human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 1 . In adult humans with growth hormone deficiency , treatment with growth hormone has recently been shown to have major anabolic effects and to improve exercise performance . The cardiovascular effects of growth hormone in adults with growth hormone deficiency were examined in 24 patients treated with recombinant human growth hormone ( 0.07 units/kg at night ) in a double-blind , placebo-controlled trial lasting 6 months . 2 . Compared with placebo , resting M-mode echocardiography showed increases in left ventricular end-diastolic dimension and stroke volume in the group treated with recombinant human growth hormone . No differences were noted between the groups with respect to left ventricular end-systolic dimension , fractional shortening , wall thicknesses or mean arterial blood pressure . Left ventricular myocardial mass increased in the group given recombinant human growth hormone . 3 . The supine plasma renin activity was increased and remained elevated over the 6 months , whereas the plasma aldosterone concentration was unchanged , after treatment with recombinant human growth hormone . Clinical signs of sodium retention were evident during the first 3 months of treatment with recombinant human growth hormone . 4 . We conclude that treatment with recombinant human growth hormone in adults with growth hormone deficiency result ed in small increases in left ventricular pre-load , due to the sodium-retaining action of growth hormone . Activation of the renin-aldosterone system was involved in such changes . Myocardial hypertrophy was observed without changes in mean arterial pressure , reflecting the anabolic action of growth hormone OBJECTIVES The goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A ( PAPP-A ) in patients with acute coronary syndromes ( ACS ) . BACKGROUND Pregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization . METHODS In 547 patients with angiographically vali date d ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain , respectively , PAPP-A as well as markers of myocardial necrosis ( troponin T [ TnT ] ) , ischemia ( vascular endothelial growth factor [ VEGF ] ) , inflammation ( high-sensitivity C-reactive protein [ hsCRP ] ) , anti-inflammatory activity ( interleukin [IL]-10 ) , and platelet activation ( soluble CD40 lig and [ sCD40L ] ) were determined . Patients were followed for the occurrence of death or myocardial infa rct ion . RESULTS In patients with ACS , elevated PAPP-A levels ( > 12.6 mIU/l ) indicated an increased risk ( odds ratio 2.44 [ 95 % confidence interval ( CI ) 1.43 to 4.15 ] ; p = 0.001 ) . When the analysis was restricted to TnT-negative patients , PAPP-A still identified a subgroup of high-risk patients ( odds ratio [ OR ] 2.72 [ 95 % confidence interval ( CI ) 1.25 to 5.89 ] ; p = 0.009 ) . In a multivariable model , PAPP-A ( OR 2.01 ; p = 0.015 ) , sCD40L ( OR 2.37 ; p = 0.003 ) , IL-10 ( OR 0.43 ; p = 0.003 ) , and VEGF ( OR 2.19 ; p = 0.018 ) were independent predictors . Prospect i ve validation in patients with chest pain confirmed that  PAPP-A levels reliably identify high-risk patients ( adjusted OR 2.32 [ 95 % CI 1.32 to 4.26 ] ; p = 0.008 ) . Patients negative for all three markers ( TnT , sCD40L , and PAPP-A ) were at very low cardiac risk ( 30 days : 3.0 % event rate ; no death ) . CONCLUSIONS The PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS . Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS CONTEXT Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient ( GHD ) adults are limited . OBJECTIVES The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults . DESIGN The study was a 6-month double-blind , placebo-controlled r and omized trial . SETTING The study was conducted at the General Clinical Research Center . PARTICIPANTS Thirty hypopituitary adults with GHD were studied . INTERVENTION Subjects were r and omized to recombinant human GH or placebo for 6 months , followed by open-label recombinant human GH for 12 months . MAIN OUTCOME MEASURES Primary endpoints were exercise duration , maximal oxygen consumption , and left ventricular ejection fraction . Secondary endpoints were echocardiographic indices of systolic and diastolic function , left ventricular mass , lipids , and body composition . RESULTS In the 6-month double-blind phase , mean GH dose was 