Pre-operative recombinant interleukin-2 and increased nephrotoxicity.
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Acetylglucosaminidase↗
Biomedical subjects
J Broom
Publications and source records attributed to J Broom.
Tumour and host tissue responses to branched-chain amino acid supplementation of patients with cancer.
1. Rates of protein synthesis have been measured from the incorporation of 57 mg of L-[1-13C]leucine/kg for 90 min into muscle tissue and colorectal tumours removed at surgery from cancer patients. 2. For the 20 h preceding surgery and during the measurement of protein synthesis, the patients received intravenous saline, conventional intravenous nutrition (0.2 g of N and 103 non-protein kJ/kg body weight) or intravenous nutrition enriched with the branched-chain amino acids leucine, isoleucine and valine (0.2 g of N with 30% from branched-chain amino acids and 103 non-protein kJ/kg body weight). 3. Conventional intravenous nutrition resulted in a significant stimulation of the rate of protein synthesis in both muscle tissue (2.64 +/- 0.75%/day versus 1.78 +/- 0.51%/day in saline control, means +/- SD) and tumour tissue (43.9 +/- 10.3%/day versus 22.6 +/- 5.6%/day in saline control). 4. Pre-operative nutrition enriched with branched-chain amino acids was less effective than conventional intravenous nutrition in stimulating protein synthesis in both muscle and tumour. The rates of protein synthesis were 2.12 +/- 0.41%/day in muscle and 33.7 +/- 5.3%/day in the tumours. 5. The expression of proliferating cell nuclear antigen in sections of the tumours showed changes with intravenous feeding of the two different amino acid mixtures that were similar to the changes in protein synthesis, and these two variables were significantly correlated. This is evidence that feeding with conventional mixtures and mixtures enriched with branched-chain amino acids stimulates tumour growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Renal impairment associated with the pre-operative administration of recombinant interleukin-2.
1. The T-cell-derived cytokine interleukin-2 may be used to reverse the immune suppression associated with major surgery. However, both major surgical procedures and recombinant interleukin-2 therapy are known to induce renal dysfunction. 2. Eighteen patients were randomized to receive either recombinant interleukin-2 (18 x 10(6) i.u./day) or placebo, given subcutaneously for 3 days before undergoing curative colorectal cancer surgery. Indices of renal function were determined pre-operatively and for 21 days after surgery. 3. Pre-operative recombinant interleukin-2 was found to significantly increase, compared with placebo controls, N-acetyl-beta-D-glucosaminidase [peak levels 28 (SEM 2) versus 11 (SEM 3) i.u./mmol of Cr] and gamma-glutamyltransferase [peak levels 5.3 (SEM 0.6) versus 2.4 (SEM 0.2) i.u./mmol/l] and decrease urinary fractional excretion of sodium [peak difference 0.32 (SEM 0.06) versus 0.76 (SEM 0.08)] (all P < 0.05). Significantly increased urinary excretions of creatinine, N-acetyl-beta-D-glucosaminidase and gamma-glutamyltransferase were also identified after surgery. All variables returned to pretreatment limits by the seventh day post-operatively, except N-acetyl-beta-D-glucosaminidase, which was still significantly elevated 21 days after surgery. No differences in the serum concentrations of sodium, creatinine or urea were observed before or after surgery in either group. 4. Recombinant interleukin-2, when given in the preoperative period, was associated with significant renal dysfunction. However, routine monitoring of serum indices (i.e. sodium, urea, creatinine and albumin) failed to detect such renal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylglucosaminidase↗
Correlation of serum cytokine and acute phase reactant levels with alterations in weight and serum albumin in patients receiving immunotherapy with recombinant IL-2.
Recombinant IL-2 (rIL-2) has been used alone or in combination with other chemotherapeutic agents to enhance host defences against cancer. Prolonged administration of high doses, required for clinical efficacy, may precipitate serious dose-limiting toxicity. rIL-2-induced 'vascular leak syndrome' leads to hypotension, renal insufficiency, respiratory disturbances and other organ dysfunctions. Serial measurements of serum cytokines and the acute phase protein C-reactive protein (CRP) were performed on nine patients who received high-dose i.v. continuous therapy with rIL-2. The influence of these immunological parameters upon alterations in patients' weight and serum albumin, as indicators of toxicity, was assessed. All patients experienced weight increases during the cycle (3-11% of total body weight). The serum levels of tumour necrosis factor (TNF-alpha) and CRP were highly predictive of alterations in patients' weight (both P < 0.001), while no correlation was found with IL-6 and weight change. Serum albumin fell linearly throughout the infusion cycle, but this showed no correlation with variations in serum levels of IL-6, TNF-alpha, or CRP. The complement components C3 and C4 were significantly reduced at the end of the infusion, suggesting a possible role for this cascade system in mediating these clinical changes. The strong association between serum TNF-alpha and weight change, not previously documented, further supports the hypothesis that TNF-alpha is a key mediator in the pathogenesis of the 'vascular leak syndrome'.
