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Growth hormone stimulation due to dietary supplementation with ornithine α ketoglutarate (OKG) in trauma rats
P.72 Insulin-like growth factor-l improves protein metabolism and reduces gut mucosal atrophy after surgery in rats with cirrhosis. T. Inaba, H. Saito, M. Lin, T. Inoue, R. Fukushima and T.
comitant levels of stress hormones and interleukin-6 (IL-6) was investigated. Methods: 31 patients, otherwise healthy, operated electively for inguinal hernia repair (group H, n = 7) or open cholecystectomy (group C) were included in the study. insulin sensitivity was determined using the hyperinsulinemic, normoglycemic clamp technique (plasma insulin approximately 380 pmol/ml. blood glucose 4.5 mmol/l) preoperatively and on the first postoperative day. In addition, 5 of the patients in group C were studied on day 5, 9 and 20 postoperatively. Immediately prior to each clamp, blood sampling for plasma levels of stress hormones (glucagon, adrenaline, noradrenaline, cortisol, GH) and IL-6 was performed. The relative insulin sensitivity is given as per cent of preoperative values. Simple regression analysis and nonparametric methods were used. Results: All patients displayed reduced insulin sensitivity on the first postoperative day. More pronounced reductions in insulin sensitivity was found after surgery in group C. No such difference was seen in any of the stress hormones. There was a linear relationship between relative insulin sensitivity and concomitant levels of IL-6 (r = 0.63, p < 0.001). However, no such correlation could be confirmed for any of the stress hormones (r < 0.16, p 2 0.24) Conclusions: The observation of significantly higher plasma levels of IL-6 between groups on the first postoperative day, together with the significant relationship between relative insulin sensitivity and IL-6, suggests a possible role for this cytokine in the development of postoperative insulin resistance, while the role of the stress hormones remains uncertain.
Muto Department of Surgery, University of Tokyo, Tokyo, Japan The altered protein metabolism and endotoxin translocation appear to be related to a high risk of postoperative morbidity and mortality in liver cirrhosis. Insulin-like growth factor-l (IGF-1) has been shown to improve nitrogen metabolism and to reduce gut mucosal atrophy after surgical trauma. However, these effects on cirrhotic subjects are not well understood. The purpose of this study was to examine the effects of IGF-1 on postoperative protein metabolism and gut integrity in cirrhotic rats. Cirrhosis was induced by oral administration of 0.05% thioacetamide for 6 months. Fifteen cirrhotic rats received total parenteral nutrition (100 kcal/kg/ day and 0.49 gN/kg/day) after gastrectomy. In addition, continuous intravenous infusion of 4 mg/kg/day of IGF-1, the most effective dose in non-cirrhotic rats, or placebo were given for 3 postoperative days. Whole-body protein turnover and fractional synthesis rate (FSR) of tissue protein were determined using 15 N-glycine constant infusion method on the third postoperative day. Mucosal height of the small intestine was also determined. Control Serum IGF-1 724i123 @g/ml) Nitrogen Excretion 595*29 hMk9/dav) Nitrogen Balance -267+28 (ms/ks/dw) Whole-body Protein Flux (gN/kg/day) 2 23iO.10 Svnthew 1.62kO.12 (3WWdav) Breakdown 1.73+0.10 ‘9N’;;ij;;j Liver FSR 14.lk1.3 Gastrocnemius FSR 1.24t0.12 Intestinal mucosal height 540 + 26 ‘“~?I MeankSE ‘p < 0.05 YS control “p: 0.06 vs co&l “‘p Student t-test
P.71 Influences on insulin-like growth factor1 in burned infected rats. D. D. Lazarus, S. A. Stackpole, W. J. Montegut, E. Fischer,
The result suggests that IGF-1 improves protein metabolism and reduces intestinal mucosal atrophy after surgery in cirrhotic rats. We conclude that exogenous IGF-1 infusion may be useful for the postoperative treatment in patients with liver cirrhosis.
