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: BACKGROUND / AIMS A total of 213 patients with compensated cirrhosis , portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices . Predictors of the development of hepatocellular carcinoma ( HCC ) , including hepatic venous pressure gradient ( HVPG ) were analyzed . METHODS Baseline laboratory tests , ultrasound and HVPG measurements were performed . Patients were followed prospect ively every three months until development of varices or variceal bleeding or end of the study in 09/02 . The endpoint was HCC development according to st and ard diagnostic criteria . Univariate and multivariate Cox regression models were developed to identify predictors of HCC . RESULTS In a median follow-up of 58 months 26/213 ( 12.2 % ) patients developed HCC . Eight patients were transplanted and 28 patients died without HCC . Twenty-one ( 84 % ) HCC developed in patients with HCV . On multivariate analysis HVPG ( HR 1.18 ; 95%CI 1.08 - 1.29 ) , albumin ( HR 0.34 ; 95%CI 0.14 - 0.83 ) and viral etiology ( HR 4.59 ; 95%CI 1.51 - 13.92 ) were independent predictors of HCC development . ROC curves identified 10 mmHg of HVPG as the best cut-off ; those who had an HVPG above this value had a 6-fold increase in the HCC incidence . CONCLUSIONS Portal hypertension is an independent predictor of HCC development . An HVPG > 10 mmHg is associated with a 6-fold increase of HCC risk BACKGROUND & AIMS This prospect i ve study evaluates the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis ( NASH ) . METHODS Consecutive patients with biopsy-proven nonalcoholic fatty liver disease ( NAFLD ) were enrolled ( 2000 - 2001 ) . Patients with other liver diseases and significant alcohol consumption ( > 20 g/day ) were excluded . Clinicodemographic data were gathered at the time of liver biopsy . Each biopsy specimen was assessed by a hepatopathologist . Each patient underwent a limited abdominal ultrasonography ( US ) , computerized tomography ( CT ) , and magnetic resonance imaging ( MRI ) . Films were interpreted by a radiologist who used a predetermined radiological protocol . Each radiological study was reread by the same radiologist and a second radiologist . RESULTS Patients with NASH had greater aspartate aminotransferase levels ( P = 0.03 ) , greater ferritin levels ( P = 0.05 ) , more hepatocyte ballooning ( P < 0.0001 ) , and more fibrosis ( P = 0.002 ) . None of the radiological features distinguished between NASH and other types of NAFLD . No radiological modality detected the presence of hepatocyte ballooning , Mallory 's hyaline , or fibrosis , which are important features in the diagnosis of NASH . The presence of > 33 % fat on liver biopsy was optimal for detecting steatosis on radiological imaging . CONCLUSIONS Differences between NASH and nonprogressive NAFLD were not apparent with any radiological modality . Of the pathologic features important for establishing the diagnosis of NASH , only the severity of steatosis was reflected in these radiological modalities . Good intraobserver agreement was evident for each modality ( US , CT , and MRI ) that was superior to interobserver agreement BACKGROUND & AIMS Liver biopsy analysis is the st and ard method used to diagnose nonalcoholic fatty liver disease ( NAFLD ) . Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis , but is expensive . Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity , specificity , and quantitative accuracy , and results vary among technicians . A new quantitative ultrasound ( QUS ) technique can identify steatosis in animal models . We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis , comparing findings with those from magnetic resonance imaging proton density fat fraction ( MRI-PDFF ) analysis as a reference . METHODS We performed a prospect i ve , cross-sectional analysis of a cohort of adults ( N = 204 ) with NAFLD ( MRI-PDFF , ≥5 % ) and without NAFLD ( controls ) . Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California , San Diego , from February 2012 through March 2014 . QUS parameters and backscatter coefficient ( BSC ) values were calculated . Patients were assigned r and omly to training ( n = 102 ; mean age , 51 ± 17 y ; mean body mass index , 31 ± 7 kg/m(2 ) ) and validation ( n = 102 ; mean age , 49 ± 17 y ; body mass index , 30 ± 6 kg/m(2 ) ) groups ; 69 % of patients in each group had NAFLD . RESULTS BSC ( range , 0.00005 - 0.25 1/cm-sr ) correlated with MRI-PDFF ( Spearman ρ = 0.80 ; P < .0001 ) . In the training group , the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 ( 95 % confidence interval , 0.95 - 1.00 ; P < .0001 ) . The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93 % and 87 % sensitivity , 97 % and 91 % specificity , 86 % and 76 % negative predictive values , and 99 % and 95 % positive predictive values , respectively . CONCLUSIONS QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis , based on a cross-sectional analysis that used MRI-PDFF as the reference . With further validation , QUS could be an inexpensive , widely available method to screen the general or at-risk population for NAFLD BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis , which is characterized by insulin resistance , steatosis , and necroinflammation with or without centrilobular fibrosis . Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus . METHODS We r and omly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet  ( a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight ) plus pioglitazone ( 45 mg daily ) or a hypocaloric diet plus placebo . Before and after treatment , we assessed hepatic histologic features , hepatic fat content by means of magnetic resonance spectroscopy , and glucose turnover during an oral glucose tolerance test ( [14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion ) . RESULTS Diet plus pioglitazone , as compared with diet plus placebo , improved glycemic control and glucose tolerance ( P<0.001 ) , normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels ( by 40 % vs. 21 % , P=0.04 ) , decreased alanine aminotransferase levels ( by 58 % vs. 34 % , P<0.001 ) , decreased hepatic fat content ( by 54 % vs. 0 % , P<0.001 ) , and increased hepatic insulin sensitivity ( by 48 % vs. 14 % , P=0.008 ) . Administration of pioglitazone , as compared with placebo , was associated with improvement in histologic findings with regard to steatosis ( P=0.003 ) , ballooning necrosis ( P=0.02 ) , and inflammation ( P=0.008 ) . Subjects in the pioglitazone group had a greater reduction in necroinflammation ( 85 % vs. 38 % , P=0.001 ) , but the reduction in fibrosis did not differ significantly from that in the placebo group ( P=0.08 ) . Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone ; no other adverse events were observed . CONCLUSIONS In this proof-of-concept study , the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis . Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone . ( Clinical Trials.gov number , NCT00227110 [ Clinical Trials.gov ] . ) The aim of this study was to determine if orlistat , an inhibitor of fat absorption , combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology .  Fifty overweight subjects ( body mass index = > or=27 ) with biopsy proven nonalcoholic steatohepatitis were r and omized to receive a 1,400 Kcal/day diet plus vitamin E ( 800 IU ) daily with or without orlistat ( 120 mg three times a day ) for 36 weeks . Liver biopsies were repeated at week 36 . Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study . The mean age was 47 + /- 9.0 ( st and ard deviation ) years and mean body mass index was 36.4 + /- 6.3 kg/m(2 ) . Four subjects were diabetic . The orlistat group lost a mean of 8.3 % body weight compared to 6.0 % in the diet plus vitamin E group ( not significant ) . Both groups also had similarly improved serum aminotransferases , hepatic steatosis , necroinflammation , ballooning , and nonalcoholic fatty liver disease activity scores . Stratified according to weight loss instead of treatment group , a loss of > or=5 % body weight ( n = 24 ) compared to < 5 % body weight ( n = 17 ) correlated with improvement in insulin sensitivity ( P = 0.001 ) and steatosis ( P = 0.015 ) . Comparing subjects who lost > or=9 % of body weight ( n = 16 ) , to those that did not ( n = 25 ) , improved insulin sensitivity ( P < 0.001 ) , adiponectin ( P = 0.03 ) , steatosis ( P = 0.005 ) , ballooning ( P = 0.04 ) , inflammation ( P = 0.045 ) , and nonalcoholic fatty liver disease activity score ( P = 0.009 ) were seen . Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score ( P = 0.03 ) . Orlistat did not enhance weight loss or improve liver enzymes , measures of insulin resistance , and histopathology . However , subjects who lost > or=5 % of body weight over 9 months improved insulin resistance and steatosis , and those subjects who lost > or=9 % also achieved improved hepatic histologic changes Paradoxically , meta- analysis of human r and omized controlled trials revealed that natural but not synthetic α-tocopherol supplementation significantly increases all-cause mortality at 95 % confidence interval . The root cause was that natural α-tocopherol supplementation significantly depressed bioavailability of other forms of vitamin E that have better chemo-prevention capability . Meta- analysis outcome demonstrated flaws in the underst and ing of vitamin E. Reinterpretation of reported data provides plausible explanations to several important observations . While α-tocopherol is almost exclusively secreted in chylomicrons , enterocytes secrete tocotrienols in both chylomicrons and small high-density lipoproteins . Vitamin E secreted in chylomicrons is discriminately repacked by α-tocopherol transfer protein into nascent very low-density lipoproteins in the liver . Circulating very low-density lipoproteins undergo delipidation to form intermediate-density lipoproteins and low-density lipoproteins . Uptake of vitamin E in intermediate-density lipoproteins and low-density lipoproteins takes place at various tissues via low-density lipoproteins receptor – mediated endocytosis . Small high-density lipoproteins can deliver tocotrienols upon maturation to peripheral tissues independent of α-tocopherol transfer protein action , and uptake of vitamin E takes place at selective tissues by scavenger receptor – mediated direct vitamin E uptake . Dual absorption pathways for tocotrienols are consistent with human and animal studies . α-Tocopherol  depresses the bioavailability of α-tocotrienol and has antagonistic effect on tocotrienols in chemo-prevention against degenerative diseases . Therefore , it is an undesirable component for chemo-prevention . Future research directions should be focused on tocotrienols 
    Output:
    
agent
***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: BACKGROUND / AIMS A total of 213 patients with compensated cirrhosis , portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices . Predictors of the development of hepatocellular carcinoma ( HCC ) , including hepatic venous pressure gradient ( HVPG ) were analyzed . METHODS Baseline laboratory tests , ultrasound and HVPG measurements were performed . Patients were followed prospect ively every three months until development of varices or variceal bleeding or end of the study in 09/02 . The endpoint was HCC development according to st and ard diagnostic criteria . Univariate and multivariate Cox regression models were developed to identify predictors of HCC . RESULTS In a median follow-up of 58 months 26/213 ( 12.2 % ) patients developed HCC . Eight patients were transplanted and 28 patients died without HCC . Twenty-one ( 84 % ) HCC developed in patients with HCV . On multivariate analysis HVPG ( HR 1.18 ; 95%CI 1.08 - 1.29 ) , albumin ( HR 0.34 ; 95%CI 0.14 - 0.83 ) and viral etiology ( HR 4.59 ; 95%CI 1.51 - 13.92 ) were independent predictors of HCC development . ROC curves identified 10 mmHg of HVPG as the best cut-off ; those who had an HVPG above this value had a 6-fold increase in the HCC incidence . CONCLUSIONS Portal hypertension is an independent predictor of HCC development . An HVPG > 10 mmHg is associated with a 6-fold increase of HCC risk BACKGROUND & AIMS This prospect i ve study evaluates the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis ( NASH ) . METHODS Consecutive patients with biopsy-proven nonalcoholic fatty liver disease ( NAFLD ) were enrolled ( 2000 - 2001 ) . Patients with other liver diseases and significant alcohol consumption ( > 20 g/day ) were excluded . Clinicodemographic data were gathered at the time of liver biopsy . Each biopsy specimen was assessed by a hepatopathologist . Each patient underwent a limited abdominal ultrasonography ( US ) , computerized tomography ( CT ) , and magnetic resonance imaging ( MRI ) . Films were interpreted by a radiologist who used a predetermined radiological protocol . Each radiological study