DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes.

OBJECTIVE: Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes. METHODS: We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry. RESULTS: We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth. CONCLUSION: Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D.

Integrative analysis reveals novel associations between DNA methylation and the serum metabolome of adolescents with type 2 diabetes: A cross-sectional study.

Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D. Methods: We performed a cross sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through Research (iCARE) cohort study, to explore the molecular changes in adolescents with T2D. Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others. Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

Maternal diabetes promotes offspring lung dysfunction and inflammation in a sex-dependent manner.

Exposure to maternal diabetes is increasingly recognized as a risk factor for chronic respiratory disease in children. It is currently unclear; however, whether maternal diabetes affects the lung health of male and female offspring equally. This study characterizes the sex-specific impact of a murine model of diet-induced gestational diabetes (GDM) on offspring lung function and airway inflammation. Female adult mice are fed a high-fat (45% kcal) diet for 6 wk prior to mating. Control offspring are from mothers fed a low-fat (10% kcal) diet. Offspring were weaned and fed a chow diet until 10 wk of age, at which point lung function was measured and lung lavage was collected. Male, but not female, offspring exposed to GDM had increased lung compliance and reduced lung resistance at baseline. Female offspring exposed to GDM displayed increased methacholine reactivity and elevated levels of proinflammatory cytokines [e.g., interleukin (IL)-1ß, IL-5, and CXCL1] in lung lavage. Female GDM offspring also displayed elevated abundance of matrix metalloproteinases (MMP) within their airways, namely, MMP-3 and MMP-8. These results indicate disparate effects of maternal diabetes on lung health and airway inflammation of male and female offspring exposed to GDM. Female mice may be at greater risk of inflammatory lung conditions, such as asthma, whereas male offspring display changes that more closely align with models of chronic obstructive pulmonary disease. In conclusion, there are important sex-based differences in the impact of maternal diabetes on offspring lung health that could signal differences in future disease risk.

Adiponectin deficiency induces hepatic steatosis during pregnancy and gestational diabetes in mice.

AIMS/HYPOTHESIS: Obesity and hepatic steatosis are risk factors for gestational diabetes mellitus (GDM), a common complication of pregnancy. Adiponectin is a fat-derived hormone that improves hepatic steatosis and insulin sensitivity. Low levels of circulating adiponectin are associated with GDM development. We hypothesised that adiponectin deficiency causes fatty liver during pregnancy, contributing to the development of GDM. METHODS: To determine the role of adiponectin in fatty liver development during pregnancy, we compared pregnant (third week of pregnancy) adiponectin knockout (KO) mice (strain B6;129-Adipoqtm1Chan/J) with wild-type mice and assessed several variables of hepatic lipid metabolism and glucose homeostasis. The impact of adiponectin supplementation was measured by administering adenovirus-mediated full-length adiponectin at the end of the second week of pregnancy and comparing with green fluorescent protein control. RESULTS: In the third week of pregnancy, fasted pregnant adiponectin KO mice were hyperglycaemic on a low-fat diet (9.2 mmol/l vs 7.7 mmol/l in controls, p<0.05) and were glucose and pyruvate intolerant relative to wild-type mice. Pregnant adiponectin KO mice developed hepatic steatosis and a threefold elevation in hepatic triacylglycerols (p<0.05) relative to wild-type mice. Gestational weight gain and food consumption were similar in KO and wild-type mice. Adenoviral-mediated adiponectin supplementation to pregnant adiponectin KO mice improved glucose tolerance, prevented fasting hyperglycaemia and attenuated fatty liver development. CONCLUSIONS/INTERPRETATION: Adiponectin deficiency increased hepatic lipid accumulation during the period of pregnancy associated with increased fat utilisation. Consequently, adiponectin deficiency contributed to glucose intolerance, dysregulated gluconeogenesis and hyperglycaemia, all of which are characteristic of GDM. Increasing adiponectin in the last week of pregnancy alleviated hepatic steatosis and restored normal glucose homeostasis during pregnancy.

Exploiting Polyelectrolyte Complexation for the Development of Adhesive and Bioactive Membranes Envisaging Guided Tissue Regeneration.

