Introdução: A doença de Machado-Joseph (DMJ) ou ataxia espinocerebelar tipo 3 (SCA3) é causada por uma expansão de trinucleotídeos CAG no gene ATXN3, que leva à degeneração de múltiplos sistemas neurológicos. Seu curso é invariavelmente progressivo, não havendo tratamento específico. Objetivos: Descrever novos biomarcadores, aspectos não motores e definir quais escalas clínicas devem ser utilizadas como desfechos principais nos futuros ensaios clínicos randomizados (ECR) para a DMJ/SCA3. Além de avaliar se o tratamento com carbonato de lítio é seguro e efetivo em reduzir a progressão desta condição. Métodos: Em estudo caso-controle avaliamos: 1) a relação dos sintomas depressivos na DMJ/SCA3, pelo inventário de Beck (BDI), com aspectos de gravidade clínica e molecular; 2) alterações no índice de massa corporal (IMC) e sua correlação com aspectos clínico-moleculares e de neuroimagem; e 3) o Sistema Insulina/ IGF-1 (IIS) e o potencial de seus componentes como biomarcadores. Fizemos uma revisão sistemática sobre os aspectos psicométricos das escalas clínicas de SCAs já descritas, para em seguida iniciarmos um ECR, duplo-cego, paralelo, placebo-controlado de fase 2/3. Para este estudo foram randomizados 62 pacientes com diagnóstico molecular prévio de DMJ/SCA3 com marcha independente e ≤ 10 anos de doença (1:1) para tratamento com carbonato de lítio (0.5-0.8mEq/L) ou placebo. Resultados: Os escores do BDI foram mais elevados na DMJ/SCA3 (p= 0.012) e correlacionaram-se significativamente apenas com as escalas SARA (R=0.359, p=0.01) e NESSCA (R=0.412, p=0.003). Os pacientes com DMJ/SCA3 (N=46) apresentaram IMC menor (24.4 ± 4.1) do que os indivíduos controle (N=42, 27.1± 4.5, p=0.01), havendo correlação inversa (R=−0.396, p=0.015) entre o IMC e o tamanho da sequencia repetitiva CAG (CAGn). Encontramos uma maior sensibilidade periférica à insulina (HOMA2-%S, p=0.003, corrigido pelo IMC) e níveis séricos mais elevados da proteína ligante do IGF-1, IGFBP-1 (p=0.001) na DMJ/SCA3. A IGFBP1 correlacionou-se diretamente à CAGn (R=0.452; p = 0.006) e a sensibilidade à insulina inversamente à idade de início dos sintomas (R=-0.444; P = 0.003). Concluímos, na revisão sistemática, que as escalas semi-quantitativas SARA e NESSCA, e as quantitativas SCAFI e CCFS seriam os melhores desfechos para um ECR. O uso de lítio foi seguro após 24 semanas de tratamento, não havendo diferenças no número total de eventos adversos entre os grupos lítio (50,3%) e placebo (49,7%, p=1.00). O grupo placebo apresentou maior progressão (que não foi significativa) nos escores NESSCA (0.35 pontos, 95% IC -1.0 a 1.7, p=0.222, desfecho primário de efetividade) e SARA (0.96 pontos, 95% IC -0.46 a 2.38, p=0.329), após 48 semanas de tratamento. A gravidade da ataxia de marcha (p=0.008), as provas funcionais quantitativas: PATA rate (p=0.002) e Click Test ND (p=0.023), e os escores compostos SCAFI (p=0.015) e CCFS (p=0.029) apresentaram menor progressão no grupo tratado com lítio durante as 48 semanas. Conclusão: Os resultados destes estudos ajudam no entendimento da depressão e alterações nutricionais da DMJ/SCA3 e apontam a IGFBP-1 como biomarcador e a sensibilidade periférica insulínica como modificador do fenótipo. Houve efetividade do tratamento com carbonato de lítio nos desfechos secundários do ECR, sendo necessária confirmação por ensaios clínicos multicêntricos. / Background: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is caused by a CAG repeat expansion at ATXN3 gene, leading to progressive degeneration of multiple neurological systems. MJD/SCA3 is an invariably progressive disorder, with no current treatment. Objectives: To describe new disease biomarkers, non-motor aspects and to define the clinical SCA scales to be utilized as main outcomes in future randomized controlled trials (RCT) on MJD/SCA3. And further assess safety and effectiveness of lithium carbonate in reducing the progression of this condition. Methods: We performed a case-control study to evaluate: 1) the relation of MJD/SCA3 depressive symptoms, through Beck depression Inventory (BDI), with other clinical and molecular findings; 2) the Body Mass Index (BMI) of MJD/SCA3 patients and the correlation with other clinical, molecular and neuroimaging findings; and 3) the Insulin/IGF-1 system (IIS) in MJD/SCA3 and the possible biomarker properties of its components. We further performed a systematic review on the psychometric properties of the described SCAs scales in order to initiate the double-blind, parallel, placebo-controlled phase 2/3 clinical trial. 62 independently ambulatory MJD/SCA3 patients with ≤ 10 years of disease duration were randomly assigned in the RCT (1:1) to lithium (0.5-0.8mEq/L) or placebo. Results: BDI scores were higher in MJD/SCA3 patients (p= 0.012), with significant correlations only with the scales SARA (R=0.359, p=0.01) and NESSCA (R=0.412, p=0.003). MJD/SCA3 patients (N=46) presented lower BMI (24.4 ± 4.1) than control individuals (N=42, 27.1± 4.5, p=0.01). BMI correlated inversely with the length of the expanded CAG repeat (CAGn). We found higher peripheral sensitivity to insulin (HOMA2-%S, p=0.003, corrected for BMI) and serum levels of the IGF-1 binding protein, IGFBP-1 (p=0.001) in MJD/SCA3. IGFBP-1 correlated with CAGn (R=0.452; p = 0.006) and insulin sensitivity with the age of disease onset (R=-0.444; P = 0.003). In the systematic review we concluded that the semiquantitative SCA scales SARA and NESSCA and the quantitative instruments SCAFI and CCFS would be the most appropriate outcomes for the RCT. After 24 weeks, there were no differences in the number of adverse events in lithium (50.3%) and placebo (40.7%) groups (p=1.00) in the RCT. The placebo group presented a non-significant faster progression on NESSCA (0.35 points, 95% CI -1.0 to 1.7, p=0.612, primary effectiveness outcome) and SARA (0.96 points, 95% CI -0.46 to 2.38, p=0.186), after 48 weeks of treatment. Gait ataxia severity (p=0.008), the quantitative performance tasks: PATA rate (p=0.002) and Click Test ND (p=0.023), and the composite scores SCAFI (p=0.015) and CCFS (p=0.029) presented a slower progression under lithium therapy in the overall 48 weeks period. Conclusion: These studies added to the understanding of depressive and nutritional manifestations of MJD/SCA3 and points IGFBP-1 as a biomarker and peripheral insulin sensitivity as a disease phenotype modifier. The effectiveness of lithium carbonate treatment shown in secondary outcomes of the RCT opened a perspective for an effective therapy for this untreatable disorder that must be confirmed by large multicentric clinical trials.

