Mild inflammation has been documented in human HH studies during the development of fibrosis and cirrhosis.38 Deugnier et al. reported inflammatory infiltrates in approximately 50% of liver biopsies from HH patients.39 Inflammation was predominantly present in portal and periportal regions and correlated with histological iron scores, sideronecrotic changes in hepatocytes, and hepatic fibrosis. Another study showed that approximately 25% of liver biopsies from untreated HH patients displayed moderate inflammatory infiltration.40 Bridle et al. also reported that 60% of liver biopsies from HH patients showed mild inflammation consisting of scattered inflammatory foci. Furthermore, patients with

selleck hepatic inflammation had a higher incidence of hepatic fibrosis.41 Iron-loaded and apoptotic/necrotic hepatocytes are purported to induce the activation of HSCs by various signaling mechanisms, resulting in enhanced production of proinflammatory and -fibrogenic cytokines as well as the recruitment of inflammatory cells.8 Our study provides further support for the direct hepatotoxic effects of iron overload, which results from the disruption of Hfe and Tfr2, manifesting as inflammation and increased collagen

deposition, suggesting the activation of HSCs. Iron plays NVP-BKM120 an important part in the progression of hepatic injury, and it does this through its ability to catalyze the formation of highly reactive, damaging ROS. ROS induce tissue injury by promoting LPO as well as protein and DNA modification, leading, ultimately, to apoptosis and necrosis.

Further investigation into the molecular mechanisms of iron toxicity and how it causes liver injury will provide a better understanding of the role iron plays in the progression of liver disease. The Hfe−/−×Tfr2mut mouse represents a model of the genetic iron overload disorder, HH, that mimics diglyceride both iron overload and consequent liver injury observed in humans with HH. Additional Supporting Information may be found in the online version of this article. “
“At what age and risk level may warrant hepatocellular-carcinoma (HCC) screening remains to be defined. To develop risk score for stratifying average-risk population for mass HCC screening, we conducted a pooled analysis using data from three cohorts involving 12377 Taiwanese adults aged 20-80 years. During 191240.3 person-years of follow-up, 387 HCCs occurred. We derived risk scores from Cox model in two-thirds of the participants, and used another one-third for model validation. Besides assessing discrimination and calibration, we performed decision curve analysis to translate findings into public health policy. A risk score according to age, sex, alanine aminotransferase, prior chronic liver disease, family history of HCC, and cumulative smoking had good discriminatory accuracy in both model derivation and validation sets (c-statistics for 3-, 5-, and 10-year risk prediction: 0.76-0.83).

These data show that A. crinitum is a shade-adapted seaweed with modest light requirements for the initiation of net photosynthesis (1.49–2.25 μmol photons · m−2 · s−1)

and growth (0.12–0.19 mol photons · m−2 · d−1). A. crinitum maintains high photosynthetic efficiency and pigment content and a low C:N ratio throughout the year and can maintain biomass under sub-compensation (critical) light levels for at least 5 d. Nevertheless, in situ photon flux is less than the minimum light requirement for A. crinitum on at least 103 d per annum and is rarely sufficient to saturate growth. These findings reinforce the importance of understanding the physiological response of macroalgae at the extremes of environmental gradients Alpelisib nmr and highlight the need to establish minimum thresholds that modification of the subtidal light environment should not cross. “
“We investigated the effect of Zn availability on growth rate (μ), cell morphology, and elemental stoichiometry and incorporation rate in two marine diatoms. For the coastal diatom Skeletonema costatum (Grev.) Cleve, the half-saturation constant (KS) for growth was 4.1 pM Zn2+, and growth ceased at Galunisertib clinical trial ≤ 2.6 pM Zn2+, whereas for the oceanic diatom Thalassiosira oceanica Hasle, KS was 0.5 pM Zn2+, and μ remained at ∼40%μmax even at 0.3 pM Zn2+. Under Zn-limiting (Zn-L) conditions, S. costatum

decreased cell size significantly, leading to an 80% increase in surface area to volume ratio (SA/V) at Zn2+ of 3.5 pM compared to Zn-replete (Zn-R) conditions (at Zn2+ of 13.2 pM), whereas T. oceanica’s morphology did not change appreciably. Cell quotas of C, N, P, Si, and chl a significantly decreased under Zn limitation in Ponatinib cost S. costatum (at Zn2+ of 3.5 pM), whereas Zn limitation in T. oceanica (at Zn2+ of 0.3 pM) had little effect on quotas. Elemental stoichiometry