Mussels secrete protein-based byssal threads to tether to rocks, ships, and other organisms underwater. The secreted marine mussel adhesive proteins (MAPs) contain the peculiar amino acid L-3,4-dihydroxyphenylalanine (DOPA), whose catechol group content contributes greatly to their outstanding adhesive properties. Inspired by such mussel bioadhesion, we demonstrate that catechol-modified polysaccharides can be used to obtain adhesive membranes using the compaction of polyelectrolyte complexes (CoPEC) method. It is a simple and versatile approach that uses polyelectrolyte complexes as building blocks that coalesce and dry as membrane constructs simply as a result of sedimentation and mild temperature. We used two natural and biocompatible polymers: chitosan (CHI) as a polycation and hyaluronic acid (HA) as a polyanion. The CoPEC technique also allowed the entrapment of ternary bioactive glass nanoparticles to stimulate mineralization. Moreover, combinations of these polymers modified with catechol groups were made to enhance the adhesive properties of the assembled membranes. Extensive physico-chemical characterization was performed to investigate the successful production of composite CoPEC membranes in terms of surface morphology, wettability, stability, mechanical performance, in vitro bioactivity, and cellular behavior. Considering the promising properties exhibited by the obtained membranes, new adhesives suitable for the regeneration of hard tissues can be envisaged.

Applied science facilitates the large-scale expansion of protected areas in an Amazonian hot spot.

Meeting international commitments to protect 17% of terrestrial ecosystems worldwide will require >3 million square kilometers of new protected areas and strategies to create those areas in a way that respects local communities and land use. In 2000-2016, biological and social scientists worked to increase the protected proportion of Peru's largest department via 14 interdisciplinary inventories covering >9 million hectares of this megadiverse corner of the Amazon basin. In each landscape, the strategy was the same: convene diverse partners, identify biological and sociocultural assets, document residents' use of natural resources, and tailor the findings to the needs of decision-makers. Nine of the 14 landscapes have since been protected (5.7 million hectares of new protected areas), contributing to a quadrupling of conservation coverage in Loreto (from 6 to 23%). We outline the methods and enabling conditions most crucial for successfully applying similar campaigns elsewhere on Earth.

Tafazzin Deficiency Reduces Basal Insulin Secretion and Mitochondrial Function in Pancreatic Islets From Male Mice.

Tafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ affects both the species and content of CL in the inner mitochondrial membrane, which are essential for normal cellular respiration. In pancreatic ß cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown. Male 4-month-old doxycycline-inducible TAZ knock-down (KD) mice and wild-type littermate controls were used. Immunohistochemistry was used to assess ß-cell morphology in whole pancreas sections, whereas ex vivo insulin secretion, CL content, RNA-sequencing analysis, and mitochondrial oxygen consumption were measured from isolated islet preparations. Ex vivo insulin secretion under nonstimulatory low-glucose concentrations was reduced ~52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ~58% in islets from TAZ KD animals. TAZ deficiency in pancreatic islets was associated with significant alteration in CL molecular species and elevated polyunsaturated fatty acid CL content. In addition, RNA-sequencing of isolated islets showed that TAZ KD increased expression of extracellular matrix genes, which are linked to pancreatic fibrosis, activated stellate cells, and impaired ß-cell function. These data indicate a novel role for TAZ in regulating pancreatic islet function, particularly under low-glucose conditions.

Maternal resveratrol administration protects against gestational diabetes-induced glucose intolerance and islet dysfunction in the rat offspring.