Fundamentos: São necessárias avaliações do estado nutricional de povos indígenas, como forma de mensurar influências ambientais e sociais sobre as condições de vida e saúde e fornecer subsídios para intervenções. Este estudo, de base escolar, objetivou descrever o estado nutricional de crianças e adolescentes Kaingang pela antropometria e pela impedância bioelétrica (IBE) e comparar as classificações geradas pelos dois métodos. Métodos: Estudaram-se 3207 indígenas (73,6% dos matriculados) das 35 escolas de 12 Terras Indígenas Kaingang do Rio Grande do Sul, Brasil. Foram mensurados peso e estatura conforme WHO (1995) e parâmetros de resistência (R) e reactância (Xc), em Ohm, mediante impedanciômetro RJL Systems Electrode Placement. O índice estatura/idade e o índice de massa corporal/idade foram calculados e classificados segundo WHO (2007). A composição corporal foi avaliada pela Análise Vetorial de Impedância Bioelétrica (BIVA) conforme Piccoli et al (1994). A comparação entre classificações da antropometria e BIVA foi realizada graficamente, com base nas elipses de tolerância do gráfico RXc. Foram considerados significantes valores de p<0,05. Resultados: A idade média da amostra foi de 10,8 anos (+2,9), sendo 56,8% adolescentes e 50,6% do sexo masculino. Encontraram-se prevalências de déficit estatural (E/I) de 15,5% e 19,9% e de excesso de peso pelo IMC/Idade de 5,7% e 6,7%, respectivamente para crianças e adolescentes. Para ambos os sexos e faixas etárias, a amostra apresentou desvio em direção ao quadrante inferior esquerdo do gráfico RXc, indicando maior proporção de gordura em relação ao tecido não gordo. Para as crianças do sexo masculino a proporção de indivíduos além da elipse de tolerância de 95% foi de 2,7% e a proporção de indivíduos com classificações discrepantes, relativas à antropometria, foi de 94,6%. As mesmas proporções alcançaram, respectivamente, 2,3% e 77,1% para os adolescentes do sexo masculino; 2,5% e 85,4% para as crianças do sexo feminino e 0,6% e 94,8% para as adolescentes do sexo feminino. Conclusão: Aponta-se a transição nutricional entre os Kaingang, caracterizada por prevalências importantes de déficit estatural e excesso de peso. As discrepâncias entre as classificações do IMC/idade e BIVA sinalizam a necessidade de estudos que procurem conciliar maior número de técnicas de avaliação nutricional, como a conciliação da antropometria com a IBE. / Background: Indigenous nutritional status evaluations are necessary, as a way to measure social and environmental influences on health and life conditions and to provide subsidies for interventions. This school-based study aimed to describe the nutritional status of Kaingang children and adolescents by anthropometry and bioelectrical impedance (BIA), and to compare classifications obtained by both methods. Methods: 3207 indigenous (73.6% of the enrolled) of the 35 schools in 12 Indigenous Lands Kaingang of Rio Grande do Sul, Brazil were studied. Weight and height were measured according to WHO (1995) and resistance parameters (R) and reactance (Xc), in Ohm, by impedanciometer RJL Systems Electrode Placement. Height/ age index and body mass/ age index were classified based on WHO (2007). Body composition was evaluated by Bioelectric Impedance Vector Analysis (BIVA) according to Piccoli et al (1994). Comparisons between anthropometry and BIVA classifications were done graphically, based on the tolerance ellipses of RXc graph. Significant p values <0.05. Results: The average age of the sample was 10.8 years (+2.9), 56.8% of adolescents and 50.6% of males. Prevalence of stunting (H/A) of 15.5% and 19.9% and overweight (BMI/ age) of 5.7% and 6.7% were found, respectively for children and adolescents. For both sexes and age groups deviation toward the lower left quadrant of RXC graph was shown, indicating a higher proportion of fat in relation to not fat tissues. For male children, proportion of subjects beyond the 95% tolerance ellipse was 2.7% and proportion of subjects with discrepant classifications, relative to anthropometry, was 94.6%. The same proportions achieved, respectively, 2.3% and 77.1% of male adolescents, 2.5% and 85.4% of female children, and 0.6% and 94.8% of female adolescents. Conclusions: The study points the nutritional transition among the Kaingang, characterized by important prevalence of stunting and overweight. Discrepancies between classifications of BMI/age and BIVA signal the necessity of studies that look for the conciliation of differents nutritional evaluation techniques, as anthropometry and BIA.

