Skeletal muscle anabolic and insulin sensitivity responses to a mixed meal in adult patients with active Crohn's disease.

BACKGROUND AND AIMS: We have previously shown reduced protein balance in response to nutrition in paediatric Crohn's disease (CD) in remission, associated with reduced lean mass (sarcopenia) and reduced protein intake in males. We aim to compare skeletal muscle metabolic response to feeding in adult active CD and healthy volunteers. METHODS: Eight CD participants with active disease (41.3 ± 4.5 yrs; BMI 26.9 ± 1.5 kg/m2) and eight matched healthy volunteers (Con) (41.2 ± 4.3 yrs; BMI 25.1 ± 1.1 kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialized hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20mins for 2hrs after the ingestion of a standardized mixed liquid meal. Net balance of branched chain amino acids (BCAA), glucose and free fatty acids across the forearm were derived. RESULTS: No differences in muscle BCAA, glucose or FFA net balance were found between CD and Con. Neither were differences in muscle mass and function, physical activity or diet found. CD did not differ from Con in whole body insulin and lipid responses, or in energy expenditure and fuel oxidation. CONCLUSIONS: Skeletal muscle mass, function, dietary protein intake and response to a test meal in an adult CD cohort with active disease is similar to that seen in healthy volunteers. Combining these results with our previous findings in paediatric patients suggests that age of onset and/or disease burden over time, as well as daily protein intake, may be significant in the development of sarcopenia in CD. Longitudinal studies investigating these factors are required.

Effect of acute and short-term dietary fat ingestion on postprandial skeletal muscle protein synthesis rates in middle-aged, overweight, and obese men.

Muscle anabolic resistance to dietary protein is associated with obesity and insulin resistance. However, the contribution of excess consumption of fat to anabolic resistance is not well studied. The aim of these studies was to test the hypothesis that acute and short-term dietary fat overload will impair the skeletal muscle protein synthetic response to dietary protein ingestion. Eight overweight/obese men [46.4 ± 1.4 yr, body mass index (BMI) 32.3 ± 5.4 kg/m2] participated in the acute feeding study, which consisted of two randomized crossover trials. On each occasion, subjects ingested an oral meal (with and without fat emulsion), 4 h before the coingestion of milk protein, intrinsically labeled with [1-13C]phenylalanine, and dextrose. Nine overweight/obese men (44.0 ± 1.7 yr, BMI 30.1 ± 1.1 kg/m2) participated in the chronic study, which consisted of a baseline, 1-wk isocaloric diet, followed by a 2-wk high-fat diet (+25% energy excess). Acutely, incorporation of dietary amino acids into the skeletal muscle was twofold higher (P < 0.05) in the lipid trial compared with control. There was no effect of prior lipid ingestion on indices of insulin sensitivity (muscle glucose uptake, pyruvate dehydrogenase complex activity, and Akt phosphorylation) in response to the protein/dextrose drink. Fat overfeeding had no effect on muscle protein synthesis or glucose disposal in response to whey protein ingestion, despite increased muscle diacylglycerol C16:0 (P = 0.06) and ceramide C16:0 (P < 0.01) levels. Neither acute nor short-term dietary fat overload has a detrimental effect on the skeletal muscle protein synthetic response to dietary protein ingestion in overweight/obese men, suggesting that dietary-induced accumulation of intramuscular lipids per se is not associated with anabolic resistance.

Reduced skeletal muscle protein balance in paediatric Crohn's disease.

BACKGROUND & AIMS: An inability to respond to nutrition could be implicated in low muscle mass in Crohn's disease. We aim to determine skeletal muscle metabolic response to feeding in Crohn's disease and healthy volunteers. METHODS: Twenty asymptomatic Crohn's disease participants (15.6 ± 0.5 yrs; BMI 20.6 ± 0.9 kg/m2); 9 with active disease (faecal calprotectin, 808 ± 225 ug/g and C-reactive protein, 2.2 ± 1.2 mg/dl), 11 in deep remission (faecal calprotectin, 61 ± 12 ug/g and C-reactive protein, 0.3 ± 0.2 mg/dl) and 9 matched healthy volunteers (16.0 ± 0.6 yrs; BMI 20.7 ± 0.6 kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialised hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20 min for 2 hrs after the ingestion of a standardised liquid meal. Net balance of branched chain amino acids (BCAA) and glucose were derived. RESULTS: Controls had a positive mean BCAA balance. CD participants had an initial anabolic response to the meal, with increasing BCAA balance between t = 0 & t = 20, but returned to negative by t = 60. This was associated with reduced FFM z-scores in CD but not with insulin resistance or disease activity. Exploratory analyses suggest that negative postprandial BCAA response seen in CD is predominant in males (p = 0.049), with associated lower appendicular muscle mass (p = 0.034), higher muscle fatigue (p = 0.014) and reduced protein intake (p = 0.026). CONCLUSIONS: The inability to sustain a positive protein balance postprandially could provide an explanation for the reduced muscle mass seen in CD. Further mechanistic studies will be needed to confirm these findings.