Acute-Phase Proteins↗
Subarachnoid local anesthetic block does not affect morphine absorption from paired intramuscular and subcutaneous injection sites in the elderly patient.
Morphine absorption from subcutaneous and intramuscular injection sites is dependent on local skin and muscle blood flow. Normally, drug absorption from intramuscular and subcutaneous injections at the same anatomical site is comparable, but spinal anesthesia alters muscle and skin blood flow in the blocked area. This study measured morphine absorption from pairs of intramuscular and subcutaneous injection sites at vastus lateralis and deltoid following a single dose of morphine sulfate in the presence of spinal anesthesia. Differences between the maximum concentration achieved after injection (Cmax) and the time at which this occurred (Tmax) were not significant when absorption for each "same-site" pair of injections was compared, but Tmax after intramuscular injection at vastus lateralis was significantly longer than that observed following either intramuscular or subcutaneous injection at the deltoid (P < 0.05 for both comparisons). Cmax/Tmax ratios and the area under concentration time curve (AUC) also were analyzed, but there were no statistically significant differences among any of the four groups.
Absorption↗
Lithium clearance measurements during recombinant interleukin 2 treatment: tubular dysfunction in man.
Renal tubular function was evaluated in nine patients undergoing recombinant interleukin 2 (rIL2) treatment for metastatic colorectal carcinoma. A lithium clearance technique was used and the activities of the lysosomal enzyme N N-acetyl-beta-D-glucosaminidase were also measured in the patients' urine, before treatment, during treatment, and then 2 days and 23 days after rIL2 therapy had finished. Significant reductions in clearances of creatinine, sodium, and lithium were observed. The fractional excretions of sodium and lithium were also reduced. Twenty-three days following cessation of rIL2 treatment, there was still a significant reduction in creatinine clearance compared with pretreatment values (p < .01). The clearances of sodium and lithium were also reduced compared with pretreatment values although this did not achieve significance. The fractional reabsorption of sodium and water by the proximal nephron increased during rIL2 treatment, from 0.707 +/- 0.030 (pretreatment) to 0.793 +/- 0.043. This increased reabsorption of sodium and water persisted, rising to 0.849 +/- 0.029, 2 days following cessation of treatment (p < .001, means +/- SEM). Twenty-three days later this had returned toward the pretreatment value, being 0.781 +/- 0.036. The fractional reabsorption of sodium by the distal nephron was also significantly elevated, both during and 2 days after completing rIL2 treatment. Twenty-three days after cessation of rIL2, this value had returned to the pretreatment value. However, in contrast, the fractional reabsorption of water by the distal nephron demonstrated no change during rIL2 treatment, but 2 days posttreatment was significantly reduced and remained low for a further 3 weeks.
Acetylglucosaminidase↗
Interleukin 2 therapy in cancer: identification of responders.
C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.
Adult↗
Glomerulotubular function in patients undergoing moderate surgical stress.
Glomerular function and renal tubular function assessed by measurements of creatinine clearance rates (CCR), lithium clearance rates (CLi, and N-acetyl-beta-D-glucosaminidase (NAG) enzymuria were measured immediately prior to and within 24 h of operation (average operative time 150 min) in 16 patients undergoing a moderate surgical stress. Although serum creatinine concentrations and CCR were similar pre- and postsurgery at 105 +/- 21 and 108 +/- 21 mumol/L and 108 +/- 67 and 110 +/- 59 mL/min/100 kg body weight (mean +/- SD), respectively, both CLi and NAG were significantly increased following the surgical insult. CLi was increased from 19.7 +/- 6.1 to 31.7 +/- 16.7 mL/min/100 kg (p less than 0.01) and NAG from 71 +/- 58 to 164 +/- 10 U/mmol urinary creatinine (p less than 0.001). In addition, the absolute distal tubular reabsorption of sodium and water increased from 18.3 +/- 5.9 and 15.8 +/- 9.7 to 30.6 +/- 16.4 and 27.6 +/- 12.2 mL/min/100 kg body weight (both p less than 0.05), respectively. These results indicate early postoperative renal tubular dysfunction following a moderate surgical stress, undetected by conventional screening.
Aged↗
Plasma-specific proteins: their response to surgical trauma and tumour load, and modification of this response by post-operative metabolic support.