0.64 mg/d . Mean IGF-I sd score increased from -4.5 to -1.0 . Exercise duration , maximal oxygen consumption , left ventricular ejection fraction , and other echocardiographic parameters were normal at baseline and did not change . GH decreased total and low-density lipoprotein cholesterol by 7.5 % ( P = 0.016 ) and 14.7 % ( P = 0.002 ) ( P = 0.04 vs. placebo ) . Mean lean body mass increased by 2.2 kg ( P = 0.004 ) , fat mass decreased by 1.7 kg ( P = 0.21 ) , and percent body fat decreased by 2.5 % ( P = 0.018 ) , although between-group changes were not significant . CONCLUSIONS Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol , increased IGF-I , and increased lean body mass . These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment The onset of adult GH deficiency may be during either adulthood ( AO ) or childhood ( CO ) , but potential differences have not previously been examined . In this study the baseline and GH therapy ( 12.5 micrograms/kg per day ) data from CO ( n = 74 ; mean age 29 yr ) and AO ( n = 99 ; mean age 44 yr ) GH-deficient adult patients have been compared . The first 6 months comprised r and omized , double-blind treatment with GH or placebo , then all patients were GH-treated for a further 12 months . At baseline the height , body weight , body mass index , lean body mass , and waist/hip ratio of AO patients were significantly ( P < 0.001 ) greater than in CO patients . Serum insulin-like growth factor-I ( IGF-I ) levels were below normal but were lower in CO than AO patients ( P < 0.001 ) , and the correlation with IGF binding protein-3 was stronger in CO than in AO patients . Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients . Both groups had significant psychosocial distress , but the deviation from normality was greater in AO patients . Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group . Wais/hip ratio was decreased by long-term therapy in AO but not CO patients . Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy . IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups . Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy , whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease . Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients . GH-induced side effects were mainly reported by AO patients ; very few CO patients reported treatment-emergent adverse events . These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome . This is consistent with the existence of two entities , developmental ( CO ) and metabolic ( AO ) , and the different functions of GH at different periods of life Objective Adult onset GH deficiency ( GHD ) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol . Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor ( statin ) therapy . We have examined this possibility during prospect i ve follow‐up of adult onset hypopituitary patients enrolled in KIMS ( Pfizer International Metabolic Data base ) , a pharmacoepidemiological study of GH replacement in adult hypopituitary patients Objective Few studies have determined the effects of more than 5–10 years of GH replacement  in adults on  body composition and cardiovascular risk factors . Design / patients In this prospect i ve , single-center , open-label study , the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults ( 93 men ) with adult-onset GH deficiency ( GHD ) . Mean age was 50.5 ( range 22–74 ) years at study start .  Body composition was measured using dual-energy X-ray absorptiometry . Results The mean initial GH dose of 0.55 ( s.e.m . 0.03 ) mg/day was gradually lowered to 0.40 ( 0.01 ) mg/day after 15 years . The mean serum IGF1 SDS increased from −1.53 ( 0.10 ) at baseline to 0.74 ( 0.13 ) at study end ( P<0.001 vs baseline ) . Lean soft tissue ( LST ) increased to 3 % above the baseline level at study end ( P<0.001 ) . After a 9 % decrease during the first year of treatment ( P<0.001 vs baseline ) , body fat ( BF ) started to increase and had returned to the baseline level after 15 years . Serum levels of total cholesterol and LDL-cholesterol decreased and serum HDL-cholesterol level increased . Fasting plasma glucose increased from 4.4 ( 0.1 ) at baseline to 4.8 ( 0.1 ) mmol/l at study end ( P<0.001 ) . However , blood HbA1c decreased from 5.0 ( 0.1 ) to 4.6 ( 0.1 ) % ( P<0.001 ) . Conclusions Fifteen-year GH replacement in GHD adults induced a transient decrease in BF and sustained improvements of LST and serum lipid profile . Fasting plasma glucose increased whereas blood HbA1c was reduced Assessed by conventional echocardiography the influence of growth hormone deficiency ( GHD ) and effects of replacement therapy on left ventricle ( LV ) function and mass ( LVM ) have shown inconsistent results . We aim ed to evaluate cardiac function before and during replacement therapy employing the gold st and ard method cardiac magnetic resonance imaging ( CMRI ) and measurements of circulating levels of B-type natriuretic peptides .  