In schizophrenia, subtle aberrations in the brain cause functional disturbances like psychotic symptoms and social disability. There are, however, also disturbances outside the CNS indicating a systemic manifestation in the disease. The aim of the present thesis was to gain deeper understanding of the pathophysiological mechanisms underlying schizophrenia with a particular interest in peripheral and systemic manifestations with relevance for the increased risk of obesity and metabolic complications seen in the disease. Therefore, resting energy expenditure (REE), physical capacity, and relevant body composition variables were measured in patients with schizophrenia and in healthy controls. Also niacin skin flush response and electrodermal activity (EDA) were studied. Patients with schizophrenia exhibited significantly lower REE expressed as kJ/kg, and also lower values compared with predicted levels than the controls. The difference could not be attributed to medication or variations in body composition between the two groups. There was a gender difference with the lowest levels found in male patients. Male patients exhibited significantly lower physical capacity in terms of predicted maximal oxygen uptake capacity and faster increase in respiratory quotient than male controls. The oral niacin test revealed a significantly delayed skin flush reaction in patients compared with controls. The patients also exhibited lower EDA response. There was a significant association in response patterns for the niacin and the EDA tests in the patients, but not in controls. In a test-retest study in patients there was acceptable stability for EDA measures but low test-retest stability for niacin variables. The previously found association in responses for the two tests was, however, replicated. The results gain support for the concept of schizophrenia as a disease with systemic manifestations including metabolic dysregulation. The findings add to the understanding of the weight gain and the increased risk for cardiovascular morbidity seen in this condition.

No description available.

Background: Rheumatoid arthritis (RA) is characterised by excessive production of tumour necrosis factor alpha (TNFα). This leads to rheumatoid cachexia, a condition characterised by increased resting energy expenditure (REE) and loss of fat-free mass (FFM) leading to functional disability, decreased strength and balance. The aims of this research work was to: a) to develop a new REE equation in order to continuously monitor abnormal changes in REE in the RA population, b) to investigate if smoking further enhances hypermetabolism and c) to examine if the new anti-TNFα medication reverses this metabolic abnormality. Methods: 68 patients with RA were assessed for demographic and anthropometrical characteristics, REE (indirect calorimetry), body composition (bioelectrical impedance), and disease activity [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), disease activity score 28 (DAS28) and health assessment questionnaire (HAQ)]. 20 of the total 68 patients, about to start anti-TNFα therapy, underwent the exact same aforementioned procedures but on three separate occasions (Baseline: two weeks prior to anti-TNFα treatment, Time-1 and Time-2: two weeks and three months, respectively, after the drug had been introduced. Results: Study 1: Based on FFM and CRP, a new equation was developed which had a prediction power of R2=0.76. The new equation revealed an almost identical mean with measured REE (1645.2±315.2 and 1645.5±363.1 kcal/day, p>0.05), and a correlation coefficient of r=0.87 (p=0.001). Study 2: Smokers with RA demonstrated significantly higher REE (1513.9±263.3 vs. 1718.1±209.2 kcal/day; p=0.000) and worse HAQ (1.0±0.8 vs. 1.7±0.8; p=0.01) compared to age and FFM matched RA non-smokers. The REE difference was significantly predicted by the interaction smoking/gender (p=0.04). Study 3: Significant increases were observed in REE (p=0.002), physical activity (p=0.001) and protein intake (p=0.001) between the three times of assessment. Moreover, disease activity significantly reduced [ESR (p=0.002), DAS28 (p=0.000), HAQ (p=0.000) and TNFα (p=0.024)] while FFM and total body fat did not change (both at p>0.05). Physical activity and protein intake were found to be significant within-subject factors for the observed REE elevation after 12-weeks on anti-TNFα treatment (p=0.001 and p=0.024, respectively). Conclusions: Findings from the first study revealed that the newly developed REE equation provides an accurate prediction of REE in RA patients. Moreover, the results from the second study showed that cigarette smoking further increases REE in patients with RA and has a negative impact on patients’ self-reported functional status. Finally, our data from the third study suggest that REE remains elevated not because of the maintenance of the RA-related hypermetabolism but due to the concomitant significant increases in physical activity and protein intake.

