Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer.

BACKGROUND: Preoperative immunonutrition has been proposed to reduce the duration of hospital stay and infective complications following major elective surgery in patients with gastrointestinal malignancy. A multicentre 2 × 2 factorial RCT was conducted to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with oesophageal cancer. METHODS: Patients were randomized before oesophagectomy to immunonutrition (IMPACT® ) versus standard isocaloric/isonitrogenous nutrition, then further randomized after operation to immunonutrition versus standard nutrition. Clinical and quality-of-life outcomes were assessed at 14 and 42 days after operation on an intention-to-treat basis. The primary outcome was the occurrence of infective complications. Secondary outcomes were other complications, duration of hospital stay, mortality, nutritional and quality-of-life outcomes (EuroQol EQ-5D-3 L™, European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-OES18). Patients and investigators were blinded until the completion of data analysis. RESULTS: Some 278 patients from 11 Australian sites were randomized; two were excluded and data from 276 were analysed. The incidence of infective complications was similar for all groups (37 per cent in perioperative standard nutrition group, 51 per cent in perioperative immunonutrition group, 34 per cent in preoperative immunonutrition group and 40 per cent in postoperative immunonutrition group; P = 0·187). There were no significant differences in any other clinical or quality-of-life outcomes. CONCLUSION: Use of immunonutrition before and/or after surgery provided no benefit over standard nutrition in patients undergoing oesophagectomy. Registration number: ACTRN12611000178943 ( https://www.anzctr.org.au).

Immunonutrition in patients undergoing esophageal cancer resection.

Specialized nutritional support containing immunonutrients such as arginine, omega-3 fatty acids, and ribonucleic acid significantly reduces the incidence of postoperative infective complications and hospital length of stay in elective surgery patients. However, immunonutrition use is not standard practice in esophago-gastric units internationally. This review provides a clinical update regarding the use of immunonutrition in patients undergoing major gastrointestinal surgery and, in particular, esophageal cancer resection, and provides direction for future collaborative research. A review of MEDLINE and Cochrane Library databases was conducted for randomized controlled trials or meta-analyses. A recent meta-analysis demonstrated that preoperative immunonutrition use significantly reduces hospital length of stay and the incidence of postoperative complications in patients undergoing major elective surgery, particularly for gastrointestinal malignancies. Only three small randomized controlled trials have evaluated immunonutrition use in patients exclusively undergoing esophageal cancer surgery. These were unable to determine whether immune-enhancing formulae positively influence key clinical outcomes such as mortality, hospital and intensive care unit length of stay, and postoperative morbidity in this patient group. Currently, there is insufficient evidence to recommend routine use of immunonutrition in patients undergoing esophageal cancer surgery. Future collaborative research should evaluate whether: (i) immunonutrition use positively influences key clinical outcomes in this population; (ii) these patients benefit from preoperative supplementation with an immune-enhancing formula or whether they require postoperative continuation (perioperative approach) to combat their risk of complications after surgery; and (iii) these formulae can be used safely in those patients who develop sepsis.

Balance dysfunction in adults with haemophilia.

The main focus of lower limb physical performance assessment in people with haemophilia (PWH) has usually been on function, muscle strength and joint flexibility. The impact of haemophilic arthropathy on balance and falls risk is relatively under-explored. The aim of this study was to evaluate balance and related performance in PWH compared with age and gender matched healthy controls. It involved a comprehensive suite of clinical and laboratory measures of static and dynamic balance, mobility, strength, physical activity and falls efficacy completed in 20 PWH (mean age 39.4, 100% male) and 20 controls. Fifty percent of PWH reported falls in the past 12 months. Moderate impairment of balance and related measures were identified in PWH compared with the controls, with an average 35% difference between groups. Significant differences were evident between groups on both clinical and laboratory measures, including measures of dynamic bilateral stance balance [limits of stability measures on the laboratory test, functional reach; (P < 0.001); dynamic single leg balance (Step Test, P < 0.001)], gait and mobility (gait speed, step width and turning measures on the laboratory test, timed up and go test; P < 0.001); muscle strength (timed sit to stand, P = 0.002; quadriceps strength, P < 0.001); and activity level and falls efficacy, (P < 0.004). The dynamic clinical and laboratory measures testing similar domains of balance, gait and mobility had moderate correlations (0.310 < r < 0.531, P < 0.01). Moderate impairments in balance, mobility and related measures were identified in PWH, compared with the control group. Clinicians should include assessments of balance and related measures when reviewing adults with haemophilia.

Effectiveness of a balance training home exercise programme for adults with haemophilia: a pilot study.