Sixteen patients ( 8 males and 8 females , mean age 49 years ( range 18–75 ) ) with severe GHD and 16 matched control subjects were included . CMRI was performed at baseline and after 1 year of GH replacement therapy .  IGF-I , B-type natriuretic peptide ( BNP ) and N-terminal pro-BNP ( NT-proBNP ) were measured after 0 , 1 , 2 , 3 , 6 and 12 months of treatment . IGF-I Z-score increased from ( median ( IQR ) ) −2.3 ( −3.8 to −1.4 ) to 0.5 ( −0.3 to 1.7 ) . LVM index ( LVMI ) , ejection fraction ( range 63–80 % ) , cardiac output index and levels of BNP and NT-proBNP were similar at baseline in patients compared to controls ( P-values from 0.09 to 0.37 ) . The patients had significantly smaller LV end-diastolic volume index ( P = 0.032 ) and end-systolic volume index ( P = 0.038 ) . No significant change in LV systolic function or LVM occurred during 1 year of GH treatment . BNP levels were unchanged ( P = 0.88 ) , whereas NT-proBNP tended to decrease ( P = 0.052 ) . Assessed by the highly sensitive and precise CMRI method , untreated GHD was not associated with impaired systolic function or reduced LVMI and 1 year of GH replacement using physiological doses did not influence cardiac mass or function BACKGROUND Four retrospective studies have reported premature mortality in patients with hypopitu 
    Output:
    
agent
Emerging cardiovascular risk factors/markers such as proinflammatory cytokines , C-reactive protein , and adipokines are also increased in GHD patients .
Increased cardiovascular morbidity and mortality have also been reported in GHD .
GH treatment has been shown to improve both traditional and emerging cardiovascular risk factors and markers .
The GHD population may be considered at high cardiovascular risk , and GH substitution may be expected to bring an added value to patients with hypopituitarism in terms of cardiovascular protection .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 1 . In adult humans with growth hormone deficiency , treatment with growth hormone has recently been shown to have major anabolic effects and to improve exercise performance . The cardiovascular effects of growth hormone in adults with growth hormone deficiency were examined in 24 patients treated with recombinant human growth hormone ( 0.07 units/kg at night ) in a double-blind , placebo-controlled trial lasting 6 months . 2 . Compared with placebo , resting M-mode echocardiography showed increases in left ventricular end-diastolic dimension and stroke volume in the group treated with recombinant human growth hormone . No differences were noted between the groups with respect to left ventricular end-systolic dimension , fractional shortening , wall thicknesses or mean arterial blood pressure . Left ventricular myocardial mass increased in the group given recombinant human growth hormone . 3 . The supine plasma renin activity was increased and remained elevated over the 6 months , whereas the plasma aldosterone concentration was unchanged , after treatment with recombinant human growth hormone . Clinical signs of sodium retention were evident during the first 3 months of treatment with recombinant human growth hormone . 