The purpose of this work was to further understand nutritional status, especially body weight and composition, during colorectal cancer progression. Population-based studies of colorectal cancer patients were conducted using administrative health data (primary and co-morbid diseases, demographics), and computed tomography (CT) imaging (body composition). In cohort 1, administrative health data was used to study comorbidities and nutritional status in 574 colorectal cancer patients referred for chemotherapy. Multivariate Cox regression revealed several comorbidities, performance status and weight loss 20% predicted survival. In cohort 2, a serial CT image analysis assessed longitudinal body composition changes during the last 12 months preceding death from colorectal cancer (n=34). Body composition changes were typified by exponential increases in liver metastases with concurrent accelerations of muscle and fat loss. These results have the potential to make a difference in how colorectal cancer patients are treated and researched by dietitians, oncologists, and health services researchers. / Nutrition and Metabolism

Human ageing is accompanied by characteristic metabolic and endocrine changes, including altered hormone profiles, insulin resistance and deterioration of skeletal muscle. Obesity and diabetes may themselves drive an accelerated ageing phenotype. Untangling the causal web between ageing, obesity and diabetes is a priority in order to understand their aetiology and improve prevention and management. The role of biological ageing in determining the risk of obesity and associated conditions has often been examined using mean leukocyte telomere length (LTL), a marker of replicative fatigue and senescence. However, considering phenotypes which represent different domains of biological and functional ageing as exposures for obesity and related traits could allow the elucidation of new understudied phenotypes relevant to cardio-metabolic risk in the wider population. This PhD considers the causal role of (1) hand grip strength (HGS), a marker of overall strength and physical functioning, and (2) resting energy expenditure, an indicator of overall energy metabolism and the major component of daily energy expenditure, in cardio-metabolic risk. I also characterise a new and readily-quantifiable marker of age-related genomic instability, mosaic loss of the Y chromosome (mLOY). Observational evidence implicates each of these phenotypes in cardio-metabolic conditions and intermediate phenotypes. However, it is not possible to infer causality from these observational associations due to confounding and reverse-causality. Mendelian randomisation offers a solution to these limitations and can allow the causal nature of these relationships to be investigated. Using population-based data including UK Biobank, this thesis presents the first large-scale genetic discovery effort for each trait and provides new biological insight into their shared and separate aetiology. I used identified variants to investigate the bidirectional causal associations of each trait with cardio-metabolic outcomes, intermediate phenotypes and other related traits such as frailty and mortality. In total I identified 16 loci for hand grip strength, 19 for mLOY, and one signal for REE. I have shown that HGS is likely to be causally linked to fracture risk, and I have identified the important shared genetic architecture between mLOY, glycaemic traits and cancer. I have also demonstrated that at least one known genetic variant contributing to obesity risk acts partially via reduced REE. Overall the findings of my PhD contribute to our wider understanding of the aetiological role of ageing processes in metabolic dysfunction, and have implications for both basic science and translational applications.