was reread by the same radiologist and a second radiologist . RESULTS Patients with NASH had greater aspartate aminotransferase levels ( P = 0.03 ) , greater ferritin levels ( P = 0.05 ) , more hepatocyte ballooning ( P < 0.0001 ) , and more fibrosis ( P = 0.002 ) . None of the radiological features distinguished between NASH and other types of NAFLD . No radiological modality detected the presence of hepatocyte ballooning , Mallory 's hyaline , or fibrosis , which are important features in the diagnosis of NASH . The presence of > 33 % fat on liver biopsy was optimal for detecting steatosis on radiological imaging . CONCLUSIONS Differences between NASH and nonprogressive NAFLD were not apparent with any radiological modality . Of the pathologic features important for establishing the diagnosis of NASH , only the severity of steatosis was reflected in these radiological modalities . Good intraobserver agreement was evident for each modality ( US , CT , and MRI ) that was superior to interobserver agreement BACKGROUND & AIMS Liver biopsy analysis is the st and ard method used to diagnose nonalcoholic fatty liver disease ( NAFLD ) . Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis , but is expensive . Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity , specificity , and quantitative accuracy , and results vary among technicians . A new quantitative ultrasound ( QUS ) technique can identify steatosis in animal models . We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis , comparing findings with those from magnetic resonance imaging proton density fat fraction ( MRI-PDFF ) analysis as a reference . METHODS We performed a prospect i ve , cross-sectional analysis of a cohort of adults ( N = 204 ) with NAFLD ( MRI-PDFF , ≥5 % ) and without NAFLD ( controls ) . Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California , San Diego , from February 2012 through March 2014 . QUS parameters and backscatter coefficient ( BSC ) values were calculated . Patients were assigned r and omly to training ( n = 102 ; mean age , 51 ± 17 y ; mean body mass index , 31 ± 7 kg/m(2 ) ) and validation ( n = 102 ; mean age , 49 ± 17 y ; body mass index , 30 ± 6 kg/m(2 ) ) groups ; 69 % of patients in each group had NAFLD . RESULTS BSC ( range , 0.00005 - 0.25 1/cm-sr ) correlated with MRI-PDFF ( Spearman ρ = 0.80 ; P < .0001 ) . In the training group , the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 ( 95 % confidence interval , 0.95 - 1.00 ; P < .0001 ) . The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93 % and 87 % sensitivity , 97 % and 91 % specificity , 86 % and 76 % negative predictive values , and 99 % and 95 % positive predictive values , respectively . CONCLUSIONS QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis , based on a cross-sectional analysis that used MRI-PDFF as the reference . With further validation , QUS could be an inexpensive , widely available method to screen the general or at-risk population for NAFLD BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis , which is characterized by insulin resistance , steatosis , and necroinflammation with or without centrilobular fibrosis . Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus . METHODS We r and omly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet  ( a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight ) plus pioglitazone ( 45 mg daily ) or a hypocaloric diet plus placebo . Before and after treatment , we assessed hepatic histologic features , hepatic fat content by means of magnetic resonance spectroscopy , and glucose turnover during an oral glucose tolerance test ( [14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion ) . RESULTS Diet plus pioglitazone , as compared with diet plus placebo , improved glycemic control and glucose tolerance ( P<0.001 ) , normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels ( by 40 % vs. 21 % , P=0.04 ) , decreased alanine aminotransferase levels ( by 58 % vs. 34 % , P<0.001 ) , decreased hepatic fat content ( by 54 % vs. 0 % , P<0.001 ) , and increased hepatic insulin sensitivity ( by 48 % vs. 14 % , P=0.008 ) . Administration of pioglitazone , as compared with placebo , was associated with improvement in histologic findings with regard to steatosis ( P=0.003 ) , ballooning necrosis ( P=0.02 ) , and inflammation ( P=0.008 ) . Subjects in the pioglitazone group had a greater reduction in necroinflammation ( 85 % vs. 38 % , P=0.001 ) , but the reduction in fibrosis did not differ significantly from that in the placebo group ( P=0.08 ) . Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone ; no other adverse events were observed . CONCLUSIONS In this proof-of-concept study , the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis . Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone . ( Clinical Trials.gov number , NCT00227110 [ Clinical Trials.gov ] . ) The aim of this study was to determine if orlistat , an inhibitor of fat absorption , combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology .  Fifty overweight subjects ( body mass index = > or=27 ) with biopsy proven nonalcoholic steatohepatitis were r and omized to receive a 1,400 Kcal/day diet plus vitamin E ( 800 IU ) daily with or without orlistat ( 120 mg three times a day ) for 36 weeks . Liver biopsies were repeated at week 36 . Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study . The mean age was 47 + /- 9.0 ( st and ard deviation ) years and mean body mass index was 36.4 + /- 6.3 kg/m(2 ) . Four subjects were diabetic . The orlistat group lost a mean of 8.3 % body weight compared to 6.0 % in the diet plus vitamin E group ( not significant ) . Both groups also had similarly improved serum aminotransferases , hepatic steatosis , necroinflammation , ballooning , and nonalcoholic fatty liver disease activity scores . Stratified according to weight loss instead of treatment group , a loss of > or=5 % body weight ( n = 24 ) compared to < 5 % body weight ( n = 17 ) correlated with improvement in insulin sensitivity ( P = 0.001 ) and steatosis ( P = 0.015 ) . Comparing subjects who lost > or=9 % of body weight ( n = 16 ) , to those that did not ( n = 25 ) , improved insulin sensitivity ( P < 0.001 ) , adiponectin ( P = 0.03 ) , steatosis ( P = 0.005 ) , ballooning ( P = 0.04 ) , inflammation ( P = 0.045 ) , and nonalcoholic fatty liver disease activity score ( P = 0.009 ) were seen . Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score ( P = 0.03 ) . Orlistat did not enhance weight loss or improve liver enzymes , measures of insulin resistance , and histopathology . However , subjects who lost > or=5 % of body weight over 9 months improved insulin resistance and steatosis , and those subjects who lost > or=9 % also achieved improved hepatic histologic changes Paradoxically , meta- analysis of human r and omized controlled trials revealed that natural but not synthetic α-tocopherol supplementation significantly increases all-cause mortality at 95 % confidence interval . The root cause was that natural α-tocopherol supplementation significantly depressed bioavailability of other forms of vitamin E that have better chemo-prevention capability . Meta- analysis outcome demonstrated flaws in the underst and ing of vitamin E. Reinterpretation of reported data provides plausible explanations to several important observations . While α-tocopherol is almost exclusively secreted in chylomicrons , enterocytes secrete tocotrienols in both chylomicrons and small high-density lipoproteins . Vitamin E secreted in chylomicrons is discriminately repacked by α-tocopherol transfer protein into nascent very low-density lipoproteins in the liver . Circulating very low-density lipoproteins undergo delipidation to form intermediate-density lipoproteins and low-density lipoproteins . Uptake of vitamin E in intermediate-density lipoproteins and low-density lipoproteins takes place at various tissues via low-density lipoproteins receptor – mediated endocytosis . Small high-density lipoproteins can deliver tocotrienols upon maturation to peripheral tissues independent of α-tocopherol transfer protein action , and uptake of vitamin E takes place at selective tissues by scavenger receptor – mediated direct vitamin E uptake . Dual absorption pathways for tocotrienols are consistent with human and animal studies . α-Tocopherol  depresses the bioavailability of α-tocotrienol and has antagonistic effect on tocotrienols in chemo-prevention against degenerative diseases . Therefore , it is an undesirable component for chemo-prevention . Future research directions should be focused on tocotrienols 
    Output:
    