was ∼85C:10N:9Si:1P and 81C:9N:5Si:1P for S. costatum, and 66C:5N:2Si:1P and 52C:6N:2Si:1P for T. oceanica, under Zn-R and Zn-L conditions, respectively. Incorporation rates of all elements were significantly reduced under Zn limitation for both diatoms, but particularly for Si in S. costatum, and for C in T. oceanica, despite its apparent tolerance of low Zn conditions. With [Zn2+] in some parts of the ocean being of the same order (∼0.2 to 2 pM) as our low Zn conditions for T. oceanica, our results support the hypothesis that in situ growth and C acquisition may be limited by Zn in some oceanic species. “
“Size increments following interindividual fusions appear as a general benefit for organisms, such as coalescing seaweeds and modular invertebrates, with the capacity to fuse with conspecifics. Using sporelings of the red algae Gracilaria chilensis C. J. Bird, McLachlan et E. C. Oliveira and Mazzaella laminarioides (Bory) Fredericq, we measured the growth patterns of sporelings built with different numbers of spores, and the magnitude and persistence of the size increments gained by fusions.

Results: Of ninety (90) patients enrolled, 66 were male (73.3%) and 24 were female (26.7%); majority with chronic hepatitis B. Sixty (66.7%) of the 90 patients were found to have large EV. The distribution of large EV according to CTP classification was as follows: A, 63.16%; B, 62.8% and C, 75%. Large EV was independently associated with total bilirubin higher than 1.9 mg/dL (p = 0.010), INR higher than 1.65 (p = 0.018), Lenvatinib and platelet count lower than 105,500/mm3 (p = 0.02). Platelet count lower

than 105,500/mm3 had the highest discriminative value for presence of large EV (sensitivity = 73.33%; specificity = 73.33%; area under receiver operating characteristics = 0.783). Conclusions: Large EV were found in 66.7% of patients with liver cirrhosis who underwent hospitalization. In patients with liver cirrhosis, the existence of thrombocytopenia may predict large EV which warrant prophylactic therapy. Key Word(s): 1. large esophageal varices; 2. liver cirrhosis; 3. platelets Presenting Author: GSK126 ic50 LU CHIN HUANG Additional Authors: MING CHE LEE, YUNG HSIANG HSU Corresponding Author: LU CHIN HUANG Affiliations: Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi General Hospital Objective: The patients who had simultaneous hepatocellular carcinoma and cholangiocarcinoma was not frequent. In order to investigate the

manifestations of patients with hepatocholangiocarcinoma, we performed this retrospective study. Methods: From August 1986 to April 2014, the from patients with diagnosis of hepatocholangiocarcinoma were included. The age,

gender, alpha fetoprorein (AFP), carbohydrate antigen 19-9 (CA 19-9), HBsAg and anti-HCV was recorded. The size, location of tumor, treatment, follow up duration and survival status was recorded. Results: A total of 10 patients (M 8, F2) were included. The average age was 58.1 years (49–71). The AFP was 38414 ng/mL (5.3–382000 ng/mL, normal <8.1), CA 19-9 was 378 IU/mL (25–1632 IU/mL, normal <37). Hepatitis B, hepatitis C infection rate was 50%, 30%. The size of tumor was 6.7 cm (2–13 cm). The location of tumor was right lobe 50%, left lobe 30%, and both lobes 20%. The treatments included surgery (2), surgery plus chemotherapy (2), surgery plus radiotherapy (2), transarterial chemoembolization (1), chemotherapy (1), and supportive care (2). The follow up duration was 10.6 months (1 month-2.6 years). The 3 months, 6 months, and 1 year survival rate was 90%, 70%, and 55.6%. Conclusion: 1. Hepatocholangiocarcinoma was not a frequent disease. We collected 10 patients in the past 27 years. 2. The average age was 58.1 years. 3. The average AFP was 38414 ng/mL. 4. Hepatitis B, hepatitis C infection rate was 50%, 30%. 5. The 6 months, and 1 year survival rate was 70% and 55.6%, respectively. Key Word(s): 1. hepatocholangiocarcinoma; 2.

