Summary Background Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. Methods Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m 2 etoposide taken intravenously on days 1–5; 60 mg/m 2 prednisone taken orally on days 1–15; and 40 mg/m 2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m 2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m 2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m 2 prednisone taken orally on days 1 to 15; and 100 mg/m 2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m 2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy ana...

Two bulls, each fitted with rumen and duodenal cannulas, received (in addition to a hay-grain diet) twice daily an infusion of 200 g glycerol into the rumen over a period of six days. During this preliminary in vivo investigation, the influence of a glycerol application on the rumen environment over a six-day adaptation period was examined. Samples of rumen fluid were collected daily, two hours after glycerol infusion. An additional 15N-urea application into the rumen was given on days 1 (without glycerol infusion), 3 and 7 (with glycerol infusion). Extra samples of rumen fluid and blood plasma (from puncture of vena jungularis) were taken through the 12th hour following urea application. Rumen fluid pH was reduced due to glycerol intake from 6.3 (day 1, without glycerol) to 5.4 by day 7. Molar proportion of acetic acid to propionic acid decreased from 3.5 (day 1) to 2.1 (days 6 and 7). Average glycerol disappearance rate from the rumen was 4.7 gl-1 h-1 for the first hour. Only small amounts of glycerol could be detected in the duodenal digesta. Blood plasma glycerol content was significantly higher after glycerol application (0.061 mmol l-1 vs. 0.019 mmol l-1). The incorporation of 15N into the rumen bacteria and the proportion of bacterial N (as percent of TCA-precipitable N in the rumen fluid) were lower after glycerol influsion. These results, coupled with the lower concentration of iso-acids (isobutyric and isovaleric acids) in the rumen fluid, indicate that the high amount of glycerol infusion (10% of DMI) reduced protein metabolism of rumen bacteria throughout the experimental period.

In addition to its role as an essential protein component, leucine (Leu) displays several other metabolic functions such as activation of protein synthesis. This property makes it an interesting amino acid for the therapy of human muscle atrophy and for livestock production. However, Leu can stimulate its own degradation via the branched-chain keto acid dehydrogenase complex (BCKDH). To examine the response of several tissues to excessive Leu, pigs were fed diets containing two- (L2) and four-fold (L4) higher Leu contents than the recommended amount (control). We found that the L4 diet led to a pronounced increase in BCKDH activity in the brain (2.5-fold, P < 0.05), liver (1.8-fold, P < 0.05) and cardiac muscle (1.7-fold, P < 0.05), whereas we found no changes in enzyme activity in the pancreas, skeletal muscle, adipose tissue and intestinal mucosa. The L2 diet had only weak effects on BCKDH activity. Both high Leu diets reduced the concentrations of free valine and isoleucine in nearly all tissues. In the brain, high Leu diets modified the amount of tryptophan available: for serotonin synthesis. Compared to the controls, pigs treated with the high Leu diets consumed less food, showed increased plasma concentrations of 3-hydroxybutyrate and reduced levels of circulating serotonin. In conclusion, excessive Leu can stimulate BCKDH activity in several tissues, including the brain. Changes in cerebral tryptophan, along with the changes in amino acid-derived metabolites in the plasma may limit the use of high Leu diets to treat muscle atrophy or to increase muscle growth.