4 . We conclude that treatment with recombinant human growth hormone in adults with growth hormone deficiency result ed in small increases in left ventricular pre-load , due to the sodium-retaining action of growth hormone . Activation of the renin-aldosterone system was involved in such changes . Myocardial hypertrophy was observed without changes in mean arterial pressure , reflecting the anabolic action of growth hormone OBJECTIVES The goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A ( PAPP-A ) in patients with acute coronary syndromes ( ACS ) . BACKGROUND Pregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization . METHODS In 547 patients with angiographically vali date d ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain , respectively , PAPP-A as well as markers of myocardial necrosis ( troponin T [ TnT ] ) , ischemia ( vascular endothelial growth factor [ VEGF ] ) , inflammation ( high-sensitivity C-reactive protein [ hsCRP ] ) , anti-inflammatory activity ( interleukin [IL]-10 ) , and platelet activation ( soluble CD40 lig and [ sCD40L ] ) were determined . Patients were followed for the occurrence of death or myocardial infa rct ion . RESULTS In patients with ACS , elevated PAPP-A levels ( > 12.6 mIU/l ) indicated an increased risk ( odds ratio 2.44 [ 95 % confidence interval ( CI ) 1.43 to 4.15 ] ; p = 0.001 ) . When the analysis was restricted to TnT-negative patients , PAPP-A still identified a subgroup of high-risk patients ( odds ratio [ OR ] 2.72 [ 95 % confidence interval ( CI ) 1.25 to 5.89 ] ; p = 0.009 ) . In a multivariable model , PAPP-A ( OR 2.01 ; p = 0.015 ) , sCD40L ( OR 2.37 ; p = 0.003 ) , IL-10 ( OR 0.43 ; p = 0.003 ) , and VEGF ( OR 2.19 ; p = 0.018 ) were independent predictors . Prospect i ve validation in patients with chest pain confirmed that  PAPP-A levels reliably identify high-risk patients ( adjusted OR 2.32 [ 95 % CI 1.32 to 4.26 ] ; p = 0.008 ) . Patients negative for all three markers ( TnT , sCD40L , and PAPP-A ) were at very low cardiac risk ( 30 days : 3.0 % event rate ; no death ) . CONCLUSIONS The PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS . Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS CONTEXT Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient ( GHD ) adults are limited . OBJECTIVES The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults . DESIGN The study was a 6-month double-blind , placebo-controlled r and omized trial . SETTING The study was conducted at the General Clinical Research Center . PARTICIPANTS Thirty hypopituitary adults with GHD were studied . INTERVENTION Subjects were r and omized to recombinant human GH or placebo for 6 months , followed by open-label recombinant human GH for 12 months . MAIN OUTCOME MEASURES Primary endpoints were exercise duration , maximal oxygen consumption , and left ventricular ejection fraction . Secondary endpoints were echocardiographic indices of systolic and diastolic function , left ventricular mass , lipids , and body composition . RESULTS In the 6-month double-blind phase , mean GH dose was 0.64 mg/d . Mean IGF-I sd score increased from -4.5 to -1.0 . Exercise duration , maximal oxygen consumption , left ventricular ejection fraction , and other echocardiographic parameters were normal at baseline and did not change . GH decreased total and low-density lipoprotein cholesterol by 7.5 % ( P = 0.016 ) and 14.7 % ( P = 0.002 ) ( P = 0.04 vs. placebo ) . Mean lean body mass increased by 2.2 kg ( P = 0.004 ) , fat mass decreased by 1.7 kg ( P = 0.21 ) , and percent body fat decreased by 2.5 % ( P = 0.018 ) , although between-group changes were not significant . CONCLUSIONS Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol , increased IGF-I , and increased lean body mass . These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment The onset of adult GH deficiency may be during either adulthood ( AO ) or childhood ( CO ) , but potential differences have not previously been examined . In this study the baseline and GH therapy ( 12.5 micrograms/kg per day ) data from CO ( n = 74 ; mean age 29 yr ) and AO ( n = 99 ; mean age 44 yr ) GH-deficient adult patients have been compared . The first 6 months comprised r and omized , double-blind treatment with GH or placebo , then all patients were GH-treated for a further 12 months . At baseline the height , body weight , body mass index , lean body mass , and waist/hip ratio of AO patients were significantly ( P < 0.001 ) greater than in CO patients . Serum insulin-like growth factor-I ( IGF-I ) levels were below normal but were lower in CO than AO patients ( P < 0.001 ) , and the correlation with IGF binding protein-3 was stronger in CO than in AO patients . Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients . Both groups had significant psychosocial distress , but the deviation from normality was greater in AO patients . Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group . Wais/hip ratio was decreased by long-term therapy in AO but not CO patients . Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy . IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups . Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy , whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease . Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients . GH-induced side effects were mainly reported by AO patients ; very few CO patients reported treatment-emergent adverse events . These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome . This is consistent with the existence of two entities , developmental ( CO ) and metabolic ( AO ) , and the different functions of GH at different periods of life Objective Adult onset GH deficiency ( GHD ) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol . Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor ( statin ) therapy . We have examined this possibility during prospect i ve follow‐up of adult onset hypopituitary patients enrolled in KIMS ( Pfizer International Metabolic Data base ) , a pharmacoepidemiological study of GH replacement in adult hypopituitary patients Objective Few studies have determined the effects of more than 5–10 years of GH replacement  in adults on  body composition and cardiovascular risk factors . Design / patients In this prospect i ve , single-center , open-label study , the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults ( 93 men ) with adult-onset GH deficiency ( GHD ) . Mean age was 50.5 ( range 22–74 ) years at study start .  Body composition was measured using dual-energy X-ray absorptiometry . Results The mean initial GH dose of 0.55 ( s.e.m . 0.03 ) mg/day was gradually lowered to 0.40 ( 0.01 ) mg/day after 15 years . The mean serum IGF1 SDS increased from −1.53 ( 0.10 ) at baseline to 0.74 ( 0.13 ) at study end ( P<0.001 vs baseline ) . Lean soft tissue ( LST ) increased to 3 % above the baseline level at study end ( P<0.001 ) . After a 9 % decrease during the first year of treatment ( P<0.001 vs baseline ) , body fat ( BF ) started to increase and had returned to the baseline level after 15 years . Serum levels of total cholesterol and LDL-cholesterol decreased and serum HDL-cholesterol level increased . Fasting plasma glucose increased from 4.4 ( 0.1 ) at baseline to 4.8 ( 0.1 ) mmol/l at study end ( P<0.001 ) . However , blood HbA1c decreased from 5.0 ( 0.1 ) to 4.6 ( 0.1 ) % ( P<0.001 ) . Conclusions Fifteen-year GH replacement in GHD adults induced a transient decrease in BF and sustained improvements of LST and serum lipid profile . Fasting plasma glucose increased whereas blood HbA1c was reduced Assessed by conventional echocardiography the influence of growth hormone deficiency ( GHD ) and effects of replacement therapy on left ventricle ( LV ) function and mass ( LVM ) have shown inconsistent results . We aim ed to evaluate cardiac function before and during replacement therapy employing the gold st and ard method cardiac magnetic resonance imaging ( CMRI ) and measurements of circulating levels of B-type natriuretic peptides .  Sixteen patients ( 8 males and 8 females , mean age 49 years ( range 18–75 ) ) with severe GHD and 16 matched control subjects were included . CMRI was performed at baseline and after 1 year of GH replacement therapy .  IGF-I , B-type natriuretic peptide ( BNP ) and N-terminal pro-BNP ( NT-proBNP ) were measured after 0 , 1 , 2 , 3 , 6 and 12 months of treatment . IGF-I Z-score increased from ( median ( IQR ) ) −2.3 ( −3.8 to −1.4 ) to 0.5 ( −0.3 to 1.7 ) . LVM index ( LVMI ) , ejection fraction ( range 63–80 % ) , cardiac output index and levels of BNP and NT-proBNP were similar at baseline in patients compared to controls ( P-values from 0.09 to 0.37 ) . The patients had significantly smaller LV end-diastolic volume index ( P = 0.032 ) and end-systolic volume index ( P = 0.038 ) . No significant change in LV systolic function or LVM occurred during 1 year of GH treatment . BNP levels were unchanged ( P = 0.88 ) , whereas NT-proBNP tended to decrease ( P = 0.052 ) . Assessed by the highly sensitive and precise CMRI method , untreated GHD was not associated with impaired systolic function or reduced LVMI and 1 year of GH replacement using physiological doses did not influence cardiac mass or function BACKGROUND Four retrospective studies have reported premature mortality in patients with hypopitu 
    Output:
    