L. L. Moidawer, S. F. Lowry Cornell University Medical College, NY, NY, USA 1002 I The role of insulin-like growth factor-l (IGF-1) in the loss of lean tissue that accompanies injury has not been determined. To investigate this, we measured changes in plasma levels of this hormone after a 30% BSA scald burn which was infected with Pseudomonas aeruginosa. To examine the involvement of interleukin-1 (IL-l ) and tumor necrosis factor-a (TNFa) in this model, we treated burned/infected (B/l) animals with antagonists to these cytokines: IL-I receptor antagonist, (IL-l ra, 36 mg/kg/day), and the TNF soluble receptor, (sTNFr, 2 mg/kg/2 days), respectively. Because of the decline in food intake, a group that was pairfed to untreated burned/infected animals was included. On day 7, body weights and plasma IGF-1, using an RIA after separation from IGF binding proteins, were measured. Results are mean f. SEM, n = 4-g/group, statistics used NewmanKeul’s MRT, * = p < 0.05 v. sham, ** = p < 0.05 v. sham and pair-fed. Treatment Sham PM-fed B/I+Vehicle B/l+sTNFr B/I+IL-lra
;$;il+@/mt) 575 T45’ 116&28” 191 f43” 162k46”
BW change +16+4 -29+2. -8OT6” -75*9*. -51 k6’”
IGF-1 (4 mglkglday) 2500+486* 464+35’ -144+35+ 2.73iO.12’ 2.25tO.15’ 2.31 kO.13’ l&3+0.9 1.74+0.24”’ 615+24” < 0.08;s control
P.73 Growth hormone stimulation dietary supplementation with ornithine glutarate (OKG) in trauma rats.
due to a keto-
M. Jeevanandam, N. J. Holaday, R. Ali, andS. R. Petersen Trauma Center, St. Joseph’s Hospital & Medical Center, Phoenix, AZ, USA An acute deficiency of growth hormone (GH) is noted in hypercatabolic injury state. Stimulation of this anabolic GH would enhance the metabolic status. The relative efficacy of ornithine (ORN) and its salts with u ketoglutaric acid (OKG) or ketoisocaproic acid (OKIC) in stimulating GH and insulin secretion is investigated. A group of male Sprague-Dawley rats (260+2 g) had bilateral femur fracture (T) and another group (C) without injury acted as control. All rats were provided with water alone for 2 days. On the 3rd day feeding was started and continued for 4 days. T & C rats were randomized among 4 isonitrogenous liquid diets. The basic diet was casein-based, BioServ Diet, # F1259. The other 3 test diets were the basic diet from which 10% nitrogen (N) was replaced by ORN-N or OKG-N or OKIC-N. T rats were pair-fed to respective C rats. Daily weight, intake, and urinary data were collected. After 4 days of feeding the rats were sacrificed and blood was collected for hormonal analysis. The results (mean +SEM, n = 6 each group) are:
(g/7 days)
A correlation of the IGF-1 levels in these groups with the accompanying body weight changes shows that r2 = 0.93. The diminished food intake could only partly account for the significant decline in circulating IGF-1, as well as the loss of body weight, in burned/infected animals. As blockade of IL1 and TNFa did not attenuate these changes, we conclude that these,cytokines are not important mediators of IGF-1 in this model. 56
z_! ‘P $ 0.05
f! 52+13 177’61+ 55+14 152?39+ vs respectwe control;
We conclude that IGF-1 administration after surgery improves whole-body protein metabolism and that 4 mg/kg/day of IGF-1 seems to be the most effective dose in this setting.
Insulin (;lU/ml) C i73f56 i72fi9 351+72+ 210+35 227+88 188t76 246kl5 285+40+ YS respective 8as1c diet
GH (uTg/L)
Basic ORN
‘25f6 190+54+ 41*10 139+49+ + P $ 0.05
N retention after trauma is significantly (P < 0.05) more (48+3%) with OKG than with ORN (31+5) or with OKIC (36+2%) or with Basic diet (39+4%). Hormonal effects of ORN and the synergistic metabolic effects of a ketoglutarate may be combined in rats for the anabolic nature of OKG. P.74
P.75 The effect of human growth hormone on metabolism in healthy volunteers given a normal diet.
T. Inaba. H. Saito. M. Lin, T. lnoue, Y. Hashiguchi. R. Fukushima and 7. Muto Department of Surgery, University of Tokyo, Tokyo, Japan
A. Sandgren, P. Es&n, K. Andersson. J. Wernerman Dept. of Anesthesiology & Intensive Care and Metabolic Research Laboratory St. Gbrans Hospital and Dept of Anesthesiology & Intensive Care Huddinge University Hospital, Stockholm, Sweden
Titration of insulin-like growth factor-l dosage that maximises anabolic effects in rats after gastrectomy.
