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One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.

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OBJECTIVE: This study examined the effects of varying the energy density (ED) of high carbohydrate (HC) diets on food and energy intake (EI), subjective hunger and body weight in humans. DESIGN: Randomised cross-over design. Subjects were each studied twice during 14 d, throughout which they had ad libitum access to one of two covertly-manipulated diets. SUBJECTS AND METHODS: Six healthy men (mean age (s.d.)=32.17 y s.d. (5.26 y), mean weight=69.74 kg s.d. (2.75 kg), mean height=1.76 m s.d. (0.05 m), body mass index (BMI)=22.57 (2.2) kg/m2) were studied. The fat, carbohydrate (CHO) and protein content (as % energy) and ED of each diet were 21:66:13% and 357 kJ/100 g, (low-energy density (LED)) or 22:66:12% and 629 kJ/100 g (high-energy density (HED)). A medium fat diet was provided at maintenance (1.6 x BMR, MF for 2 d) before each ad libitum period. Subjects could alter the amount, but not the composition of foods eaten. RESULTS: Mean EI was 8.67 and 14.82 MJ/d on the LED and HED diets, respectively. Subjects felt significantly more hungry on the LED diet, than on the HED diet (F(1,160)38.28; P < 0.001) and found the diets to be similarly pleasant (72.72 mm vs 71.54 mm (F(1,392)0.31; P = 0.579)). Mean body weight decreased on the LED diet at a rate of 0.1 kg/d and increased at 0.06 kg/d on the HED diet (F(1,131)86.60; P < 0.001), giving total weight changes of -1.41 kg and +0.84 kg, respectively, both of which were significantly different from zero (P < 0.01). CONCLUSION: Excess EI is possible on HC, HED diets, at least under conditions where diet selection is precluded. Comparison of these results with previous studies, which altered ED using fat, suggests that CHO may be a better cue for hunger than fat.

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Although the importance of root production and mortality to nutrient fluxes in ecosystems is widely recognized, the difficulties associated with root measurements have limited the availability of reliable data. We have used minirhizotrons and image analysis to measure root longevity of Prunus avium L., Picea sitchensis (Bong.) Carrière, Acer pseudoplatanus L. and Populus x canadensis cv. Beaupre directly in cohorts of roots. Major differences in the longevity of roots among species were identified. For example, 40% of Prunus avium roots but only 6% of Picea sitchensis roots survived for more than 14 days. Survival analysis of cohorts of roots of Prunus avium and Populus x canadensis revealed differences in the distribution of longevity among cohorts. Genetic, biotic and abiotic factors that may influence longevity are discussed.

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The relationships of N input or protein status and the concentrations of serum insulin-like growth factor-1 (IGF-1), plasma fibronectin (FN) and total protein (TP) were examined in three experiments with steers and sheep nourished by intragastric infusion of nutrients. In Expt 1, three steers (340 kg live weight) were infused with three levels of volatile fatty acids (0, 300 and 600 kJ/kg metabolic weight (W0.75) per d) and six levels of casein (0, 200, 400, 650, 1500 and 2500 mg N/kg W0.75 per d). Each N treatment was imposed for 5 d. In Expts 2 and 3, five groups of sheep (about 35 kg live weight) were infused with casein at 500 mg N/kg W0.75 per d for 2 weeks followed by 1500, 500 or 50 mg N/kg W0.75 per d in Expt 2, and in Expt 3, with 100 mg N/kg W0.75 per d for 6 weeks or 10 mg N/kg W0.75 per d for 4 weeks. Non-protein energy was maintained constant at 500 kJ/kg W0.75 per d throughout. Daily N balance and total body N content at the end were measured, and protein status was defined as a percentage of cumulative N accretion or depletion in relation to the total body N content at maintenance. It was found that IGF-1 and FN responded rapidly and substantially to altered N input, and that when daily N input was maintained constantly at sub-maintenance, their continuous declines were related closely to progressive protein depletion in the sheep. Plasma TP concentration was independent of N input when N input was altered acutely in the steers, but declined significantly and gradually with severe, chronic body protein depletion in the sheep. Plasma content of TP in the sheep however reduced acutely with a reduction in N input. Plasma volume fell substantially over the first 2 weeks of protein depletion, compensating for the declines in TP content and maintaining TP concentration plateau. The possible implications of the changes in TP concentration and content (concentration x volume) to body protein loss in sheep are discussed.