KEY POINTS: Maternal resveratrol (RESV) administration in gestational diabetes (GDM) restored normoglycaemia and insulin secretion. GDM-induced obesity was prevented in male GDM+RESV offspring but not in females. GDM+RESV offspring exhibited improved glucose tolerance and insulin sensitivity. GDM+RESV restored hepatic glucose homeostasis in offspring. Glucose-stimulated insulin secretion was enhanced in GDM+RESV offspring. ABSTRACT: Gestational diabetes (GDM), the most common complication of pregnancy, is associated with adverse metabolic health outcomes in offspring. Using a rat model of diet-induced GDM, we investigated whether maternal resveratrol (RESV) supplementation (147 mg kg-1  day-1 ) in the third week of pregnancy could improve maternal glycaemia and protect the offspring from developing metabolic dysfunction. Female Sprague-Dawley rats consumed a high-fat and sucrose (HFS) diet to induce GDM. Lean controls consumed a low-fat (LF) diet. In the third trimester, when maternal hyperglycaemia was observed, the HFS diet was supplemented with RESV. At weaning, offspring were randomly assigned a LF or HFS diet until 15 weeks of age. In pregnant dams, RESV restored glucose tolerance, normoglycaemia and improved insulin secretion. At 15 weeks of age, GDM+RESV-HFS male offspring were less obese than the GDM-HFS offspring. By contrast, the female GDM+RESV-HFS offspring were similarly as obese as the GDM-HFS group. Hepatic steatosis, insulin resistance, glucose intolerance and dysregulated gluconeogenesis were observed in the male GDM offspring and were attenuated in the offspring of GDM+RESV dams. The dysregulation of several metabolic genes (e.g. ppara, lpl, pepck and g6p) in the livers of GDM offspring was attenuated in the GDM+RESV offspring group. Glucose stimulated insulin secretion was also improved in the islets from offspring of GDM+RESV dams. Thus, maternal RESV supplementation during the third trimester of pregnancy and lactation induced several beneficial metabolic health outcomes for both mothers and offspring. Therefore, RESV could be an alternative to current GDM treatments.

Gestational Diabetes Adversely Affects Pancreatic Islet Architecture and Function in the Male Rat Offspring.

Fetal exposure to gestational diabetes mellitus (GDM) and poor postnatal diet are strong risk factors for type 2 diabetes development later in life, but the mechanisms connecting GDM exposure to offspring metabolic health remains unclear. In this study, we aimed to determine how GDM interacts with the postnatal diet to affect islet function in the offspring as well as characterize the gene expression changes in the islets. GDM was induced in female rats using a high-fat, high-sucrose (HFS) diet, and litters from lean or GDM dams were weaned onto a low-fat (LF) or HFS diet. Compared with the lean control offspring, GDM exposure reduced glucose-stimulated insulin secretion in islets isolated from 15-week-old offspring, which was additively worsened when GDM exposure was combined with postnatal HFS diet consumption. In the HFS diet-fed offspring of lean dams, islet size and number increased, an adaptation that was not observed in the HFS diet-fed offspring of GDM dams. Islet gene expression in the offspring of GDM dams was altered in such categories as inflammation (e.g., Il1b, Ccl2), mitochondrial function/oxidative stress resistance (e.g., Atp5f1, Sod2), and ribosomal proteins (e.g., Rps6, Rps14). These results demonstrate that GDM exposure induced marked changes in gene expression in the male young adult rat offspring that cumulatively interact to worsen islet function, whole-body glucose homeostasis, and adaptations to HFS diets.

Novos paradigmas em saúde

O curso de especialização saúde da família, no módulo novos paradigmas em saúde, aula 5 , aborda o paradigma biopsicossocial ou paradigma da integralidade e suas principais características. Bem como, as principais diferenças em relação ao paradigma biomédico/biotecnológico.

Clínica da Atenção Primária à Saúde II [caso dona Antônia]

O curso de especialização saúde da família, no módulo clínica da atenção primária à saúde II, apresenta o material sobre o caso dona Antônia. Espera-se que os profissionais sejam capazes de otimizar o processo de trabalho em equipe, de forma que se realize um planejamento de ações que resulte num incremento da qualidade de vida e da assistência à saúde da população sob sua responsabilidade sanitária.

Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome.

Maternal obesity is associated with a high risk for gestational diabetes mellitus (GDM), which is a common complication of pregnancy. The influence of maternal obesity and GDM on the metabolic health of the offspring is poorly understood. We hypothesize that GDM associated with maternal obesity will cause obesity, insulin resistance and hepatic steatosis in the offspring. Female Sprague-Dawley rats were fed a high-fat (45%) and sucrose (HFS) diet to cause maternal obesity and GDM. Lean control pregnant rats received low-fat (LF; 10%) diets. To investigate the interaction between the prenatal environment and postnatal diets, rat offspring were assigned to LF or HFS diets for 12 weeks, and insulin sensitivity and hepatic steatosis were evaluated. Pregnant GDM dams exhibited excessive gestational weight gain, hyperinsulinaemia and hyperglycaemia. Offspring of GDM dams gained more weight than the offspring of lean dams due to excess adiposity. The offspring of GDM dams also developed hepatic steatosis and insulin resistance. The postnatal consumption of a LF diet did not protect offspring of GDM dams against these metabolic disorders. Analysis of the hepatic metabolome revealed increased diacylglycerol and reduced phosphatidylethanolamine in the offspring of GDM dams compared to offspring of lean dams. Consistent with altered lipid metabolism, the expression of CTP:phosphoethanolamine cytidylyltransferase, and peroxisomal proliferator activated receptor-α mRNA was reduced in the livers of GDM offspring. GDM exposure programs gene expression and hepatic metabolite levels and drives the development of hepatic steatosis and insulin resistance in young adult rat offspring.