In this chapter, the principles and selleck chemicals practise of

standardization as applied to assays of coagulation factors are described, with particular emphasis on factor VIII assays, inhibitor assays, and assays for bypassing agents; assays of factor IX, von Willebrand factor (VWF), and factors of the rarer coagulation deficiencies are also considered. “
“Summary.  Inherited diseases of the megakaryocyte lineage give rise to bleeding when platelets fail to fulfill their hemostatic function upon vessel injury. Platelet defects extend from the absence or malfunctioning of adhesion (GPIb-IX-V, Bernard–Soulier syndrome) or aggregation receptors (integrin αIIbβ3, Glanzmann thrombasthenia) to

defects of primary receptors for soluble agonists, secretion from storage organelles, activation pathways and the generation of procoagulant HKI-272 price activity. In disorders such as the Chediak–Higashi, Hermansky–Pudlak, Wiskott–Aldrich and Scott syndromes the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure hemostasis. Some FT affect platelet morphology and give rise to the ‘giant platelet’ syndromes (e.g. MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may also affect other cells and in some cases interfere with development and/or functioning of major organs. Diagnosis of platelet disorders requires platelet function testing, studies often aided by the quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. New generation DNA-based procedures including whole exome sequencing offer an exciting new perspective. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is often used

for mild disorders. Substitute Methisazone therapies are available including rFVIIa and the potential use of thrombopoietin analogues for FT. Stem cell or bone marrow transplanation has been successful for several diseases while gene therapy shows promise in the Wiskott–Aldrich syndrome. This review will discuss the molecular basis, diagnosis and treatment of inherited platelet disorders (IPDs) where abnormalities of platelet function and production give rise to largely mucocutaneous bleeding syndromes of variable intensity [1–5]. The characterization of IPDs has led to novel insights into the complex biology of megakaryopoiesis and platelet production and identified functionally important platelet receptors and intracellular signaling events that have pioneered current antithrombotic therapy.

[5] Our investigations suggest multiple parallel mechanisms by which DC may regulate hepatitis. Importantly, we found that DCs in NASH liver are differentially capable of activating CD4+ T cells, in comparison with CD8+ T cells. Furthermore, upon DC depletion, the CD8/CD4 T-cell ratio is skewed markedly upward with associated diminution of Tregs. The

protective role of Tregs in CLD is well established.[29, 30] Furthermore, relative suppression of CD8+ T-cell expansion may be protective, because CD8+ T cells have recently been shown to drive adipose tissue inflammation and have an emerging role in NASH pathogenesis.[31, 32] Additionally, the exacerbated hepatic insult associated with ablation of DC populations may EPZ-6438 concentration be mechanistically related to the DC’s role in limiting sterile inflammation through clearance of apoptotic

bodies and necrotic debris. Sterile inflammation in the liver increases recruitment, viability, and activation of innate immune cells.[33] We show that liver DCs express high CLEC9A, which recognizes and binds death signals on necrotic cells and is primary in DC capacity to clear necrotic products.[26, 27] Accordingly, we selleck found that NASH liver DCs have remarkable capacity to capture necrotic cellular debris and apoptotic targets, when compared to other hepatic APC subsets and DCs from control liver. Furthermore, we found that DC depletion leads to an accentuation of sterile inflammation within the liver, because NASH(-DC) liver contains modestly higher HMGB1 and elevated markers of apoptosis, including p53, which has been demonstrated to play a pivotal role as a mediator of apoptosis Silibinin in experimental NASH.[17] This also results in augmented production of proinflammatory cytokines—including IL-1β, TNF-α, and IL-6—and enhanced viability and expression of TLR4 and TLR9 in innate effector cells. Miura et al. demonstrated that signaling

through TLR9 leads to progression of NASH by KC production of IL-1β.[4] TLR4 signaling in KCs has also been linked to severity of steatohepatitis.[6] DC production of IL-10 may also have an important role in limiting hepatic damage in NASH. Bamboat et al. recently showed that DNA released from apoptotic hepatocytes stimulates liver DC to secrete IL-10 in a TLR9-dependent manner.[28] Furthermore, IL-10 derived from hepatic DCs can ameliorate liver injury through suppression of inflammatory monocyte function.[28] Additional studies in contexts such as allergen-induced asthma and cisplatin-induced nephrotoxicity have shown that DCs attenuate sterile inflammation through release of IL-10.[34, 35] We found that NASH DCs exhibited markedly elevated IL-10 production, compared to normal liver DCs.