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OBJECTIVE: High-fat, high energy-density (HF, HED) diets promote an increase in energy intakes relative to low-fat lower-energy density diets (LF, LED). This study examined whether HF diets promote higher levels of energy intake when isoenergetically dense (IE) relative to LF (high carbohydrate) diets, as predicted by glucostatic and glycogenostatic models for energy intake regulation. SUBJECTS: Six normal-weight healthy men [mean age (SD) = 37.33 (13.32 y) mean weight = 73.03 (5.14 kg), mean height = 1.80 (0.05 m)]. DESIGN: Six men were each studied three times (factorial design) during 14-d throughout which they had ad libitum access to one of three covertly-manipulated diets. The fat, carbohydrate (CHO) and protein in each diet (as % energy) were 20:68:12, [low-fat (LF)]; 40:48:12, [medium-fat (MF)]; 60:28:12 [high-fat (HF)], with 2-d maintenance (1.4 x BMR, MF) beforehand. Within each diet every item was of the same composition and offered as a 3-d rotating menu. MEASUREMENTS: Energy and nutrient intakes, body weight, subjective pleasantness and satisfaction of the food. RESULTS: Energy intakes were 10.69, 11.02 and 10.90 MJ/d on the LF, MF and HF diets respectively. The increase in energy intake that occurred in previous studies when the energy density of the diet was increased by addition of fat was not apparent when LF, MF and HF diets were of the same energy density. CONCLUSION: Neither carbohydrate nor fat intake were tightly regulated. These data do not support an entirely glucostatic or glucogenostatic model of food intake regulation.

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OBJECTIVE: To compare the effect of isoenergetically-dense, high-protein (HP), high-fat (HF) or high-carbohydrate (HC) breakfasts (at 08.30) on subjective hunger, fullness and appetite (measured hourly on a 100 mm visual analogue scale), macronutrient balance and ad libitum energy intake (EI), at a test meal (13.30) and throughout the rest of the day (until 23.00). DESIGN: Six men each spent 24 h in a whole-body indirect calorimeter on three separate occasions during which they received breakfasts designed to match 75% of BMR and that comprised, on average 3.1 MJ of protein (HP), carbohydrate (HC) or fat (HF), respectively, the remainder being split between the other two macronutrients. Every item of the ad libitum diet comprised 13% protein, 40% fat and 47% carbohydrate by energy, with an energy density of 550 kJ/100 g. RESULTS: Subjectively-rated pleasantness did not differ between the breakfasts, or any of the subsequent ad libitum meals. Subjective hunger was significantly greater during the hours between breakfast and lunch after the HF (26) treatment relative to the HP (18) or HC (18 mm) meals (P < 0.001), although the HP treatment suppressed hunger to a greater extent than the other two treatments over 24 h. However, mean ad libitum lunch intakes were similar at 5.38, 5.30 and 5.18 MJ (NS) on the HP, HC and HF treatments, respectively. After-lunch intakes were also very similar at 6.14, 6.18 and 5.83 MJ (NS). Mean 24-h energy expenditure amounted to 11.12, 11.14 and 10.93 MJ, respectively, producing energy balances of 5.71, 5.83 and 5.04 MJ (NS), respectively. The HP, HF and HC breakfasts led to enhanced P, F and C oxidation, respectively (P < 0.003). CONCLUSIONS: Large HP, HC or HF breakfasts led to detectable changes in hunger that were not of sufficient magnitude to influence lunch-time intake 5 h later, or EI for the rest of the day. A single positive balance of each macronutrient can be buffered by oxidation and storage capacity, without leading to changes in meal-to-meal EI, when subjects feed ad libitum on unfamiliar diets of fixed composition.