A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies.

BACKGROUND: To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. METHODS: Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. RESULTS: The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3-1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4-6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. CONCLUSIONS: We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. TRIAL REGISTRATION: Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

Electronic remote blood issue: a combination of remote blood issue with a system for end-to-end electronic control of transfusion to provide a "total solution" for a safe and timely hospital blood transfusion service.

BACKGROUND: The rapid provision of red cell (RBC) units to patients needing blood urgently is an issue of major importance in transfusion medicine. The development of electronic issue (sometimes termed "electronic crossmatch") has facilitated rapid provision of RBC units by avoidance of the serologic crossmatch in eligible patients. A further development is the issue of blood under electronic control at blood refrigerator remote from the blood bank. STUDY DESIGN AND METHODS: This study evaluated a system for electronic remote blood issue (ERBI) developed as an enhancement of a system for end-to-end electronic control of hospital transfusion. Practice was evaluated before and after its introduction in cardiac surgery. RESULTS: Before the implementation of ERBI, the median time to deliver urgently required RBC units to the patient was 24 minutes. After its implementation, RBC units were obtained from the nearby blood refrigerator in a median time of 59 seconds (range, 30 sec to 2 min). The study also found that unused requests were reduced significantly from 42 to 20 percent, the number of RBC units issued reduced by 52 percent, the number of issued units that were transfused increased from 40 to 62 percent, and there was a significant reduction in the workload of both blood bank and clinical staff. CONCLUSIONS: This study evaluated a combination of remote blood issue with an end-to-end electronically controlled hospital transfusion process, ERBI. ERBI reduced the time to make blood available for surgical patients and improved the efficiency of hospital transfusion.

End-to-end electronic control of the hospital transfusion process to increase the safety of blood transfusion: strengths and weaknesses.

BACKGROUND: Incorrect blood component transfused is a frequent serious incident associated with transfusion and often involves misidentification of the patient and/or the unit of blood. STUDY DESIGN AND METHODS: This study extended the evaluation of an electronic system involving bar code technology and handheld computers. Electronic control of collection of blood from blood refrigerators was incorporated into a previously described process for blood sample collection and blood administration. Practice was evaluated before and after its introduction in cardiac surgery. RESULTS: The baseline audits revealed poor practice. Significant improvements were found following the introduction of the electronic system, including from 8 percent to 100 percent in checking that the blood group and unit number on the blood pack matched the compatibility label and the pack was in date (p < or = 0.0001). Similar significant improvements were found in blood sample collection, the collection of blood from blood refrigerators, and the documentation of transfusion. Staff found the system easy to operate and preferred it to standard procedures. CONCLUSIONS: A bar code patient identification system improved transfusion practice, although areas for improvement were identified. These results provide support for further work on the development of such systems for both transfusion and other procedures requiring patient identification.

A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting.

BACKGROUND: Total arterial grafting is increasingly preferred in coronary artery bypass grafting, but it increases blood loss. Aprotinin (Trasylol; Bayer Corp, Leverkusen, Germany) reduces blood loss in cardiac surgery but has not been subjected to a randomized trial in total arterial grafting. METHODS: A single-center, randomized, double blind, placebo-controlled trial of aprotinin administration in total arterial grafting was performed. The primary outcome variable was postoperative blood loss, and the secondary outcome variable was the number of units of donor blood or coagulant products transfused. The incidence of myocardial injury was determined from serial measurements of cardiac troponin T and creatine kinase-MB and renal injury from serum creatinine. RESULTS: The placebo group (n = 34) and aprotinin group (n = 36) were similar with respect to all preoperative and intraoperative comparisons. One patient in each group underwent reexploration for bleeding. Open-label aprotinin was administered to 9 patients in the placebo group (26%) and to 2 patients in the aprotinin group (6%). There was a highly significant reduction in the median (interquartile range) blood loss in the aprotinin group compared with the placebo group (785 mL [590-1025 mL] vs 1525 mL [1175-1920 mL], respectively). Similarly, the aprotinin group demonstrated a marked reduction in the need for blood transfusion (77% vs 39%; P =.0001), the mean number of transfused blood units (2.6 vs 0.8, P <.001), and the number of patients requiring coagulant products (24% vs 3%; P <.001). There was no difference in myocardial injury in the 2 groups. Four patients in the aprotinin group had persistently elevated creatinine levels in the postoperative period (3 of whom had elevated preoperative creatinine levels and perioperative complications). CONCLUSIONS: Aprotinin significantly reduces blood loss and the need for blood component transfusion in patients undergoing total arterial grafting without increasing the risk of myocardial injury. Aprotinin should be considered routinely in patients undergoing total arterial grafting but cautiously in patients with an elevated preoperative creatinine level.