@article{ZebgerGongMuellerDierckeetal.2011,
  author    = {Zebger-Gong, Hong and Mueller, Dominik and Diercke, Michaela and Haffner, Dieter and Hocher, Berthold and Verberckmoes, Steven and Schmidt, Sven and D'Haese, Patrick C. and Querfeld, Uwe},
  title     = {1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix},
  series = {Journal of hypertension},
  volume    = {29},
  journal   = {Journal of hypertension},
  number    = {2},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0b013e328340aa30},
  pages     = {339 -- 348},
  year      = {2011},
  abstract  = {Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro. Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol. Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix.},
  language  = {en}
}
@article{WengenmayerKrikovMuelleretal.2011,
  author    = {Wengenmayer, Christina and Krikov, Maxim and Mueller, Susanne and Lucht, Kristin and Villringer, Arno and Hocher, Berthold and Unger, Thomas and Thoene-Reineke, Christa},
  title     = {Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival},
  series = {Neurological research : a journal of progress in neurosurgery and neurosciences},
  volume    = {33},
  journal   = {Neurological research : a journal of progress in neurosurgery and neurosciences},
  number    = {2},
  publisher = {Routledge, Taylor \& Francis Group},
  address   = {Leeds},
  issn      = {0161-6412},
  doi       = {10.1179/016164111X12881719352534},
  pages     = {201 -- 207},
  year      = {2011},
  abstract  = {Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats. Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging. Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner. Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.},
  language  = {en}
}
@article{VignonZellwegerRelleKienlenetal.2011,
  author    = {Vignon-Zellweger, Nicolas and Relle, Katharina and Kienlen, Elodie and Alter, Markus L. and Seider, Patrick and Sharkovska, Juliya and Heiden, Susi and Kalk, Philipp and Schwab, Karima and Albrecht-Kuepper, Barbara and Theuring, Franz and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {Endothelin-1 overexpression restores diastolic function in eNOS knockout mice},
  series = {Journal of hypertension},
  volume    = {29},
  journal   = {Journal of hypertension},
  number    = {5},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0b013e3283450770},
  pages     = {961 -- 970},
  year      = {2011},
  abstract  = {Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.},
  language  = {en}
}
@article{SharkovskaKalkvonWebskyetal.2011,
  author    = {Sharkovska, Yuliya and Kalk, Philipp and von Websky, Karoline and Relle, Katharina and Pfab, Thiemo and Alter, Markus L. and Fischer, Yvan and Hocher, Berthold},
  title     = {Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {57},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {7-8},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  pages     = {507 -- 515},
  year      = {2011},
  abstract  = {Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 \% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 \% mortality in vehicle-treated rats, but only 20 \% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.},
  language  = {en}
}
@article{SchildrothRettigZimmermannKalketal.2011,
  author    = {Schildroth, Janice and Rettig-Zimmermann, Juliane and Kalk, Philipp and Steege, Andreas and Faehling, Michael and Sendeski, Mauricio and Paliege, Alexander and Lai, En Yin and Bachmann, Sebastian and Persson, Pontus B. and Hocher, Berthold and Patzak, Andreas},
  title     = {Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice},
  series = {Nephrology, dialysis, transplantation},
  volume    = {26},
  journal   = {Nephrology, dialysis, transplantation},
  number    = {3},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0931-0509},
  doi       = {10.1093/ndt/gfq534},
  pages     = {779 -- 789},
  year      = {2011},
  abstract  = {Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established. Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused. Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA. Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.},
  language  = {en}
}
@article{LiWangSchlemmetal.2011,
  author    = {Li, Jian and Wang, Zi-Neng and Schlemm, Ludwig and Pfab, Thiemo and Xiao, Xiao-Min and Chen, You-Peng and Hocher, Berthold},
  title     = {Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations},
  series = {Journal of hypertension},
  volume    = {29},
  journal   = {Journal of hypertension},
  number    = {9},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0b013e328349a2e6},
  pages     = {1712 -- 1718},
  year      = {2011},
  abstract  = {Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life. Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain. Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.},
  language  = {en}
}
@article{KalkSharkovskaKashinaetal.2011,
  author    = {Kalk, Philipp and Sharkovska, Yuliya and Kashina, Elena and von Websky, Karoline and Relle, Katharina and Pfab, Thiemo and Alter, Markus L. and Guillaume, Philippe and Provost, Daniel and Hoffmann, Katrin and Fischer, Yvan and Hocher, Berthold},
  title     = {Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner},
  series = {HYPERTENSION},
  volume    = {57},
  journal   = {HYPERTENSION},
  number    = {4},
  publisher = {LIPPINCOTT WILLIAMS \& WILKINS},
  address   = {PHILADELPHIA},
  issn      = {0194-911X},
  doi       = {10.1161/HYPERTENSIONAHA.110.163972},
  pages     = {755 -- 763},
  year      = {2011},
  abstract  = {Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by <= 46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media: lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-beta 1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-beta 1 expression. (Hypertension. 2011;57:755-763.)},
  language  = {en}
}
@article{HocherSchlemmHaumannetal.2011,
  author    = {Hocher, Berthold and Schlemm, Ludwig and Haumann, Hannah and Li, Jian and Rahnenf{\"u}hrer, Jan and Guthmann, Florian and Bamberg, Christian and Kalk, Philipp and Pfab, Thiemo and Chen, You-Peng},
  title     = {Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy},
  series = {Journal of the renin angiotensin aldosterone system},
  volume    = {12},
  journal   = {Journal of the renin angiotensin aldosterone system},
  number    = {3},
  publisher = {Sage Publ.},
  address   = {London},
  issn      = {1470-3203},
  doi       = {10.1177/1470320310387843},
  pages     = {254 -- 261},
  year      = {2011},
  abstract  = {Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism. Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done. Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70\% vs. 6.21 +/- 0.66\% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80\%) compared to II mothers delivering boys (6.21 +/- 0.81\%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension. Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.},
  language  = {en}
}
@article{HocherHeimerlSlowinskietal.2011,
  author    = {Hocher, Berthold and Heimerl, Dirk and Slowinski, Torsten and Godes, Michael and Halle, Horst and Priem, Friedrich and Pfab, Thiemo},
  title     = {Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {57},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {9-10},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  pages     = {651 -- 657},
  year      = {2011},
  abstract  = {Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth. Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy. Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin. Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.},
  language  = {en}
}
@article{HocherHeidenvonWebskyetal.2011,
  author    = {Hocher, Berthold and Heiden, Susi and von Websky, Karoline and Arafat, Ayman M. and Rahnenf{\"u}hrer, Jan and Alter, Markus L. and Kalk, Philipp and Ziegler, Dieter and Fischer, Yvan and Pfab, Thiemo},
  title     = {Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats},
  series = {PLoS one},
  volume    = {6},
  journal   = {PLoS one},
  number    = {3},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0017891},
  pages     = {8},
  year      = {2011},
  abstract  = {Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5\%, p < 0.05), especially in those receiving furosemide (-41.9\%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17\% vs. 54\%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.},
  language  = {en}
}