Insulin-like growth factor-l (IGF-1) has been shown to improve nitrogen metabolism after surgical trauma in rats. However, the most effective dose of IGF-1 has not been well known in surgical models. The purpose of this study was to identify the appropriate dose of IG F-l on nitrogen metabolism in rats after gastrectomy. Thirty-two rats received total parenteral nutrition (200 kcal/kg/day and 0.99 gN/kg/day) after gastrectomy. Continuous intravenous infusions of 1, 2 or 4 mg/kg/day of IGF-1 or placebo were also given for 3 postoperative days. Whole-body protein turnover and fractional synthesis rate (FSR) of tissue protein were determined using 15 N-glycine constant infusion method on postoperative day 3. Results were statistically analyzed using analysis of variance. Nitrogen Excretion (mglkgldw) Natrogen Balance (mglkgldw) Whole Body Protein (gN/kgfdw) Synthesis (gN/kg/dwl Breakdown (gN/kgldw Synthesis/Breakdown (%) Liver FSR Ga??$&i)mius (%/day)
Control 1009+101 -33Ok98
IGF-1
Introduction: Earlier studies have shown that exogenous human growth hormone (hGH) has effects on protein, fat and glucose metabolism in patients. However the effects of hGH on metabolism in normal man given a normocaloric normonitrogenous diet is unclear. The aim of this study was to evaluate the effects on nitrogen balance and serum concentrations of hormones and metabolites in healthy volunteers, given a daily subcutaneous injection of hGH. Methods: Healthy male volunteers (n = 15) were given a standardised diet as 4 daily meals during a period of 8 days. Their individual basal energy expenditure was measured with indirect calorimetry, and they received 150% of the measured caloric value. Days l-2 was a conditioning period. On days 3-8 half of the group (n = 8) received a subcutaneus injection with hGH (Genotropin) 0.3 E/kg/24 h and the other half (n = 7) a subcutaneus saline injection. Blood samples were taken daily before food intake for analyses of the concentration of urea, glucose, insulin and triglycerides. The total urinary nitrogen excretion was determined in 24 h portions. The results show significant changes in serum concentrations of urea, glucose, insulin, and triglycerides before and after 6 days of daily hGH-injections compared to the control group. In the hGH-group there was a decrease in serum urea (mmol/l) from 5.OkO.3 to 2.5kO.3 compared to 5410.4 to 5.310.3 in the control group. The total nitrogen excretion (g) in urine declined from ?2.4& 1.4 to 6.750.8 in the hGHgroup compared to the controls 12.0+ 1 .Ito 11.5& 0.6. The glucose level (mmol/l) rose from 5.2kO.3 to 5.8+0.1 (hGHgroup) compared to 4.8kO.2 to 5.520.4. Insulin (@J/l) increased from 6.9+0.8 to 20.2k3.4 (hGH) and was unchanged in the controls 6.6kl.8 to 7.4k2.2. The triglycerides increased from 1.1 10.1 to 1.5+0.1 (hGH) and was unchanged in the control group 1 .I kO.2 to 0.9+0.2. Conclusion: In normal man a daily dose of hGH for 6 days makes whole body nitrogen economy 50% more effective. In addition hyperlipidemia. hyperinsulinemia and hyperglycemia were seen.