Made available in DSpace on 2016-03-15T19:39:57Z (GMT). No. of bitstreams: 1 Amanda Faria Barrozo.pdf: 1566091 bytes, checksum: 3c248574803f27665cfda719bb460313 (MD5) Previous issue date: 2013-02-04 / Introduction: Down syndrome (DS) is the leading genetic cause of intellectual disability. The clinical characterization is broad and includes: hypotonic, muscle weakness, low physical fitness, stunting and overweight. The literatures shows a relationship between physical fitness and body composition, which can be assessed by anthropometric indicators such as body mass index (BMI), waist circumference (WC) and skinfold thickness along with bioelectrical impedance analysis (BIA). Physical fitness can be assessed by 6-minute walk test (6MWT). Objective: To evaluate and correlate the distance covered on the 6MWT with anthropometric measurements and body composition of adolescents with DS that not practicing sport in competition regime. Methods: It was conducted an observational study of 22 young males with DS between September and October 2012. The data collected were: height and weight to calculate BMI and realize the nutritional classification, waist circumference to assess the presence of central fat and skinfold thickness to calculate %body fat (% BF). Furthermore, it was evaluated the lean mass (LM) using BIA and performed the 6MWT to assess the physical fitness of the individuals. The adolescents were divided into three age groups. It was adopted as the level of statistical significance set at p <0.05. Results: The mean of the sample variables were: age: 15.59 years, body mass: 62.28 kg, height: 1.53 m, BMI: 26.31 kg/m2, WC: 87.57 cm, %BF: 37.8%, LM: 50.87 kg and 6MWT distance was 478m. Among the participantes, 9 were classified as normal weight, 12 overweight and 1 obese. WC had increased in 13 adolescents and only 1 participant showed a normal %BF. There was significant difference between groups for BMI, WC and LM lean mass and a positive correlation between all anthropometric measurements and lean mass mesured by BIA. However, it was not observed for the 6MWT. Conclusions: All anthropometric indicators showed good correlation with each other and LM given by the BIA. There has been a growing trend among age groups for BMI and WC and decreasing for lean mass. However, no difference was observed between groups for both BF% given by the skinfold thickness and the distance covered in 6MWT. Moreover, the distance did not correlate with any other variable. The distance walked during the 6MWT may be impaired in people with intellectual deficit by understanding issues, since no correlations were obtained between anthropometric data, body composition and performance in the test. / Introdução: A síndrome de Down (SD) representa a principal causa genética de deficiência intelectual. Sua caracterização clínica é ampla e inclui: hipotonia, fraqueza muscular, baixo condicionamento físico, baixa estatura e excesso de peso. A literatura aponta relações entre o condicionamento físico e a composição corporal, que pode ser avaliada por indicadores antropométricos como o índice de massa corpórea (IMC), circunferência abdominal (CA) e as dobras cutâneas (DC), juntamente com a bioimpedância elétrica (BIA). O condicionamento físico pode ser avaliado pelo Teste de Caminhada de 6 minutos (TC6M). Objetivo: Avaliar e correlacionar a distância percorrida no TC6M com as medidas antropométricas e a composição corporal de adolescentes com SD não praticantes de modalidade desportiva em regime de competição. Casuística e Método: Foi realizado um estudo observacional com uma amostra de 22 jovens do gênero masculino com SD entre setembro e outubro de 2012. Os dados coletados foram: estatura e massa corporal para calcular o IMC e realizar a classificação nutricional, a circunferência abdominal para avaliar a presença de gordura central e as dobras cutâneas do tríceps e subescapular para calcular o %gordura corporal (%GC). Além disso, foi avaliada a massa magra (MM) utilizando a bioimpedância elétrica e realizado o TC6M para avaliar o condicionamento físico dos sujeitos. Os jovens foram distribuídos em três grupos etários. Adotou-se como nível de significância estatística o valor de p < 0,05. Resultados: As médias das variáveis da amostra foram: idade: 15,59 anos, massa corporal: 62,28kg, estatura: 1,53m, IMC: 26,31kg/m2 , CA: 87,57cm, %GC 37,8%, massa magra: 50,87kg e a distância percorrida no TC6M foi 478m. Dentre os participantes, 9 foram classificados como eutróficos, 12 com sobrepeso e um obeso. Apresentavam CA aumentada 13 participantes e apenas um apresentou %GC normal. Foi observada diferença significativa entre os grupos para IMC, CA e massa magra. Houve correlação positiva entre todos os indicadores antropométricos e a massa magra avaliada pela BIA. Entretanto, o mesmo não foi observado para o TC6M. Conclusões: Todos os indicadores antropométricos apresentaram boa correlação entre si e com a massa magra e %GC dado pela BIA. Houve uma corrrelação linear positiva entre os grupos etários para IMC e circunferência abdominal e negativa para massa magra. Porém, não foi observada diferença entre grupos tanto para %GC dado pela DC quanto para a distância percorrida no TC6M. Conclui-se que a distância percorrida no teste de caminhada de seis minutos pode ser prejudicada em populações com déficit intelectual por questões de compreensão da prova, uma vez que não foram obtidas correlações entre os dados antropométricos, composição corporal e desempenho no teste.