Background: Excess white adipose tissue (WAT) in humans is considered as a harmful health index. However, increased brown adipose tissue (BAT) and brown-like adipose tissue activity are associated with increased resting energy expenditure (REE) that may help to control body weight. Exercise may enhance browning formation of WAT and reduce WAT that may lead to health improvements. Aims: a) to examine the effects of physical activity on the link between peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) and fibronectin type III domaincontaining protein 5 (FNDC5) genes in muscle, circulating Irisin and uncoupling protein one (UCP1) of WAT in humans (study 1); b) to examine the relationship between UCP1 mRNA and protein expression as well as PGC-1α, peroxisome proliferatoractivated receptor alpha (PPARα) and PPARγ genes with physical activity levels in WAT of healthy men (study 2); c) to examine the effects of different types of exercise and de-training on the UCP1 mRNA and protein expression (study 3), and d) on leptin mRNA in WAT of healthy men (study 4). Method: Study 1: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta- Analyses. Studies 2-4: The total of 46 healthy men subjected to measurements for physical activity levels, diet, anthropometry, body composition, REE, peak oxygen consumption, 1-repetition maximum and provided subcutaneous fat biopsies to determine mRNA and protein expression of six genes in one cross-sectional study and one randomized controlled trial. Results: Study 1: No link was found between PGC- 1α and FNDC5, circulating Irisin and UCP1 of WAT in response to physical activity. Study 2: The mRNA of, UCP1, PGC-1α, PPARα and PPARγ genes of WAT were not associated with physical activity levels. The UCP1 protein expression however, was negatively associated with physical activity levels. Studies 3-4: Different types of chronic exercise and de-training do not affect UCP1 mRNA and protein expression 3 and leptin mRNA in WAT. However, effect size analyses demonstrated increased UCP1 mRNA and protein expression, PPARγ and leptin in response to chronic exercise. Conclusions: There is no evidence to support the link between PGC-1α and FNDC5 in human muscle or the link between FNDC5 and circulating Irisin and UCP1 in WAT in response to exercise. There are no effects of exercise and de-training on browning formation of WAT and no link between browning formation indices and REE, body weight as well as leptin mRNA in healthy men. Further research is required to elaborate the aforementioned phenomena.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Terezie Poláková Supervisor of master thesis: PharmDr. Miroslav Kovařík, Ph.D. Title of master thesis: Assessment of energy metabolism in patients with chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is the name for lung disease with systemic consequences. Besides the respiratory symptoms there are also described changes in body metabolism, which could lead to the development of serious metabolic syndrome called cachexia. The main aim of this study was to compare the resting energy expenditure (REE) and nutrition substrate utilization in 12 patients with advanced form of COPD from the Czech Multicentre Research Database of COPD (5 females and 7 males, mean age 68 ± 6 years) and in 9 patients of control group without respiratory impairment (5 females and 4 males, 62 ± 4 years). Assessment of body metabolism was determined by method of indirect calorimetry. Measured REE was then compared with prediction based on Harris-Benedict equation. The utilization of main nutrition substrates was determined from the respiratory quotient and urea nitrogen loss in urine. We found that measured REE in COPD patients was about 20 % higher than in control group....

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Magdaléna Doleželová Supervisor of master thesis: PharmDr. Miroslav Kovařík, Ph.D. Title of master thesis: Body composition parameters in dependence on the metabolism degrese in patiens with COPD Chronic Obstructive Pulmonary Disease (COPD) is a very serious illness characterized by incompletely reversible airflow obstruction and lung emphysema. Contributes to its overall severity are extrapulmonary manifestations, especially cachexia and loss of lean tissue mass. Chronic inflammation of the respiratory airways and increased respiratory effort cause the hypermetabolic state to some patients with COPD. This thesis investigates the impact of increased metabolism on body composition in patients with COPD. Our study included 50 COPD patients (38 men, 12 women) who were examined by bioelectrical impedance. In this study, we compared the parameters of body composition of men with resting energy expenditure REE > 130% (hereinafter Men over 130%) (n = 9) and the group of men with REE < 130 % (hereinafter Men below 130 %) (n = 29). In the group of Men over 130 % we found a lower average value of body weight by 18 % compared to Men below 130 %. Total body and intracellular water were 12 %...