1 mg
812+79 -138k80
Flux 3.64 i 0.24
4.01 ir0 36
2.60 t_ 0.24
3.1010
2.61 kO.24
3.00 i_ 0.36
lOOk4
103+5
15.0+1.6
17.3+0.8
39
FSR 1.34+0.09 IGF-1
Nitrogen Excretion (mglkgldav) Nitrogen Balance (mglkgldw) Whole Body Protein (gN/kg/day) Synthesis (gN/kg/dw) Breakdown (gN/kg/dw) Synthesis/Breakdown
769*
1.26iOO9 2 mg
93”
-99+84”
4 mg
61 +41’
Flux 4.04+0.17
4.79+0
38’
3.19tO.18
4.24+0
39’
3.04*0.15
3.81 +O 3’
105*4 L,zFSR (%/dw) Gastrocnemius FSR (%/day) Mean+SE ‘p < 0.01
IGF-1 595*41*
17.0fl
YS control
*‘p
112+2** 2
15.9*1.4
1.44+0.08 1.24*0.09 < 0 05 vs control
57
comitant levels of stress hormones and interleukin-6 (IL-6) was investigated. Methods: 31 patients, otherwise healthy, operated electively for inguinal hernia repair (group H, n = 7) or open cholecystectomy (group C) were included in the study. insulin sensitivity was determined using the hyperinsulinemic, normoglycemic clamp technique (plasma insulin approximately 380 pmol/ml. blood glucose 4.5 mmol/l) preoperatively and on the first postoperative day. In addition, 5 of the patients in group C were studied on day 5, 9 and 20 postoperatively. Immediately prior to each clamp, blood sampling for plasma levels of stress hormones (glucagon, adrenaline, noradrenaline, cortisol, GH) and IL-6 was performed. The relative insulin sensitivity is given as per cent of preoperative values. Simple regression analysis and nonparametric methods were used. Results: All patients displayed reduced insulin sensitivity on the first postoperative day. More pronounced reductions in insulin sensitivity was found after surgery in group C. No such difference was seen in any of the stress hormones. There was a linear relationship between relative insulin sensitivity and concomitant levels of IL-6 (r = 0.63, p < 0.001). However, no such correlation could be confirmed for any of the stress hormones (r < 0.16, p 2 0.24) Conclusions: The observation of significantly higher plasma levels of IL-6 between groups on the first postoperative day, together with the significant relationship between relative insulin sensitivity and IL-6, suggests a possible role for this cytokine in the development of postoperative insulin resistance, while the role of the stress hormones remains uncertain.
Muto Department of Surgery, University of Tokyo, Tokyo, Japan The altered protein metabolism and endotoxin translocation appear to be related to a high risk of postoperative morbidity and mortality in liver cirrhosis. Insulin-like growth factor-l (IGF-1) has been shown to improve nitrogen metabolism and to reduce gut mucosal atrophy after surgical trauma. However, these effects on cirrhotic subjects are not well understood. The purpose of this study was to examine the effects of IGF-1 on postoperative protein metabolism and gut integrity in cirrhotic rats. Cirrhosis was induced by oral administration of 0.05% thioacetamide for 6 months. Fifteen cirrhotic rats received total parenteral nutrition (100 kcal/kg/ day and 0.49 gN/kg/day) after gastrectomy. In addition, continuous intravenous infusion of 4 mg/kg/day of IGF-1, the most effective dose in non-cirrhotic rats, or placebo were given for 3 postoperative days. Whole-body protein turnover and fractional synthesis rate (FSR) of tissue protein were determined using 15 N-glycine constant infusion method on the third postoperative day. Mucosal height of the small intestine was also determined. Control Serum IGF-1 724i123 @g/ml) Nitrogen Excretion 595*29 hMk9/dav) Nitrogen Balance -267+28 (ms/ks/dw) Whole-body Protein Flux (gN/kg/day) 2 23iO.10 Svnthew 1.62kO.12 (3WWdav) Breakdown 1.73+0.10 ‘9N’;;ij;;j Liver FSR 14.lk1.3 Gastrocnemius FSR 1.24t0.12 Intestinal mucosal height 540 + 26 ‘“~?I MeankSE ‘p < 0.05 YS control “p: 0.06 vs co&l “‘p Student t-test
P.71 Influences on insulin-like growth factor1 in burned infected rats. D. D. Lazarus, S. A. Stackpole, W. J. Montegut, E. Fischer,
The result suggests that IGF-1 improves protein metabolism and reduces intestinal mucosal atrophy after surgery in cirrhotic rats. We conclude that exogenous IGF-1 infusion may be useful for the postoperative treatment in patients with liver cirrhosis.