A hipercolesterolemia familiar (HF) é caracterizada por concentrações elevadas de LDL-c e alta prevalência de doença arterial coronária (DAC) precoce. Entretanto, o curso da DAC nos portadores de HF é variável e pode ser influenciado por outros fatores de risco. O objetivo foi avaliar parâmetros clínicos e nutricionais de adultos portadores de HF heterozigótica por estudo do tipo transversal. Coletou-se do prontuário dos pacientes resultados de exames laboratoriais, medidas de pressão arterial e diagnósticos clínicos. Verificou-se a concordância ou não entre as categorias de risco pelos escores de Framingham (ERF) e pelos critérios estabelecidos para os portadores de HF. Antecedentes pessoais e familiares para DAC, tabagismo, atividade física, consumo alimentar de gorduras, fibras e bebidas alcoólicas foram obtidos por questionário e medidas antropométricas foram aferidas. Foram comparados os grupos com e sem Síndrome Metabólica (SM) e os grupos com e sem DAC por análise univariada. Após, foram verificados os fatores determinantes para o desenvolvimento da DAC mediante modelo de regressão multivariada. Foram entrevistados 110 pacientes (68 mulheres) com média de idade de 48,9 ± 16,2 anos. A presença de história familiar de DAC precoce foi relatada por 67 (61,5%) pacientes. A hipertensão foi encontrada em 59 (53,6%), SM em 38 (34,9%), DAC em 30 (27,3%), HDL-c baixo em 28 (25,5%), diabete melito em 17 (15,5%), 25 (22,7%) eram ex-fumantes e 12 (10,9%) tabagistas. Com a comparação das categorias de risco observou-se discrepância em 77,5% dos casos entre os ERF e os critérios estabelecidos para a população de HF. Quanto ao estado nutricional, 47 (42,7%) eram pré-obesos e 61 (55,4%) com circunferência da cintura alterada. O consumo de gorduras, fibras e bebidas alcoólicas foi considerado adequado. Encontrou-se grande número de sedentários (77%). O grupo dos pacientes com SM tinha idade mais avançada (55 vs 46 anos; p = 0,002), maior número de mulheres (76,3%; p = 0,02) e portadores de DAC (42,1%; p = 0,013). O grupo dos coronarianos tinha idade mais avançada (55 vs 47 anos; p = 0,004), mais pacientes do sexo masculino (60%; p = 0,004), maior presença de hipertensos (90%; p = 0,001), exfumantes (40%; p = 0,008), com SM (53,3%; p = 0,013), HDL-c baixo (53,3%; p = 0,001) e antecedente de infarto agudo do miocárdio (IAM) em irmãos (50%; p = 0,012). As medidas antropométricas, o consumo alimentar e a atividade física não foram diferentes entre os grupos. Após análise de regressão multivariada os fatores de risco determinantes para o desenvolvimento da DAC foram HDL-c baixo (OR 8,4; IC 95% 2,7-27,6), sexo masculino (OR 7,3; IC 95% 2,1-24,7), história de IAM em irmãos (OR 3,4; IC 95% 1,1-10,5) e idade avançada (OR 1,06; IC 95% 1,02-1,1). Em nossa população, HDL-c baixo, sexo masculino, história de IAM em irmãos e idade foram fatores independentes para o desenvolvimento da DAC. / Familial hypercholesterolaemia (FH) is characterized by raised concentrations of LDL-c and high prevalence of premature coronary artery disease (CAD). However, the course of the CAD in the FH is variable and can be influenced by other risk factors. The aim of the study was to assess clinical and nutritional parameters in adults with heterozigous FH by a cross sectional study. Laboratory exams, blood pressure measurement and clinical diagnosis were collected. Agreement or not between the categories of risk by Framingham scores and for established criteria for the FH subjects was verified. Personal and familial history for CAD, smoken habit, physical activity, fats, fibers and alcohol consumption were assessed by questionnaire and anthropometric measurement were verified. The groups with and without Metabolic Syndrome (MS) and groups with and without CAD were compared by univariated analysis. After, multivaried analysis (MVA) was used to assess the significance of differences in risk factors. The sample was composed by 110 patients (68 women) with average of age of 48.9 ± 16.2 years. The presence of familial history of premature CAD was detected in 67 (61.5%)subjects. Hypertension was found in 59 (53.6%), MS in 38 (34.9%), CAD in 30 (27.3%), low HDL-c in 28 (25.5%), diabetes in 17 (15.5%), 25 (22,7%) and 12 (10,9%) were respectively former and current smokers. In the comparison of the risk categories discrepancy was observed in 77.5% of the cases between the Framingham scores and the established criteria for the FH population. Analyzing the nutritional profile, 47 (42.7%) were overweight and 61 (55.4%) had increased waist circumference. The consumption of fats, fibers and alcohol were considered satisfactory. A great number of sedentary subjects was found (77%). The patients with MS were older (55 vs. 46 years; p = 0.002), had a greater number of women (76.3%; p = 0.02) and CAD (42.1%; p = 0.013). CAD subjects were older (55 vs. 47 years; p = 0.004), had a higher prevalence of males (60%; p = 0.004), hypertension (90%; p = 0.001), former smokers(40%; p = 0.008), MS (53.3%; p = 0.013), low HDL-c (53.3%; p = 0.001) and history of myocardial infarction in brothers (50%; p = 0.012). There were no differences between the groups regarding anthropometric measurements, consumption of fats, fiber and alcohol and physical activity. After MVA, independent risk factors for CAD were low HDL-c (OR 8.4; CI 95% 2.7-27.6), male gender (OR 7.3; CI 95% 2.1-24.7), history of myocardial infarction in brothers (OR 3.4; CI 95% 1.1-10.5) and advanced age (OR 1.06; CI 95% 1.02-1.1). In our population, low HDL-c, male gender, history of myocardial infarction in brothers and age were independently associated with the risk of CAD.

Neste estudo, foi avaliada a relação entre polimorfismos dos genes da leptina (LEP) e receptores da leptina (LEPR) e parâmetros antropométricos, leptinemia glicemia e lipídeos séricos, em indivíduos da população brasileira. Foram incluídos 238 indivíduos com idade entre 30 e 80 anos. Foram medidos o índice de massa corporal (IMC), a cintura abdominal (CA) e a razão cintura quadril (RCQ). Amostras de sangue periférico foram obtidas para análise do perfil bioquímico e extração de DNA. Os polimorfismos de nuleotideo único (SNPs) LEP G-2548A e LEPR Lys109Arg, Gln223Arg e Lys656Asn foram detectados por PCR-RFLP. Os SNPs LEPR Lys109Arg e Gln223Arg foram associados com obesidade e com IMC e CA aumentados (p<0.05). Estes polimorfismos também foram associados com leptina e glicose elevada (p<0,05). O perfil lipídico sérico foi influenciado pelo polimorfismo LEPR Lys109Arg (p<0.05). A relação entre os SNPs LEPR Lys109Arg e Gln223Arg e o perfil lipídico foi modificada pelo gênero. Os haplótipos LEP G-2548/ LEPR Lys109Arg foram relacionados com diferenças no IMC de obesos. Os haplotipos LEPR Lys109Arg/Gln223Arg foram associados com diferenças na CA e glicemia e lipídeos séricos. Em conclusão, os polimorfismos LEPR Lys109Arg e Gln223Arg estão associados com obesidade e alterações de leptina, glicose e lipídeos circulantes de forma dependente do gênero. / We have assessed the relationship between polymorphisms of the leptin (LEP) and the leptin receptor (LEPR) genes and anthropometric parameters, plasma leptin and glucose and serum lipids in individuals of the Brazilian population. We included 238 individuais with 30 to 80 years. Body mass index (BMI), abdominal circumference (AC) and waist-to-hip ratio (WHR) were measured. Peripheral blood samples were collected for analysis of the biochemical profile and DNA extraction. The single nucleotide polymorphisms (SNP) LEP G-2548A and LEPR Lys109Arg, Gln223Arg and Lys656Asn were detected by PCR-RFLP. The SNPs LEPR Lys109Arg and Gln223Arg were associated with obesity and with increased BMI and AC (p <0.05). These polymorphisms were also associated with increase leptin and glucose (p<0,05). The serum lipid profile was influenced by the LEPR Lys 1 09Arg (p<0.05). The relationship between the SNPs LEPR Lys 1 09Arg and Gln223Arg and the lipid profile was modified by gender. The haplotypes LEP G-2548A1 LEPR Lys109Arg were related with differences on BMI in obese group. The haplotypes LEPR Lys109Arg/Gln223Arg were associated with differences on AC, glucose and serum lipids. In conclusion, the LEPR Lys109Arg and Gln223Arg polymorphisms are associated with obesity and alterations in blood leptin, glucose and lipids in a gender-dependent manner.