Concentrations of plasma proteins with short half-life have been suggested as indicators of nutritional state in surgical patients. Trauma also affects the circulating concentrations of these proteins. Serum concentrations of retinol binding protein (RBP), pre-albumin and transferrin were determined pre- and post-operatively on different supporting regimens. The circulating concentration of these liver proteins displayed no differential effect of the supporting regimen during the first 5 post-operative days. None of the patients with tumour demonstrated any indication of hepatic metastases pre-operatively or at the time of laparotomy but, as a group, had lower pre-operative concentrations of RBP (p < 0.001) and pre-albumin (p < 0.01) than patients with no tumour load. In addition 55% of patients (15:27) with tumour had RBP concentrations <3.5 mg/dl; all of the non-tumour bearing patients (13/13) had RBP concentrations >3.5 mg/dl. RBP and pre-albumin appear to act as non-specific tumour markers, but not to serve a useful function as short-term nutritional markers of post-operative support.
Journal Article↗
The effect of insulin suppression on postprandial nutrient metabolism: studies with infusion of somatostatin and insulin.
Utilization of fat, carbohydrate and protein before and after feeding was studied in six healthy subjects using simultaneous respiratory gas exchange measurement and [1-13C] leucine infusion. The role of insulin was investigated by repeating a control study with the addition of an infusion of somatostatin, a hormone which can suppress insulin release. Where near-complete insulin suppression was effected, subjects were studied on a third occasion with the further addition of exogenous insulin infusion. The normal switch on feeding from fat to carbohydrate as principal energy source was reproduced at insulin levels of only 17%-33% of control values, which were inadequate to prevent hyperglycaemia. At fed levels below 10%, a fat-predominant pattern persisted unless insulin was infused. Protein degradation was reduced and synthesis unaffected by feeding, regardless of insulin concentration. Leucine oxidation was dependent on its plasma concentration in the presence of circulating insulin. Thus insulin appears to be necessary for the normal switch to carbohydrate oxidation on feeding but not for postprandial changes in protein metabolism.
Adult↗
Nutrient oxidation patterns and protein metabolism in lean and obese subjects.
The immediate metabolic response to eating has been compared in a group of grossly obese subjects (W/H2 = 45) with that in lean controls (W/H2 = 22). Dietary intake of energy for obese subjects was based on their estimated basal energy expenditure for ideal body weight (given at an hourly rate of 3 X BMR over a 4-h period). Lean subjects were measured twice: control 1 with the same intake of energy as the obese in terms of ideal body weight and control 2 with the same energy intake in relation to each subject's measured resting energy expenditure (2.2 X REE). The changes in energy expenditure and nutrient disposal with the onset of eating have been assessed by a method of combined respiratory gas analysis and intravenous infusion of 13C-labelled leucine. Leucine kinetics were used to quantitate rapid changes in protein oxidation and to assess protein synthesis and degradation. 1) Total energy expenditure was 20-30 per cent greater in obese subjects than lean subjects in fasting and feeding. Energy expenditure expressed per kg fat-free mass, from D2O dilution, was similar in obese and lean subjects in both fasting (5.8 v. 5.5 kJ/kg FFM/h) and feeding [6.7 v. 6.3 (Control 2) kJ/kg FFM/h]. 2) The onset of eating was associated with increased carbohydrate and protein oxidation with decreased fat oxidation in both lean and obese individuals. In obese subjects, however, both the decrease in fat oxidation and the increase in protein oxidation were significantly smaller (P less than 0.05) than the corresponding increments in lean subjects (Control 2). 3) The rate of protein synthesis was significantly (P less than 0.05) higher in obese subjects both in the fasting state (99 v. 84 mumols leucine/kg FFM/h) and in the fed state [94 v. 67 (Control 2) mumols leucine/kg FFM/h]. The rate of protein degradation was also higher in obese individuals in fasting (117 +/- 6 v. 106 +/- 4 mumol leucine/kg FFM/h) and feeding [65 +/- 4 v. 54 +/- 6 (Control 2) mumol leucine/kg FFM/h] though these differences are not statistically significant (P greater than 0.05). 4) The observed differences between obese and lean individuals in protein and energy metabolism in the fasted state and in the immediate response to eating do not support a hypothesis of greater metabolic efficiency in obesity.
Adult↗
The role of degradation in the acute control of protein balance in adult man: failure of feeding to stimulate protein synthesis as assessed by L-[1-13C]leucin infusion.
The effect of feeding on whole-body protein turnover was measured in six healthy volunteers using the essential amino acid, L-[1-13C]leucine, as a tracer for protein metabolism. Varied lengths of periods of feeding and isotope infusion produced different apparent responses to feeding. When parameters of protein turnover were estimated from 8-hour infusions, the change from post-absorptive in the first four hours to mixed feeding during the final four hours was found to produce positive leucine balance by decreasing degradation from 89.5 +/- 5.0 to 31.7 +/- 7.3 mumol leucine/kg/h (P less than .001), with no apparent change in synthesis. By contrast, when tracer was infused for 24 hours with 12 hours of feeding followed by 12 hours of fasting, the estimate of protein synthesis during feeding was 35% higher than during fasting (P less than .01). However, when tracer infusion during the 12-hour feeding/12-hour fasting protocol was limited to the last four hours of each nutritional period, the estimates of fed and fasted protein synthesis showed no significant difference, 71.3 +/- 6.5 and 66.2 +/- 5.6 respectively, while the calculated rate of protein degradation was 43% lower during feeding (P less than .002). As relatively higher levels of enrichment in plasma leucine were detected in comparable nutritional states following longer infusions, the possibility of significant recycling of label was investigated. Residual tracer was still detectable in both breath and plasma 12 hours after cessation of a 12-hour tracer infusion, supporting the conclusion that significant errors in estimates of protein turnover due to recycling of label arise with prolonged infusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lactic acidosis due to metformin therapy in a low risk patient.