Introdução: A síndrome do intestino curto (SIC) representa um estado clínico de má absorção grave, e a gestão dietética de pacientes com SIC é extremamente desafiadora. Uma vez que o grau de desnutrição é frequentemente considerável, a intervenção dietética bem sucedida depende da estimativa mais exata possível das necessidades energéticas para prever as metas da terapia nutricional. Objetivo: Quantificar o gasto energético total (GET) em pacientes com SIC pelo método da água duplamente marcada (ADM). Materiais e Métodos: Neste estudo observacional, o GET foi mensurado pelo método da água duplamente marcada em 22 voluntários, 11 com SIC e 11 controles pareados por sexo, idade e IMC (grupo Controle). O GET foi estimado pela equação de Escott-Stump e a partir de acelerômetro, e foi comparado com o GET determinado pela ADM. O gasto energético em repouso (GER) foi mensurado por calorimetria indireta (CI) e comparado com o GER estimado pela equação de Harris e Benedict. O acelerômetro também foi utilizado para estabelecer o nível de atividade física. Resultados: Os participantes tinham idade (média ± DP) de 53 ± 8 anos. O GET medido por ADM foi significativamente menor no grupo SIC comparado ao grupo Controle (p < 0,01); no entanto, o GET estimado não diferiu significativamente entre os grupos. O GET medido foi significativamente maior do que o GET estimado por fórmula no grupo SIC, (respectivamente 1875 ± 276 e 1517 ± 175 kcal/dia, p < 0,01), assim como para o grupo Controle (2393 ± 445 e 1532 ± 178 kcal/dia, p < 0,01). No entanto, o GET medido foi significativamente menor do que o GET predito a partir do acelerômetro no grupo SIC (2075 ± 298 kcal/dia, p = 0,02), e não diferiu significativamente no grupo Controle (2207 ± 355 kcal/dia, p = 0,21). Não foram verificadas diferenças significantes entre o GER medido e predito para ambos, e entre os grupos. Conclusão: O GET medido em pacientes com SIC foi significativamente maior do que o GET estimado por fórmula, e foi menor quando comparado com os valores dos sujeitos controles. No entanto, o GET estimado a partir do acelerômetro, superestima o GET medido por ADM. As fórmulas atualmente utilizadas na prática clínica parecem subestimar as necessidades de energia de pacientes com SIC. Desta forma, adaptações da estimativa atual, aumentando as prescrições de ingestão energética nestes pacientes parecem ser adequadas para apoiar as necessidades diárias de energia e evitar a subnutrição. / Background: Short bowel syndrome (SBS) is a serious malabsorption disorder, and dietetic management of SBS patients is extremely challenging. Once the degree of undernutrition has been assessed, successful dietary intervention depends on the most accurate estimation and provision of energy needs to provide nutritional therapy goals. Objective: To quantify total energy expenditure (TEE) in SBS patients using the doubly labeled water (DLW) method. Design: In this observational study, TEE was measured by the DLW method in 22 participants, 11 with SBS and 11 gender-age-and BMI-matched controls (Control group). Predicted energy requirements were determined using the Escott-Stump equation and by using and accelerometer, and they were compared with TEE determined with DLW. Resting energy expenditure (REE) was measured using indirect calorimetry and compared with predict REE using the Harris and Benedict equation. The accelerometer was also used to determine physical activity level. Results: Participants were aged (mean ± SD) 53 ± 8 years. Measured TEE was significantly lower in the SBS group compared to the Control group (p < 0.01); however, predicted TEE did not differ significantly between the groups. Measured TEE was significantly higher than predicted TEE for the SBS group, (1875 ± 276 and 1517 ± 175 kcal/d, p < 0.01) and also for the Control group (2393 ± 445 and 1532 ± 178 kcal/d, p < 0.01) when determined by formula. However, measured TEE was significantly lower than predicted TEE (2075 ± 298 kcal/d, p = 0.02) for the SBS group, and did not differ for the Control group (2207 ± 355 kcal/d, p = 0.21) when determined by accelerometer. No significant differences were seen between measured and predicted REE both within and between groups. Conclusion: Measured TEE in SBS patients was significantly higher than predicted using standard equations, but also lower than values for age, BMI and gender-matched non-SBS controls. However, predicted TEE using accelerometer overestimated the measured TEE. Currently-used formulas in clinical practice appear to underestimate energy requirements of SBS patients. Therefore, adjustments to the current estimation, increasing the energy intake requirements in these patients appear to be adequate to support the daily energy requirements and avoid undernutrition.