Abstract Respiratory tract infections are the most common acute illnesses, and innate immunity and inflammation are important in defence against these infections. Mannose-binding lectin (MBL) mediates innate immune defences by recognising microbial structures. MBL deficiency caused by polymorphisms in the MBL2 gene has been associated with susceptibility to recurrent infections. Interleukin-6 (IL-6) is a mediator of inflammatory response. Polymorphisms in the IL-6 and IL-6 receptor (IL-6R) genes have been previously associated mainly with metabolic disorders and cardiovascular diseases. Chlamydia pneumoniae is a common pathogen in acute respiratory tract infections, but it also has a tendency to cause persistent infections, which have been associated with cardiovascular diseases and its risk factors, such as obesity. The aims of this study were to investigate if selected polymorphisms of the MBL2, IL-6 and IL-6R genes are associated with respiratory tract infections and markers of C. pneumoniae infection, and to study if persistent C. pneumoniae infection is connected with an elevated body mass index (BMI) in 893 Finnish male military conscripts. Respiratory tract infections were followed during their military service and serum samples were collected at the beginning and end of their service and during each infectious episode. A variation in serum MBL levels between different MBL2 genotypes and a MBL deficiency in homozygous exon 1 variant genotypes (at codons 52, 54 and 57) were observed. Low MBL levels and MBL2 polymorphisms in exon 1 and promoter region were found to be risk factors for susceptibility to respiratory tract infections as well as for positivity and a rise in C. pneumoniae antibodies during military service. Associations between IL-6R gene polymorphisms in the promoter region (-183G/A) and in intron 1 and respiratory tract infections were found. In addition, the IL-6 -174G/C polymorphism was associated with persistently elevated C. pneumoniae antibodies and with slightly elevated serum C-reactive protein (CRP) levels, pointing to chronic C. pneumoniae infection. Furthermore, persistent C. pneumoniae antibodies as a suggestive marker of chronic infection, and elevated serum CRP levels as a marker of systemic inflammation, were associated with an elevated BMI. In conclusion, the findings support the role for MBL in susceptibility to infections and provide new information about the association between MBL and common respiratory tract infections. The results also suggest that the 5’ area of the IL-6R gene may be a possible candidate region for respiratory tract infection susceptibility, and that IL-6 genetics may be associated with C. pneumoniae infection. The study also provides new information about the role of possible chronic C. pneumoniae infection in obesity. / Tiivistelmä Hengitystieinfektiot ovat yleisimpiä äkillisiä sairauksia, ja synnynnäisellä immuunivasteella ja tulehduksella on tärkeä rooli puolustuksessa näitä infektioita vastaan. Synnynnäiseen immuniteettiin kuuluva mannoosia sitova lektiini (MBL) tunnistaa infektioita aiheuttavien mikrobien rakenteita. MBL2-geenin polymorfismien aiheuttaman MBL-proteiinin puutteen on todettu altistavan toistuville infektioille. Interleukiini-6 (IL-6) on tulehduksen välittäjänä toimiva sytokiini. IL-6- ja IL-6-reseptori (IL-6R) -geenien polymorfismit on aikaisemmin yhdistetty lähinnä metabolisiin häiriöihin sekä sydän- ja verisuonitauteihin. Chlamydia pneumoniae eli keuhkoklamydia on yleinen hengitystieinfektioiden aiheuttaja, mutta se voi myös aiheuttaa kroonisia infektioita, jotka on yhdistetty sydän- ja verisuonitauteihin sekä niiden riskitekijöihin kuten lihavuuteen. Työn tarkoituksena oli tutkia tiettyjen MBL2-, IL-6- ja IL-6R-geenien polymorfismien yhteyttä hengitystieinfektiohin ja keuhkoklamydiavasta-ainetasoihin sekä keuhkoklamydiainfektion yhteyttä painoindeksiin 893 suomalaisella varusmiehellä. Hengitystieinfektioita seurattiin palveluksen aikana, ja seeruminäytteet kerättiin palveluksen alussa, lopussa ja jokaisen infektion aikana. Tutkimuksessa havaittiin vaihtelua seerumin MBL-pitoisuudessa eri MBL2-genotyyppien välillä sekä MBL:n puute homotsygooteissa eksoni 1 -alueen varianttigenotyypeissä (kodoneissa 52, 54 ja 57). Alhaiset MBL-tasot sekä MBL2-geenin polymorfismit eksoni 1 -alueella ja säätelyalueella olivat riskitekijöitä hengitystieinfektioalttiudelle sekä keuhkoklamydiavasta-aineiden esiintymiselle ja vasta-aineiden nousulle palveluksen aikana. IL-6R-geenin polymorfismit säätelyalueella (-183G/A) ja introni 1 -alueella liittyivät hengitystieinfektioihin. Lisäksi IL-6-geenin -174G/C polymorfismi oli yhteydessä jatkuvasti kohonneisiin keuhkoklamydiavasta-aineisiin sekä seerumin C-reaktiivisen proteiinin (CRP) tasoihin, jotka mahdollisesti osoittaisivat kroonista keuhkoklamydiainfektiota. Lisäksi krooniseen keuhkoklamydia-infektioon viittaavat vasta-ainetasot sekä tulehdukseen liittyvä kohonnut CRP-pitoisuus olivat yhteydessä ylipainoon. Tutkimuksen tulokset tukevat aikaisemmin havaittua MBL:n vaikutusta infektioalttiuteen ja lisäksi antavat uutta tietoa MBL:n yhteydestä tavallisiin hengitystieinfektioihin. Tulokset viittaavat myös siihen, että IL-6R-geenin 5’-alueella voi olla yhteyttä hengitystieinfektioalttiuteen ja että IL-6-polymorfismi olisi yhteydessä keuhkoklamydiainfektioon. Tutkimus antaa myös uutta tietoa mahdollisen kroonisen keuhkoklamydiainfektion liittymisestä ylipainoon.