Eixos Centrais do Processo de Trabalho em Atenção Primária à Saúde : Disciplina 3

Apresenta temáticas essenciais que norteiam o trabalho em Atenção Primária à Saúde. Aprimora o conhecimento sobre temas como: acolhimento, trabalho em equipe multidisciplinar, importância das reuniões de serviço, papel dos cuidadores e da educação em saúde com foco na Estratégia de Saúde da Família. Espera que o profissional da Saúde da Família tenha oportunidade de refletir sobre como atuar na comunidade, conhecer os pacientes em sua individualidade, saber seu histórico familiar e diagnosticar com mais mais precisão cada caso, aumentando suas competências no âmbito da Abordagem Centrada na Pessoa, na Família e na Comunidade.

O Caso do Seu Agenor

Aprimora o conhecimento sobre temas como: acolhimento, trabalho em equipe multidisciplinar, importância das reuniões de serviço, papel dos cuidadores e da educação em saúde com foco na Estratégia de Saúde da Família.

A Clínica da Atenção Primária I : Disciplina 2

Aborda o cuidado em saúde com base no paradigma da integralidade biopsicossocial e na atenção integral à saúde na APS. Apresenta a Abordagem Centrada na Pessoa e a Abordagem Familiar e Comunitária como eixo estruturante do processo de trabalho e como um diferencial no atendimento das equipes da Saúde da Família. Apropria do Caso da Dona Antônia e do Caso da Ana Maria e explora a necessidade de integração das ações de promoção, educação em saúde, prevenção de agravos, assistência e reabilitação dos problemas mais relevantes no âmbito individual, familiar e comunitário. Discute como desenvolver ações na perspectiva do cuidado integrado e interdisciplinar.

O Caso da Dona Antônia

Explora a necessidade de integração das ações de promoção, educação em saúde, prevenção de agravos, assistência e reabilitação dos problemas mais relevantes no âmbito individual, familiar e comunitário. Discute como desenvolver ações na perspectiva do cuidado integrado e interdisciplinar.

O Caso Ana Maria

Explora a necessidade de integração das ações de promoção, educação em saúde, prevenção de agravos, assistência e reabilitação dos problemas mais relevantes no âmbito individual, familiar e comunitário. Discute como desenvolver ações na perspectiva do cuidado integrado e interdisciplinar.

O caso da Vila Santo Antônio

Aborda os princípios que norteiam o Sistema Único de Saúde e a importância da Atenção Primária à Saúde na sua consolidação e qualificação. Retrata aspectos relacionados ao processo de trabalho das equipes, como: cobertura de área, atendimento da população adscrita, resolutividade, referência e contra-referência, apoio matricial, intersetorialidade, entre outros. Apresenta partir de situações concretas, casos comuns ao cotidiano das equipes de Saúde da Família, como o da Vila Santo Antônio. Contextualiza e discute aspectos importantes para o conhecimento dos profissionais que atuam na Saúde da Família, como o histórico, as experiências, a conceituação e os princípios da APS e da Estratégia Saúde da Família (SF) no Brasil e no mundo.

Influência da Dieta e da Higiene Oral na Prevalência da Cárie Dentária de Crianças Com Paralisia Cerebral / Influence of Diet and Oral Hygiene on Dental Caries Prevalence of Children with Cerebral Palsy

