 1.3 and 1.4 respectively. The highest yield was observed in CGP, reaching an amount of 1794 kg ha-1(17,455 MJ); however, this system expends more energy than it converts. Thus, over those points, OF is the most sustainable system.

An Infant with Food Allergy and Eczema in the Family – The Mental and Economic Burden of Caring

Allergic diseases including food allergy and eczema in an infant in combination with the everyday activities of caring for a family will pose challenges to parents. Only fragments of these challenges are revealed to health care professionals. Families have varying mental, social and economic resources to help them care for an allergic infant, and all such resources are important in determining how families succeed in meeting these challenges and the quality of the infant’s care. This study evaluated the whole burden to the family caused by an infant's allergic disease during the first 24 months of life. As the primary caregiver during this period is usually the mother, her perspective was considered important. Ecocultural theory, which considers families as capable of modifying the positive and negative forces facing them, was taken as the frame of reference. Data were collected as part of an ongoing prospective mother-infant study, and the methods included severity scoring of atopic dermatitis, dietary records, health-related quality of life measurements and assessments of the use of health care services and medications for treating the infant’s eczema, food allergy and asthma. Interviews with mothers were analysed by deductive content analysis on the basis of ecocultural theory and the family empowerment model. The theme “Living an ordinary family life” guided the organization of family activities essential for treating the infant's food allergy and eczema. These activities were sources of both strain and support for the mothers, the allergy-related supporting factors being the mother’s own knowledge of the allergy, hopes for an improvement in the infant’s condition, social support and work. An infant’s food allergy at the age of one year caused considerable strain for the mother in cases where the introduction of new foods into the child’s diet was delayed. This delay was still causing the mother additional strain when the child was 24 months of age. The infants waking at night at the ages of 12 and 24 months because of itching related to eczema caused strain for the mothers. The infants’ health-related quality of life was impaired at ages of 6 and 12 months compared with healthy infants. The principal reasons for impairments were itching, scratching and sleep disturbances at 6 and 12 months and treatment difficulties at 6 months. Problems with getting to sleep were reported at all stages irrespective of eczema and were also present in healthy infants. The economic impact of the treatment of allergic diseases on families during the first 24 months was 131 EUR (2006 value) in cases of eczema and 525 EUR in cases of food allergy. From the societal perspective, the costs of food allergy were a median of 3183 EUR (range 628–11 560 EUR) and of eczema a median of 275 EUR (range 94–1306 EUR). These large variations in costs in food allergy and eczema indicate that disease varies greatly . In conclusion, food allergy and eczema cause extra activities and costs to families which arrange these disease-related activities in such a way that they support the leading family theme “Living an ordinary family life”. Health care professionals should consider this thematic character of family life and disease-related activities in order to ensure that new treatments are sustainable, meaningful and tailored to daily activities. In addition, those mothers who are experiencing difficulties with food allergic infants or infants with eczema should be recognized early and provided with individual encouragement and support from health clinics. In the light of the present results, early detection of symptoms and effective parental guidance can contribute to the well-being and health-related quality of life of the child and family.