Abstract Morbid obesity is the most rapidly increasing health threat of developed countries, and the costs caused by it are already higher than those of smoking. In an increasing number of developing countries both starvation and morbid obesity are increasing simultaneously. Obesity in children and adolescents is also increasing rapidly. Conservative treatment almost invariably fails when treating morbid obesity. Results of pharmacotherapy have been disappointing after great expectations. Laparoscopic gastric banding has been used in the treatment of morbid obesity since 1993. The method was first used mostly in Europe. In the USA either an open or laparoscopic gastric bypass have been the most common methods of surgery. The aim of this study was to investigate the operation results of 280 patients operated in Vaasa Central Hospital during the 11 years after March 1996. Of these patients, 123 have been followed at least 5 years. The results have been analyzed with BAROS that measures the quality of life. Quality of life was measured prospectively 1 year after surgery with the 15D questionnaire that is validated in the Finnish population. The effect of gastric banding in esophageal motility and reflux was studied prospectively in 31 patients. Late results were analyzed in 123 patients 11 years after the first operation. Mean excess weight loss (EWL) was 56% in patients who had their band in place 7 years after surgery, and 46% in all patients. There was no mortality related to the operation, and there was only one serious complication. Disease-specific quality of life improved in 78.8% of the patients in 28 months of follow-up. Health-related quality of life was significantly improved 12 months after surgery, but improvement was not connected to the amount of weight loss. The band inhibited reflux 19 months after surgery. Complications, failures, and reoperations increase with longer follow-up. Weight loss is moderate 9 years after a gastric banding operation, and in carefully selected patients this operation is still a good option in the treatment of morbid obesity.

Sachant que l’Athérosclérose commence durant l’enfance par des marqueurs subcliniques, cette étude explore l’association entre l’indice de masse corporelle (IMC) et l’élastographie vasculaire non-invasive (NIVE) des artères carotides communes chez les enfants. On compare aussi les techniques de mesure de l’intima-média (IMT) des artères carotides en se basant sur le mode-B et la radiofréquence (RF) chez les enfants avec IMC normal et élevé. Il s’agit d’une étude prospective effectuée entre 2005 et 2011. Les paramètres de « NIVE » ont été comparés pour deux groupes d’IMC (normal et élevé) de 60 enfants respectivement, faisant tous partie de la cohorte de l’étude QUebec Adipose and Lifestyle Investigation in Youth (QUALITY). Les paramètres de NIVE incluent la contrainte axiale cumulative (CAS) en %, la translation axiale cumulative (CAT) en mm. L’épaisseur de l’intima-média est calculée selon trois méthodes : logiciel «M’ath-Std» (mode-B), « echotracking » des signaux de RF et probabilité de distribution des signaux de RF sur la plateforme NIVE. Une analyse ANOVA et corrélation Pearson ont été effectuées sur le logiciel SAS version 9.3. Une corrélation intra-class (ICC) a été effectuée sur un logiciel MedCalc version 17.2. L’âge moyen était 11,4 ans pour le groupe IMC normal et 12 pour le groupe IMC élevé. Cinquante-huit pourcent étaient des garçons dans le groupe IMC normal et 63% dans le groupe IMC élevé. Les deux groupes étaient différents selon l’âge, stade de Tanner, tension artérielle (systolique et diastolique), et LDL mais similaire pour le sexe. En contrôlant pour les variables confondantes, la CAS n’est pas différente entre les deux groupes. La CAT est plus basse chez les enfants avec IMC normal (CAT=0.51 +/-0.17 mm pour le groupe « IMC normal » et 0.67+/-0.24 mm pour le groupe « IMC élevé » (p<0.001)). Il y a une très faible corrélation entre les trois techniques de mesure d’IMT ICC=0,34 (95% intervalle de confiance 0,27-0,39). L’IMT est significativement plus élevé dans le groupe d’enfants « IMC élevé ». Mode-B (0.55 mm « IMC normal » vs. 0.57 mm « IMC élevé »; p=0.02); IMT RF (0.45 mm « IMC normal » vs. 0.48 mm « IMC élevé »; p=0.03) et IMT probabilité de distribution des signaux RF (0.32 mm « IMC normal » vs. 0.35 mm « IMC élevé »; p=0.010). La NIVE montre une différence significative dans la CAT de l'artère carotide commune des enfants avec un IMC normal par rapport à l'IMC élevé. Des variations significatives de la mesure des IMT ont été observées entre les différentes techniques. Cependant, les enfants avec IMC élevé ont des valeurs IMT plus élevées, indépendamment de la méthode utilisée. Les deux marqueurs subcliniques peuvent être utilisés pour la stratification des enfants à risque de maladies cardiovasculaires. La même méthode devrait toujours être utilisée. / Knowing that cardiovascular disease risk factors are present in asymptomatic children, this study explores the association between non-invasive vascular elastography (NIVE) as a subclinical marker of atherosclerosis and obesity in children. In the absence of a gold standard, we also compare B-mode and Radiofrequency (RF) based ultrasound measurements of intima-media thickness (IMT) in children with normal and increased body mass index (BMI). This is a prospective study between 2005 and 2011. NIVE parameters and IMT of the common carotid artery were compared between 60 children with normal BMI and 60 children with increased BMI enrolled in the QUebec Adipose and Lifestyle Investigation in Youth cohort (QUALITY). NIVE parameters included cumulated axial strain (CAS) (%) and cumulated axial translation (CAT) in mm. The three methods of IMT measurements included M’ath Std (B-mode), RF echotracking system and RF probability distribution using NIVE platform. ANOVA analysis and Pearson correlation were calculated using SAS version 9.3. Intra-class correlation coefficient (ICC) and regression analysis was done on MedCalc software version 17.2. The mean age was 11.4 years for the normal BMI group and 12 years for the increased BMI group. Fifty-eight percent were boys in the normal BMI group and 63% in the increased BMI group. The two groups were significantly different with respect to age, Tanner stage, systolic and diastolic blood pressure and were similar with respect to sex. After controlling for confounders, the results show no difference in CAS between the two groups and a significantly lower CAT in the normal BMI group (CAT=0.51+/-0.17 mm for the normal BMI group and 0.67+/-0.24 mm for the increased BMI group (p<0.001)). There is a weak correlation among the three techniques. ICC=0.34 (95% confidence interval (CI): 0.27-0.39). There is however significantly increased IMT in children with increased BMI according to all three techniques. The results were as follow: for B-mode IMT (0.55 mm (normal BMI group) vs. 0.57 mm (increased BMI group); p=0.02); for RF echotracking IMT (0.45 mm (normal BMI group) vs. 0.48 mm (increased BMI group); p=0.03) and for RF probability distribution IMT (0.32 mm (normal BMI group) vs. 0.35 mm (increased BMI group); p=0.010).NIVE is a one-step technique for IMT and CAT measurement in children at risk. Significant IMT measurement variation is observed between the three techniques. However, children with increased BMI tend to have higher IMT values regardless of the technique. Both subclinical markers can be used for optimal stratification of children with cardiovascular disease risk factors. The same technique should be used throughout.