L. L. Moidawer, S. F. Lowry Cornell University Medical College, NY, NY, USA 1002 I The role of insulin-like growth factor-l (IGF-1) in the loss of lean tissue that accompanies injury has not been determined. To investigate this, we measured changes in plasma levels of this hormone after a 30% BSA scald burn which was infected with Pseudomonas aeruginosa. To examine the involvement of interleukin-1 (IL-l ) and tumor necrosis factor-a (TNFa) in this model, we treated burned/infected (B/l) animals with antagonists to these cytokines: IL-I receptor antagonist, (IL-l ra, 36 mg/kg/day), and the TNF soluble receptor, (sTNFr, 2 mg/kg/2 days), respectively. Because of the decline in food intake, a group that was pairfed to untreated burned/infected animals was included. On day 7, body weights and plasma IGF-1, using an RIA after separation from IGF binding proteins, were measured. Results are mean f. SEM, n = 4-g/group, statistics used NewmanKeul’s MRT, * = p < 0.05 v. sham, ** = p < 0.05 v. sham and pair-fed. Treatment Sham PM-fed B/I+Vehicle B/l+sTNFr B/I+IL-lra
;$;il+@/mt) 575 T45’ 116&28” 191 f43” 162k46”
BW change +16+4 -29+2. -8OT6” -75*9*. -51 k6’”
IGF-1 (4 mglkglday) 2500+486* 464+35’ -144+35+ 2.73iO.12’ 2.25tO.15’ 2.31 kO.13’ l&3+0.9 1.74+0.24”’ 615+24” < 0.08;s control
P.73 Growth hormone stimulation dietary supplementation with ornithine glutarate (OKG) in trauma rats.
due to a keto-
M. Jeevanandam, N. J. Holaday, R. Ali, andS. R. Petersen Trauma Center, St. Joseph’s Hospital & Medical Center, Phoenix, AZ, USA An acute deficiency of growth hormone (GH) is noted in hypercatabolic injury state. Stimulation of this anabolic GH would enhance the metabolic status. The relative efficacy of ornithine (ORN) and its salts with u ketoglutaric acid (OKG) or ketoisocaproic acid (OKIC) in stimulating GH and insulin secretion is investigated. A group of male Sprague-Dawley rats (260+2 g) had bilateral femur fracture (T) and another group (C) without injury acted as control. All rats were provided with water alone for 2 days. On the 3rd day feeding was started and continued for 4 days. T & C rats were randomized among 4 isonitrogenous liquid diets. The basic diet was casein-based, BioServ Diet, # F1259. The other 3 test diets were the basic diet from which 10% nitrogen (N) was replaced by ORN-N or OKG-N or OKIC-N. T rats were pair-fed to respective C rats. Daily weight, intake, and urinary data were collected. After 4 days of feeding the rats were sacrificed and blood was collected for hormonal analysis. The results (mean +SEM, n = 6 each group) are:
(g/7 days)
A correlation of the IGF-1 levels in these groups with the accompanying body weight changes shows that r2 = 0.93. The diminished food intake could only partly account for the significant decline in circulating IGF-1, as well as the loss of body weight, in burned/infected animals. As blockade of IL1 and TNFa did not attenuate these changes, we conclude that these,cytokines are not important mediators of IGF-1 in this model. 56
z_! ‘P $ 0.05
f! 52+13 177’61+ 55+14 152?39+ vs respectwe control;
We conclude that IGF-1 administration after surgery improves whole-body protein metabolism and that 4 mg/kg/day of IGF-1 seems to be the most effective dose in this setting.
Insulin (;lU/ml) C i73f56 i72fi9 351+72+ 210+35 227+88 188t76 246kl5 285+40+ YS respective 8as1c diet
GH (uTg/L)
Basic ORN
‘25f6 190+54+ 41*10 139+49+ + P $ 0.05
N retention after trauma is significantly (P < 0.05) more (48+3%) with OKG than with ORN (31+5) or with OKIC (36+2%) or with Basic diet (39+4%). Hormonal effects of ORN and the synergistic metabolic effects of a ketoglutarate may be combined in rats for the anabolic nature of OKG. P.74
P.75 The effect of human growth hormone on metabolism in healthy volunteers given a normal diet.
T. Inaba. H. Saito. M. Lin, T. lnoue, Y. Hashiguchi. R. Fukushima and 7. Muto Department of Surgery, University of Tokyo, Tokyo, Japan
A. Sandgren, P. Es&n, K. Andersson. J. Wernerman Dept. of Anesthesiology & Intensive Care and Metabolic Research Laboratory St. Gbrans Hospital and Dept of Anesthesiology & Intensive Care Huddinge University Hospital, Stockholm, Sweden
Titration of insulin-like growth factor-l dosage that maximises anabolic effects in rats after gastrectomy.