A acidose metabólica é um achado comum em pacientes portadores de Doença Renal Crônica (DRC). Acredita-se que a dieta pode afetar o equilíbrio ácidobase do corpo por meio do fornecimento de precursores ácidos ou de base. No entanto, os resultados inconclusivos apontados na literatura indicam que ainda são necessários estudos bem delineados para comprovar a existência dessa associação. O principal objetivo desse estudo foi determinar o potencial de carga ácida renal (PRAL) proveniente da dieta e avaliar a sua associação com o bicarbonato sérico (HCO3) em pacientes com DRC enquanto em suas dietas habituais. Associações do HCO3 com o gasto energético de repouso (GER) e com oxidações proteicas e lipícas também foram estudadas. Trata-se de um estudo transversal realizado com 100 pacientes distribuídos igualmente nos estágios 3 e 4 da DRC entre 20 e 69 anos. Avaliação do estado nutricional foi feita por meio da antropometria, registro alimentar e exames bioquímicos, o qual incluiu os produtos proteicos de oxidação avançada e os isoprostanos. O HCO3 foi determinado por meio da gasometria venosa. GER foi medido pela calorimetria indireta. O PRAL foi determinado por meio do registro alimentar usando um algoritmo que inclui dados dietéticos da ingestão de proteína, fósforo, magnésio, cálcio e potássio descritos por Remer e Manz (1995). Também foi feita a diferenciação no consumo de proteína animal e vegetal. A análise dos resultados foi feita em quartis de HCO3 para as variáveis GER e parâmetros de oxidação, o restante das análises foram feitas por quartis de PRAL. Para comparação das variações médias dos quartis foi utilizado o teste one-way ANOVA. A associação entre a estimativa do PRAL e o HCO3 foi avaliada por modelos de regressão linear ajustados. A maior parte dos nossos pacientes portadores de DRC encontravam-se com excesso de peso associado a um aumento da circunferência abdominal e da porcentagem de gordura corporal. A mediana do PRAL foi de 6,8 mEq/dia com uma variação entre -24 a 52 mEq/dia. O PRAL mais elevado foi associado com o HCO3 mais baixo de uma forma graduada (p < 0.02). Encontramos uma diferença de 2,07 mmol/L no HCO3 entre o primeiro e o último quartil, sendo o valor do último quartil de PRAL menor em relação ao primeiro. A proteína animal apresentou uma correlação inversa com o bicarbonato sérico. O GER e os marcadores de oxidação lipíca e proteica não apresentaram associações com os níveis de HCO3. Esses resultados reforçam a possibilidade de que dietas com alto teor de carga ácida podem desempenhar um papel relevante no equilíbrio ácidobase em pacientes portadores de DRC, além de consolidar o uso da carga ácida da dieta como uma abordagem diferencial e complementar às outras estratégias no tratamento dietético da DRC. / Metabolic acidosis is a common complication in patients with chronic kidney disease (CKD). Acid-inducing diets are believed to impact on acid-base balance. However, well-designed studies are still needed to prove the association between dietary acid load and serum bicarbonate. The main aim of this study was to calculate the potential renal acid load (PRAL) of selected, frequently consumed foods and to evaluate its association with serum bicarbonate (HCO3) in patients with CKD. Associations of HCO3 with resting energy expenditure (REE) and with protein and lipid oxidation were also studied. It is a cross-sectional study with 100 patients equally distributed in stages 3 and 4 of CKD between 20 and 69 years. Nutritional status was assessed by anthropometric measurements, 3-day food recall, biochemical analysis including advanced oxidation protein products and isoprostanes. Venous blood gases was used to measure HCO3. GER was measured by indirect calorimetry. PRAL was determined by food record using an algorithm that includes protein, phosphorus, magnesium, calcium and potassium intake described by Remer and Manz (1995). Dietary intake of animal and vegetable protein were also evaluate. For analysis, we used quartiles of HCO3 for GER and oxidation parameters and for the others variables we used quartilhes of PRAL. ANOVA one-way test was used to compare the mean of the quartiles. The association between PRAL and HCO3 was assessed by linear regression models. Most of the patients were overweight with increased waist circumference and body fat. The median PRAL was 6.8 mEq/day with a variation between -24 to 52 mEq/day. Higher PRAL was associated with lower serum bicarbonate in a graded fashion (P trend 0.02). Serum bicarbonate was 2.07 mEq/L lower among those in the highest compared with the lowest quartile of PRAL. Animal protein was inversely correlated with serum bicarbonate. REE and lipid and protein oxidation markers showed no association with HCO3 levels. These results reinforce the possibility that diets with high dietary acid load may play a relevant role in the acid-base balance in CKD patients. In addition to consolidating the use of PRAL as a differential and complementary approach to other strategies in the nutritional treatment of CKD.