Abstract Depression is a common mental disorder in the Finnish population. There are several biological, psychological and social factors in the background of depression. The aim of this study was to investigate depression in association with birth weight, age at menarche, obesity and metabolic syndrome using data from the Northern Finland 1966 Birth Cohort. A large, prospectively collected general population-based birth cohort of originally 12058 liveborn children was used as study population. The database provided information on birth characteristics and features of the primary family. The follow-up studies were performed at the age of 14 years by postal inquiry, and at the age of 31 years by postal inquiry and clinical examination. Information on age at menarche and weight and height was obtained from the postal questionnaire at 14 and 31 years and clinical examination at 31 years. Data on abdominal obesity and metabolic syndrome were gathered from the clinical examination. Data on depressive symptoms measured by the Hopkins Symptom Checklist-25 (HSCL-25), self-reported physician-diagnosed lifetime depression and the use of antidepressants were gathered from the postal questionnaire at 31 years. Females with high birth weight and high ponderal index (index of the birth measures, kg/m3) had a higher risk of depressive symptoms at 31 years measured by the HSCL-25 compared with females with normal birth weight and ponderal index. Males with ponderal index belonging to the lowest 5 percentile had an increased risk for physician-diagnosed depression at 31 years. Females with late menarche (≥ 16 years) had an elevated risk of depression measured by the HSCL-25, the use of antidepressants and self-reported physician-diagnosed depression compared with females with menarche at 12–15 years. Obesity measured by BMI at 14 years increased the risk of depressive symptoms measured by the HSCL-25 at 31 years among both males and females. Females who were obese both at baseline and at follow-up had an increased risk of depressive symptoms, and the proportion of those who used antidepressants was higher among females who had gained weight compared to females who had stayed normal-weighted. Males with abdominal obesity measured by waist-to-hip ratio had an increased risk of depressive symptoms and physician-diagnosed depression, and the proportion of those who used antidepressants was higher compared with subjects without abdominal obesity. Abdominal obesity did not associate with depression in females. Metabolic syndrome did not associate with depression. The results indicate an increased risk of depression at 31 years in females with high birth weight, late menarche, adolescent obesity and weight gain and in males with adolescent obesity and abdominal obesity. / Tiivistelmä Depressio on yleinen mielenterveyden häiriö suomalaisväestössä. Depression taustalla on monia biologisia, psykologisia ja sosiaalisia tekijöitä. Tämän tutkimuksen tavoitteena oli tutkia depressiota selvittäen, onko syntymäpainolla, menarkeiällä, lihavuudella ja metabolisella oireyhtymällä yhteyttä depressioon Pohjois-Suomen vuoden 1966 syntymäkohorttiaineistossa. Tutkimusaineistoon kuului alun perin 12058 elävänä syntynyttä lasta. Tietokantaan oli jo aiemmin kerätty aineistoa syntymään ja primaariperheeseen liittyen. Kohortin jäsenten ollessa 14-vuotiaita tehtiin seurantatutkimus postikyselynä ja 31-vuotiaana tehtiin sekä postikysely että kliininen tutkimus. Tiedot menarkeiästä kerättiin 31-vuotispostikyselystä, paino- ja pituustiedot sekä 14- ja 31-vuotispostikyselyistä että kliinisen tutkimuksen tiedoista. Kliininen tutkimus sisälsi tiedot myös keskivartalolihavuuden ja metabolisen oireyhtymän määrittämiseksi. 31-vuotispostikyselyssä depressio-oireita kysyttiin HSCL-25 -oirekyselyllä; lisäksi kysyttiin, oliko lääkäri todennut aiemmin masennusta sekä oliko tutkittavilla käytössä masennuslääkkeitä. Naisilla, joiden syntymäpaino ja ponderaali-indeksi (syntymäpainon ja pituuden suhdetta kuvaava indeksi, kg/m3) oli korkea, depressio-oireiden riski 31-vuotiaana mitattuna HSCL-25:lla oli suurentunut verrattuna naisiin, joilla oli normaali syntymäpaino ja ponderaali-indeksi. Miehillä, joilla oli hyvin alhainen ponderaali-indeksi kuuluen alimpaan 5 % ryhmään, riski lääkärin toteamaan masennukseen oli suurentunut. Naisilla, joiden menarkeikä oli 16-vuotta tai myöhemmin, riski depressio-oireiden esiintyvyyteen, depressiolääkkeiden käyttöön ja lääkärin toteaman depression esiintyvyyteen oli suurentunut verrattuna naisiin, joiden menarkeikä oli 12–15-vuotta. Lihavuus 14-vuotiaana lisäsi masennusoireiden riskiä mitattuna HSCL-25:lla sekä 31-vuotiailla miehillä että naisilla. Naisilla, jotka olivat lihavia sekä 14- että 31-vuotiaana, masennusoireiden riski oli suurentunut. Naisilla, joiden paino oli noussut, masennuslääkkeitten käyttö oli yleisempää verrattuna naisiin, joilla paino oli pysynyt normaalina. Keskivartalolihavuus oli miehillä yhteydessä suurentuneeseen depressio-oireiden ja lääkärin toteaman masennuksen riskiin, ja he käyttivät yleisemmin masennuslääkkeitä verrattuna miehiin ilman keskivartalolihavuutta. Naisilla keskivartalolihavuus ei ollut yhteydessä masennukseen. Metabolinen oireyhtymä ei ollut yhteydessä masennukseen. Tulokset osoittavat korkean syntymäpainon, myöhäisen menarkeiän ja nuoruusiän lihavuuden sekä painon nousun lisäävän masennusriskiä 31-vuotiailla naisilla, 31-vuotiailla miehillä nuoruusiän lihavuus sekä keskivartalolihavuus olivat yhteydessä suurentuneeseen masennusriskiin.