Insulin-like growth factor-l (IGF-1) has been shown to improve nitrogen metabolism after surgical trauma in rats. However, the most effective dose of IGF-1 has not been well known in surgical models. The purpose of this study was to identify the appropriate dose of IG F-l on nitrogen metabolism in rats after gastrectomy. Thirty-two rats received total parenteral nutrition (200 kcal/kg/day and 0.99 gN/kg/day) after gastrectomy. Continuous intravenous infusions of 1, 2 or 4 mg/kg/day of IGF-1 or placebo were also given for 3 postoperative days. Whole-body protein turnover and fractional synthesis rate (FSR) of tissue protein were determined using 15 N-glycine constant infusion method on postoperative day 3. Results were statistically analyzed using analysis of variance. Nitrogen Excretion (mglkgldw) Natrogen Balance (mglkgldw) Whole Body Protein (gN/kgfdw) Synthesis (gN/kg/dwl Breakdown (gN/kgldw Synthesis/Breakdown (%) Liver FSR Ga??$&i)mius (%/day)
Control 1009+101 -33Ok98
IGF-1
Introduction: Earlier studies have shown that exogenous human growth hormone (hGH) has effects on protein, fat and glucose metabolism in patients. However the effects of hGH on metabolism in normal man given a normocaloric normonitrogenous diet is unclear. The aim of this study was to evaluate the effects on nitrogen balance and serum concentrations of hormones and metabolites in healthy volunteers, given a daily subcutaneous injection of hGH. Methods: Healthy male volunteers (n = 15) were given a standardised diet as 4 daily meals during a period of 8 days. Their individual basal energy expenditure was measured with indirect calorimetry, and they received 150% of the measured caloric value. Days l-2 was a conditioning period. On days 3-8 half of the group (n = 8) received a subcutaneus injection with hGH (Genotropin) 0.3 E/kg/24 h and the other half (n = 7) a subcutaneus saline injection. Blood samples were taken daily before food intake for analyses of the concentration of urea, glucose, insulin and triglycerides. The total urinary nitrogen excretion was determined in 24 h portions. The results show significant changes in serum concentrations of urea, glucose, insulin, and triglycerides before and after 6 days of daily hGH-injections compared to the control group. In the hGH-group there was a decrease in serum urea (mmol/l) from 5.OkO.3 to 2.5kO.3 compared to 5410.4 to 5.310.3 in the control group. The total nitrogen excretion (g) in urine declined from ?2.4& 1.4 to 6.750.8 in the hGHgroup compared to the controls 12.0+ 1 .Ito 11.5& 0.6. The glucose level (mmol/l) rose from 5.2kO.3 to 5.8+0.1 (hGHgroup) compared to 4.8kO.2 to 5.520.4. Insulin (@J/l) increased from 6.9+0.8 to 20.2k3.4 (hGH) and was unchanged in the controls 6.6kl.8 to 7.4k2.2. The triglycerides increased from 1.1 10.1 to 1.5+0.1 (hGH) and was unchanged in the control group 1 .I kO.2 to 0.9+0.2. Conclusion: In normal man a daily dose of hGH for 6 days makes whole body nitrogen economy 50% more effective. In addition hyperlipidemia. hyperinsulinemia and hyperglycemia were seen.
1 mg
812+79 -138k80
Flux 3.64 i 0.24
4.01 ir0 36
2.60 t_ 0.24
3.1010
2.61 kO.24
3.00 i_ 0.36
lOOk4
103+5
15.0+1.6
17.3+0.8
39
FSR 1.34+0.09 IGF-1
Nitrogen Excretion (mglkgldav) Nitrogen Balance (mglkgldw) Whole Body Protein (gN/kg/day) Synthesis (gN/kg/dw) Breakdown (gN/kg/dw) Synthesis/Breakdown
769*
1.26iOO9 2 mg
93”
-99+84”
4 mg
61 +41’
Flux 4.04+0.17
4.79+0
38’
3.19tO.18
4.24+0
39’
3.04*0.15
3.81 +O 3’
105*4 L,zFSR (%/dw) Gastrocnemius FSR (%/day) Mean+SE ‘p < 0.01
IGF-1 595*41*
17.0fl
YS control
*‘p
112+2** 2
15.9*1.4
1.44+0.08 1.24*0.09 < 0 05 vs control
57