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OBJECTIVE: To test whether overfeeding isoenergetic doses protein, carbohydrate and fat would differentially influence appetite on the same day, and the subsequent day's food intake. DESIGN: Six men were each studied three times on a 5-day protocol. On days 1 and 2 they were fed a medium fat (MF) maintenance diet (comprising 40:47:13% fat, CHO and protein by energy) calculated at 1.6 x RMR. Subjects entered the calorimeter at 08.00 on day 3 for 48 h. On day 3 (manipulation day), they ate a MF diet at 1.5 x RMR with an additional 0.6 x RMR as protein (HP), carbohydrate (HC) or fat (HF). On days 4 and 5, (outcome days), subjects had ad libitum access to isoenergetically dense MF (40:47:13) foods (550kJ/100 g). Subjective hunger and satiety were tracked hourly during waking hours throughout days 1-5. RESULTS: Throughout day 3 subjects felt significantly more full and less hungry on the high protein diet relative to the other two diets (P = 0.002). Also by the end of day 3 each overfed nutrient led to a significant increase in its own balance of the other two diets (P < 0.01). These effects did not influence the subsequent day's energy intake. The alterations in nutrient balance by the end of day 3 were partially buffered by increases in the oxidative disposal of each overfed macronutrient throughout day 4 (which was proportionately greater for protein (P < 0.001) than carbohydrate (P = 0.07) or fat (P = 0.1)). CONCLUSIONS: HP diets were more satiating that isoenergetically-dense HC or HF diets on the day they are eaten. The HC diet was transiently more satiating than the HF diet after each meal. This study supports previous work which suggests that relatively large changes in nutrient balance produced on one day appear to be poorly compensated by changes in energy intake on a subsequent day in men.

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OBJECTIVE: This study examined whether isoenergetic substitution of MCT for LCT in HF, HE diets (639 kJ/100 g) limits the excess energy intakes frequently observed on high-fat diets of high energy density (HF, HE). SUBJECTS: Six healthy male volunteers [mean age (SD) = 27.17 (4.17 y) mean weight = 63.33 (7.33 kg), mean height = 1.72 (0.05 m)]. DESIGN: The subjects were each studied three times during 14 d throughout which they had ad libitum access to one of three covertly-manipulated diets, which were randomly assigned in a counter-balanced design. The fat, carbohydrate (CHO) and protein in each diet (as percent energy) were identical at 62:28:10, with 2 day maintenance (1.5 x BMR, MF) beforehand. The ratio of MCT to LCT was 1:2, 1:1 and 2:1 on the low-, (LMCT) medium- (MMCT) and high-MCT (HMCT) diets, respectively. Within each diet every item was of the same composition and offered as a 3 day rotating menu. RESULTS: Energy intakes were significantly lower on the HMCT diet [F (2,240) = 7.52; p < 0.001] giving mean values of 13.50, 13.67, and 12.43 MJ/d on the LMCT, MMCT and HMCT diets, respectively. Food intake followed a parallel trend. By day 14 body weight changes amounted to +0.45, +0.41 and -0.03 kg, respectively. CONCLUSION: These data suggest that substitution of a readily metabolised fat for a less readily metabolised fat, in very high fat diets can limit the excess energy intakes and weight gain that is usually produced by HF, energy-dense diets.

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This study assessed whether human food intake is regulated by negative feedback, directly or indirectly, from carbohydrate stores (glycogenostatic model). Six men were studied on three occasions during 7 d of whole-body indirect calorimetry, throughout which they had ad libitum access to one of three covertly manipulated diets: low fat (20% of energy as fat, 67% of energy as carbohydrate, and 13% of energy as protein; 4.80 kJ/g; LF), medium fat (40% of energy as fat, 47% of energy as carbohydrate, and 13% of energy as protein; 5.59 kJ/g; MF), or high fat (60% of energy as fat, 27% of energy as carbohydrate, and 13% of energy as protein; 7.04 kJ/g; HF). Energy intakes increased with percent fat (F[92,60] = 36.7; P < 0.001), producing average daily balances of -0.27, 0.77, and 2.58 MJ/d during the LF, MF, and HF diets, respectively. Changes in carbohydrate stores were attenuated by autoregulatory changes in carbohydrate oxidation. Carbohydrate balance showed a negative relation to the subsequent day's energy balance (t = 2.696; P = 0.0082) but explained only 5.5% of the variance. The relation for fat was positive (t = 5.245; P < 0.0001), accounting for 19.9% of the variance (stepwise regression). LF, lower-energy diets are more satiating than are HF-higher-energy diets, but carbohydrate stores per se did not entirely account for the change that diet composition had on energy intake. This study suggests that protein and carbohydrate have potential to reduce subsequent energy intake whereas there was no apparent reductive effect due to fat.

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