Objetivo: Comparar a prevalência de cárie dentária na dentadura decídua e dentição mista, o índice de higiene oral e a dieta de crianças institucionalizadas e não institucionalizadas com paralisia cerebral; verificar a influência da dieta e da higiene oral na incidência da cárie e descrever os fatores econômicos das crianças não institucionalizadas.Métodos: Foi realizado estudo transversal com trinta e três crianças institucionalizadas e trinta e sete não institucionalizadas que definiram os grupos de estudo I e II respectivamente. Os grupos foram subdivididos por idade para avaliação do CPOD e ceod. Foram obtidos dados relativos à higiene bucal diária, o diário dietético recordatório de 3 dias, os fatores socioeconômicos e à disfunção alimentar. Após exame clínico e análise dos questionários, os dados foram tabulados e analisados estatisticamente. Para a comparação entre os grupos em relação à idade, utilizou-se o teste t de Student para amostras independentes. Para a diferença entre os grupos, quanto à higiene oral e à disfunção alimentar aplicou-se o teste Qui-quadrado ou o teste exato de Fisher (nos casos em que ocorreram valores esperados >5). A comparação entre os grupos, bem como a avaliação da influência da freqüência da escovação, uso do fio dental, pasta fluoretada, o fato de receber ajuda para higienização bucal e alimentação, foi realizada utilizando-se o teste de Mann-Whitney. Para a avaliação da influência do grau de disfunção alimentar nos índices CPOD, biofilme dentário, cálculo e IHOS foi realizado o teste de Kruskal-Wallis. Todos os resultados foram considerados significativos para a probabilidade de significância inferior a 5% (p<0,05). A concordância intra-examinador foi avaliada através do índice de Kappa (89,1% e 94,6%).

Resultados: Os resultados mostraram valores menores para o grupo I no CPOD e ceod e no IHO-S quando comparados com o grupo II. Somente os valores do CPOD (3-6 anos de idade=0) foram iguais para ambos os grupos. O índice do consumo de sacarose foi 22 para o grupo I e 8.6 para o grupo II. A disfunção alimentar avaliada demonstrou presença de disfunção no grupo I (GI=54%) e no grupo II (GII=81.9%). O grupo II consistiu em 51.45% na classe econômica C e 35.1% de classe D. O índice de higiene oral e de consumo de sacarose não demonstraram relação com os índices de cárie dentária nos dois grupos. Quanto a dieta, as alterações alimentares encontradas em conjunto com as alterações motoras inerentes à doença influenciaram o IHO-S em toda amostra estudada.Conclusão: A alteração da dieta e a educação dos pais e responsáveis quanto à saúde oral devem ser objetivo de todos aqueles que trabalham com pacientes com paralisia cerebral

Objective: To compare the prevalence of dental caries in deciduous and mixed dentition, the oral hygiene index and the diet of institutionalized and non-institutionalized children with cerebral palsy; to verify the influence of the diet and of the oral hygiene in the caries incidence and to describe the economic factor of the non-institutionalized children.Methods: A cross-sectional study involving thirty-three institutionalized and thirty-seven non-institutionalized children defined the groups of study I and II respectively. The groups have been subdivided by age, for evaluation of the DMFT and dmft. Information related to the daily oral hygiene, the 3-day food record, the social and economic factors and the feeding dysfunction has been obtained. After the exam in a clinic environment, the analysis of the questionnaires and of the daily diet, the data have been analyzed statistically. For comparison between groups regarding age, we used the Student t test for independent samples. The difference between groups in respect to oral hygiene and eating disorders has applied the chi-square or Fisher exact test (where expected values were >5). The comparison between groups, as well as assessing the influence of frequency of brushing, flossing, fluoride toothpaste, the fact of receiving aid for oral hygiene and diet, was performed using the Mann-Whitney test. The evaluation of the degree of eating disorders in DMFT, dental plaque, calculus and OHI-S was performed using the Kruskal-Wallis. All results were considered significant for the probability of significance at 5% (p<0.05). The intraexaminer was assessed using the kappa index (89.1% and 94,6%).

Results: The results showed lower values for group I of DMFT and dmft and OHI-S than the group II. Only the values to the DMFT (3-6 years old =0) was equal for both groups. The sugar intake index was 22 for group I e 8.6 for group II. The evaluated feeding dysfunction has demonstrated dysfunction in group-I (GI=54%) and the group II (GII=81.9%). Group-II was consisted of 51.45% of class C and 35.1% of class D. The rate of oral hygiene and of sugar consumption has not demonstrated any relation to the rates of dental caries in both groups. Regarding the diet, the feeding alterations found together with the motor alterations inherent to the disease have influenced the OHI-S score in the entire studied sample.Conclusion: The alteration of the diet and the education of the parents and the responsible ones regarding the oral health should be the objective of all of those who work with patients with cerebral palsy