Adults with haemophilia and other bleeding disorders often develop lower limb musculoskeletal problems associated with bleeds into joints and muscles, which may affect balance performance and increase likelihood of falling. The aim of this study was to evaluate the effectiveness of an individualized balance and strength home exercise programme on improving balance and related outcomes for adults with haemophilia and other bleeding disorders. Twenty male adults with haemophilia and other bleeding disorders (mean age 39.4 years, 95% CI = 33.7-45.1) were recruited to participate. They underwent a comprehensive clinical and force platform assessment of balance and related measures. Based on assessment findings, the assessing physiotherapist provided an individualized home exercise programme of balance, strengthening and walking exercises. Re-assessment occurred after the 4-month exercise programme. Twelve participants (60%) completed the programme and were re-assessed. There were no safety problems or dropouts associated with the exercise programme aggravating joint status. Although there were no statistically significant changes in any of the measures (adjusted for multiple comparisons), there were improvements of between 5% and 22% on 10 of the 16 measures, with the Neurocom modified Clinical Test of Sensory Interaction on Balance (P = 0.036) and Timed Sit to Stand (P = 0.064) approaching significance. A tailored home exercise programme targeting balance, strengthening and walking is feasible for adults with haemophilia and other bleeding disorders. These results suggest that positive physical outcomes including improved balance and mobility may be achieved with this type of programme.

Phosphorylation of synapsin I and dynamin in rat forebrain synaptosomes: modulation by sigma (sigma) ligands.

The effects of sigma (sigma) ligands on protein phosphorylation were examined in crude, rat forebrain synaptosomes. Synaptosomes were prelabelled with 32P(i) and incubated with the sigma ligands 1,3-di-o-tolylguanidine (DTG), (+)pentazocine and (-)pentazocine (3, 10, 30, 100, 300 microM), or haloperidol, reduced haloperidol, and (+)SKF 10,047 (100 microM). Aliquots were then incubated for 10 s in control (5 mM K+) or depolarising buffer (41 mM K+). All the sigma ligands increased basal phosphorylation of synapsin Ib and other proteins including dynamin, and inhibited the depolarisation-dependent increase in phosphorylation of synapsin Ib in synaptosomes. The effects of these ligands are not directly on protein kinases or protein phosphatases. This indicates that the sigma ligands are mediating their effects via interaction with sigma binding sites, and suggest, for the first time, that protein phosphorylation may be one mechanism through which sigma ligands produce their biological effects.

Protein phosphatase activity in cyanobacteria: consequences for microcystin toxicity analysis.

Hepatotoxic microcystin levels in cyanobacteria (blue-green algae) were assessed by an assay based on inhibition of protein phosphatases type 1 (PP1) and type 2A (PP2A) in crude chicken forebrain extracts using 32P-labelled glycogen phosphorylase as substrate. While cyanobacteria are reported to be devoid of phosphorylase phosphatase activity, two samples obtained from cyanobacterial scums, containing predominantly Anabaena circinalis, were found to contain high levels of a phosphorylase phosphatase activity which completely masked the presence of microcystin. Furthermore, samples containing predominantly Microcystis aeruginosa but increasing Anabaena circinalis contained sufficient phosphorylase phosphatase activity to cause a fourfold underestimation of microcystin levels. Thus, protocols for microcystin toxicity analysis should take into account the possible presence of endogenous phosphatase activity, thereby preventing underestimation of toxin levels.

Transient translocation and activation of protein phosphatase 2A during mast cell secretion.

Okadaic acid inhibits secretion from mast cells, suggesting a regulatory role for protein Ser/Thr phosphatases type I (PP1) and/or 2A (PP2A) in the secretory process. In unstimulated RBL-2H3 cells, okadaic acid pretreatment inhibited PP2A activity in both cytosol and membrane fractions, but inhibition of secretion correlated with inhibition of membrane-bound rather than cytosolic PP2A activity. Okadaic acid had very little effect on PP1 activity. Stimulation of RBL-2H3 cells by antigen led to the activity and amount of PP2A in the membrane fraction increasing nearly 2-fold. In contrast, there was little change in the activity or distribution of PP1. Importantly, the translocation of PP2A was transient, coinciding with or marginally preceding the peak rate of secretion, suggesting a link between PP2A translocation, activity, and secretion. Phorbol 12-myristate 13-acetate plus the calcium ionophore A23187 induced a slower, prolonged rate of secretion that coincided with a similarly protracted translocation of PP2A to the membrane fraction. PP2A translocation is not the only event required for secretion as translocation was also induced by phorbol 12-myristate 13-acetate, without resulting in secretion. These results indicate that increased protein dephosphorylation in the membrane fraction mediated by PP2A is required for mast cell secretion. To our knowledge, this is the first demonstration of a signal-mediated, rapid, transient translocation and activation of PP2A in membranes in any system.

Developmental regulation of protein phosphatase types 1 and 2A in post-hatch chicken brain.

The activity and subcellular distribution of protein phosphatases 1 and 2A were measured in chicken forebrain and cerebellum during post-hatch development. At all post-hatch ages, a large proportion of PP1 and PP2A was membrane bound and these enzymes were less active than their cytosolic counterparts. The protein concentration of PP1 in the membranes increased 40% between 2 and 14 days and a further 60% between 14 days and adult, whereas the PP1 enzyme activity in the membranes progressively decreased. In contrast to PP1, the protein concentration of PP2A remained constant in all fractions during post-hatch development, and the enzyme activity of PP2A did not change except for a decrease in the membrane-bound activity between 2 and 14 days. These results show that the subcellular distribution and activity of PP1 is selectively regulated during post-hatch development and that membrane association and inactivation of PP1 are independent events.