Abstract Recognition of individuals at highest risk for psychosis is challenging and no definitive biomarkers are yet available. Physical illnesses associated with a sedentary lifestyle are common in patients with severe mental illness. Both, bodyweight and risk for psychosis are associated with brain white matter (WM) abnormalities. There are several dysregulated pathways which are common in psychiatric illnesses and weight-related processes, but it is not known how weight and vulnerability for psychosis interact in the brain. The present study examines brain WM microstructure and its association to body mass index (BMI) in young adults with a familial risk for psychosis (FR). In addition, the level of physical activity and cardiorespiratory fitness in individuals vulnerable to psychosis was examined. Participants of the present study are members of the Northern Finland Birth Cohort 1986. Two separate clinical substudies were conducted. The first having been done when the participants were at age 15–16. At that time, physical activity was defined by postal questionnaire (n=6,987) and cardiorespiratory fitness was measured by a submaximal cycle ergometer test (n=4,803). Risk for psychosis was viewed from three perspectives, with possible overlap between groups: having familial risk for psychosis, existing prodromal symptoms at age 15–16, and development of hospital treated psychosis between the ages of 16 and 20 years. The latter substudy was conducted when the participants were aged between 20 and 25 years. Diffusion tensor imaging was performed on 108 participants. Our study showed that there was no difference in WM microstructure between FR and control groups suggesting that WM abnormalities are not a genetic feature for risk of psychosis in all populations. However, the association between BMI and WM microstructure differed significantly between the FR and control groups. We also demonstrated that the level of physical activity was lower before the onset of psychotic illness. Therefore, these results imply that it would be of great importance to consider weight and physical activity levels in subjects at risk for psychosis, in order to avoid the detrimental effects of a sedentary lifestyle on overall health. / Tiivistelmä Korkeimmassa psykoosiriskissä olevien tunnistaminen on haastavaa, eikä kunnollisia biomarkkereita ole käytettävissä. Vähäiseen liikunta-aktiivisuuteen liitetyt fyysiset sairaudet ovat yleisiä vakavaa mielenterveyshäiriötä sairastavilla. Sekä kehonpaino että psykoosialttius on yhdistetty aivojen valkean aineen rakenteen poikkeavuuksiin. Useat kehon säätelymekanismien poikkeavuudet liittyvät sekä psykiatrisiin sairauksiin että painoon liittyviin prosesseihin, mutta ei ole olemassa tutkimustietoa siitä, miten paino ja psykoosialttius vaikuttavat yhdessä aivojen rakenteeseen. Tässä osajulkaisuväitöskirjassa tutkitaan aivojen valkean aineen mikrorakennetta nuorilla aikuisilla, jotka ovat sukuriskissä sairastua psykoosiin, sekä painon vaikutusta valkean aineen rakenteeseen psykoosiriskissä. Lisäksi tutkitaan psykoosialttiiden nuorten liikunta-aktiivisuutta ja kuntoa. Tutkittavat kuuluvat Pohjois-Suomen vuoden 1986 syntymäkohorttiin. Kaksi osatutkimusta toteutettiin, joista aikaisempi kliininen tutkimus tutkittavien ollessa 15–16-vuotiaita. Tuolloin selvitettiin liikunta-aktiivisuus postikyselyn avulla (n=6,987) ja aerobinen kunto mittaamalla hapenottokyky polkupyöräergometrilla (n=4,803). Psykoosialttiutta tarkasteltiin kolmella tavalla, ja ryhmien välillä esiintyi osittaista päällekkäisyyttä: sukurasitus, 15–16 v. iässä raportoidut psykoosinkaltaiset oireet ja sairaalahoitoon johtanut psykoosi 16–20 v. iässä. Toinen kliininen osatutkimus toteutettiin tutkittavien ollessa 20–25-vuotiaita. Tutkimuksen yhteydessä tehtiin aivojen diffuusiotensorikuvaus 108 osallistuneelle. Aivojen valkean aineen mikrorakenteessa ei havaittu eroa sukuriskissä olevien ja kontrollien välillä viitaten siihen, että poikkeavuudet valkean aineen rakenteessa eivät olisi psykoosiriskin geneettinen piirre kaikissa populaatioissa. Havaitsimme kuitenkin, että assosiaatio painoindeksin ja valkean aineen rakenteen välillä oli erilainen sukuriski- ja kontrolliryhmissä. Tutkimus osoitti myös, että liikunta-aktiivisuus on alentunut jo ennen psykoosisairauden puhkeamista. Psykoosiriskissä olevien liikuntatottumuksiin ja painoon tulisi kiinnittää erityistä huomiota jo varhaisessa vaiheessa elimellisten sairauksien ehkäisemiseksi.