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Acidosis, Lactic↗
The effect of indomethacin on the response of protein synthesis to feeding in rats and man.
Protein synthesis was measured in muscle of fed and fasted rats. Synthesis rates were 29% higher with feeding. Treatment with indomethacin before feeding completely blocked the stimulation of protein synthesis. Whole-body protein synthesis was measured in six healthy volunteers with [15N]glycine in fasted and fed states. Feeding increased synthesis rates by 50%. An oral dose of indomethacin 2 h before the measurement of protein synthesis had no effect in either the fasted or fed state.
Adult↗
Rates of nutrient utilization in man measured by combined respiratory gas analysis and stable isotopic labelling: effect of food intake.
Rates of oxygen consumption and carbon dioxide production have been measured in healthy adults during 4 h of fasting followed by 4 h of hourly small meals. Both rates rose to new steady values during feeding, and the respiratory quotient (RQ) increased from 0.792 to 0.924. The RQ was consistent in repeat studies on any individual (coefficient of variation: 2.5 per cent), and differences between individuals were significant in the fasted but not the fed state. Simultaneous measurements were made of the rate of protein oxidation by primed constant infusion of (1-13C)leucine for 8 h. Rates were calculated from the enrichment of plasma alpha-ketoisocaproate and the production of 13CO2 in the breath, taking account of the incomplete recovery of 13CO2 and the changes in baseline enrichment resulting from natural 13C in the food. Leucine oxidation increased by 87 per cent during the feeding period. Rates of nutrient utilization were calculated from respiratory gas exchange and rates of protein oxidation. These showed that fat was predominant in the fasted state, contributing 61 per cent of total energy expenditure, compared with 27 per cent for carbohydrate and 11 per cent for protein. On feeding there was a switch to carbohydrate as the main fuel (62 per cent), with smaller contributions from fat (20 per cent) and protein (18 per cent). During feeding total utilization of each nutrient exceeded its intake from the diet, indicating storage in the body. Dietary carbohydrate was stored without conversion to fat. It is concluded that this method is useful for studying the control of nutrient utilization by food intake.
Adult↗
The protein metabolic response to short-term starvation in man.
Plasma protein concentrations, in particular the serum albumin concentration, are often quoted as indicators of nutritional state in surgical patients. Injury also affects the circulating concentrations of these proteins. Twenty students were subjected to a 3-day total fast and the concentration of plasma proteins, generally affected by trauma, determined before and after the fast. The only protein to show any negative response was retinal binding protein which fell by 16% during the starvation period (p < 0.001). Albumin, the protein often used as a nutritional index, demonstrated a significant (p < 0.001) increase during this period. This was not related to changes in the hydration state of the subjects.
Journal Article↗
Nutritional and metabolic support following acute hepatic trauma.
A patient undergoing partial hepatectomy subsequent to trauma was maintained post-operatively on a specifically tailored total parenteral nutrition regimen. This, despite obviously impaired liver function, allowed adequate nutrition without the expected adverse metabolic sequelae associated with hepatic resection and nitrogen loading. The patient also demonstrated, in the absence of normal hepatic tissue, an ameliorated metabolic response to trauma.
Abdominal Injuries↗
Nutrient intake and anthropometric assessment of patients at home after partial gastrectomy or vagotomy.
Ten patients, six of whom had had a partial gastrectomy and four a vagotomy, took part in the study. Anthropometric measurements, weighed dietary intakes, social circumstances and amount of dietary advice and help received by patients were recorded during the first month and at 7 months after discharge from hospital. Anthropometric measurements changed little during the first month but improved in most of those with lower than normal initial values by the end of 7 months. Mean energy and protein intakes during the first month were low for the gastrectomy patients but were adequate for the vagotomy patients. By 7 months the intakes of the gastrectomy patients had increased considerably. Mean intakes of vitamin C, total folate and zinc tended to be low in both groups and mean intakes of iron were low in the gastrectomy patients. No patient ate an entirely satisfactory diet. Very little advice or encouragement on diet was available from dietitians, doctors or other health workers either prior to or after discharge.
Adult↗