Two growth assays and 1 N balance trial were conducted to determine the standardized ileal digestible (SID) Ile:Lys ratio in 8- to 25-kg pigs using spray-dried blood cells or corn gluten feed as a protein source. In Exp. 1, 48 individually penned pigs (initial BW = 7.7 kg) were used in a 6-point SID Ile titration study (analyzed SID Ile of 0.36, 0.43, 0.50, 0.57, 0.64, and 0.72%) by addition of graded levels of L-Ile. The basal diet contained 1.00% SID Lys, 18.4% CP, and 13.6 MJ of ME/kg. Diets were based on wheat, barley, corn, and 7.5% spray-dried blood cells as a protein source. Dietary SID Leu and Val levels were 1.61 and 1.02%, respectively. For the 35-d period, ADG, ADFI, and G:F increased linearly (P < 0.01) and quadratically (P < 0.04) with increasing SID Ile:Lys. Estimates of optimal SID Ile:Lys ratios were 59% for ADG and ADFI. In Exp. 2, 24 N balances were conducted using the Exp. 1 diets (12 pigs; individually penned; average BW = 11.5 kg). Pigs were fed 3 times daily with an amount equal to 1.0 MJ of ME/kg of BW(0.75). Preparation and collection periods (7 d each) were repeated after rearranging the animals to treatments. Increasing the dietary SID Ile:Lys ratio increased N retention linearly (P < 0.01), and N utilization linearly (P < 0.01) and quadratically (P < 0.01). An optimal SID Ile:Lys ratio of 54% was estimated for N retention. In Exp. 3, 48 individually penned pigs (initial BW = 8.0 kg) were fed grain-based diets in a 6-point SID Ile titration (analyzed SID Ile of 0.35, 0.41, 0.49, 0.56, 0.62, and 0.69%). Dietary SID Ile was increased by graded addition of L-Ile. The basal diet contained 0.97% SID Lys, 16.8% CP, and 13.6 MJ of ME/kg. In contrast to Exp. 1 and 2, spray-dried blood cells were excluded and corn gluten feed was used as a protein source. Dietary SID Leu and Val were set to 1.05 and 0.66%. For the 42-d period, ADG, ADFI, and G:F increased linearly (P < 0.01) and quadratically (P < 0.01) with increasing SID Ile:Lys. Estimated optimal SID Ile:Lys ratios were 54, 54, and 49 for ADG, ADFI, and G:F, respectively. These experiments suggest that the optimal SID Ile:Lys ratio depends on diet composition. In Exp. 1, AA imbalances because of increased Leu contents may have led to increased Ile nutritional needs. For ADG and ADFI, an optimum SID Ile:Lys ratio of 54% was estimated for 8- to 25-kg pigs in diets without Leu excess.

Sixteen male growing pigs of about 24 kg BW were fitted with both a duodenal re-entrant and a post-valve T-shaped cannula inserted in the caecum. The animals were divided into four groups. Each group received one of the following diets: corn starch-soybean protein isolate-based diet without (diet C) and with carboxymethylcellulose (diet CMC) or a rye-wheat-based diet without (diet RW) and with xylanase addition (diet RWX). The diets provided similar levels of apparent precaecal digestible crude protein (CP), lysine, methionine + cystine, threonine and tryptophan. Additionally, [15N]-yeast was given with the diets during the first 10 days of the experiment. For estimation of digesta viscosity, N-flow of dietary and endogenous origin, apparent precaecal digestibilities of dry matter (DM), CP, amino acids and non starch polysaccharides (NSP) (only in pigs fed diets RW and RWX), ileal and duodenal digesta were quantitatively collected on day 16 and 17, respectively. The endogenous N-proportion was measured by the ratio of 15N enrichment in the digesta and urine. The duodenal and ileal digesta supernatant viscosity increased as carboxymethylcellulose was included into the diet. Xylanase addition to the rye-wheat based diet reduced the viscosity in the ileal digesta. There were no differences in precaecal digestibilities of DM, CP and amino acids between diet C and CMC. The precaecal digestibilities of DM and soluble and insoluble NSP increased from 69.5% to 73.9%, from 1.3% to 47.9% and from 17.0% to 35.4%, respectively, as xylanase was added to the rye-wheat-based diet. The apparent precaecal digestibility of most essential amino acids increased by 2 to 5 percent units. The amounts of endogenous N at the duodenal level were estimated to be 158, 233, 313 and 276 mg per 12 h per kg0.75 BW of pigs fed diets C, CMC, RW and RWX, respectively. The corresponding values at the ileal level were 95, 107, 164 and 150 mg per 12 h per kg0.75 BW. For endogenous N amounts, significant differences were observed between diets C and CMC (duodenum) and also between semi-purified and cereal-based diets (duodenum and ileum). Methodological aspects for the estimation of endogenous N using the isotope dilution technique are discussed. Obviously, the digesta viscosity per se does not affect the nutrient absorption and endogenous N flow within the small intestine of pigs. Other properties of complex dietary fibre, digesta passage rate or bacterial activity probably contribute to the observed changes.