Ossabaw miniature swine develop metabolic syndrome along with severe liver injury and progressive fibrosis that resembles human non-alcoholic steatohepatitis (NASH) when fed high-fat, high-fructose atherogenic (NASH) diet. Aim: To test the effect of FGF21 therapy on liver histology and metabolic indices in Ossabaw Swine with metabolic syndrome and NASH. Methods: Eight Ossabaw swine were fed an average of 5000 kcal per

day of NASH diet and developed metabolic syndrome Selleckchem Enzalutamide and NASH after 30 weeks of feeding. The pigs were then treated with FGF21 at 1mg/kg subcutaneously once daily for 16 weeks while continuing on NASH diet. Pre- and post-treatment liver biopsies were evaluated according to predefined histological scoring system. Staging of fibrosis accounted for

bridging fibrous septa normally present in swine livers. Improvement in histological features after FGF21 therapy was defined as a reduction of > 1 point, whereas worsening was defined as an increase of > 1 point compared to pre-therapy biopsy. Insulin sensitivity was assessed with an oral glucose tolerance test. Results: Mean body weight was 53.5, 88, and 90 kg at study weeks 0, 30, and 46, respectively. Sixteen weeks of FGF21 therapy significantly reduced fasting total cholesterol (265 vs 173 mg/dL, p<0.05) and the peak post-prandial triglycerides (142 vs 92.5 mg/dL, p <0.05). Although fasting glucose did not significantly change, fasting insulin was significantly lower following FGF21 therapy (25 vs 14 μU/ml, p< 0.05). All liver biopsies prior to initiating PI3K Inhibitor Library cost FGF21 therapy showed significant fibrosis and extensive hepatocyte ballooning. Following FGF21 therapy, improvement in fibrosis, ballooning, portal and lobular inflammation was noted in 62.5%, 87.5%, 50%, and 25%, respectively.

Electron microscopy showed markedly decreased number of secondary lysosomes within hepatocytes and an increased number of lipid-laden Kupffer cells after FGF21 therapy. Except for itching at the injection site, FGF21 was well tolerated. Dichloromethane dehalogenase Conclusions: FGF21 therapy results in improvements in liver necroinflammation and fibrosis, insulin sensitivity, and post-prandial lipidemia in Ossabaw miniature swine with diet-induced NASH. These observations suggest that FGF21 should be further investigated as a potential treatment for NASH. Disclosures: Naga P. Chalasani – Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin The following people have nothing to disclose: Samer Gawrieh, Mouhamad Alloosh, Rachel M. Sheridan, Tiebing Liang, Howard C. Masuoka, Michael Sturek Hepatic fibrosis in NASH is the common pathophysiologic process resulting from chronic liver inflammation associated with rise in proinflammatory cytokines and oxidative stress.

However, oversedation is a risk and analgesia and mental alertness need to be carefully monitored. V KUMBHARI,1 P SAXENA,1 Y NAKAI,5 R MODAYIL,3 CS DE LA SERNA,7 K HARA,4 S STAVROPOULOS,3 M MIRANDA,1 V DHIR,2 DH PARK,6 KHASHAB MA1 1Johns Hopkins Hospital, Baltimore MD USA, 2Baladota Institute of Digestive Sciences, Mumbai India, 3Winthrop University Hospital, Rock Hill, SC, 4Aichi Cancer Center Hospital, Nagoya Japan, 5University of Tokyo, Japan, 6Asan Medical Center, Seoul, Republic of Korea, 7Hospital Universitario-Roi Hortego, Valladolid, Spain Background: Traditionally, percutaneous transhepatic biliary drainage or surgical interventions were employed in the setting

of a failed ERCP. Recently, EUS-guided biliary drainage (EUS-BD) is being recognized as a suitable alternative as it can facilitate rendezvous ERCP or direct transluminal access. The latter method can performed transgastrically by the formation of a hepaticogastrostomy MLN8237 ic50 (HG) or transduodenally by formation of choledochoduodenostomy (CDS) without accessing OSI 906 the papilla. There is no consensus to guide the clinician as to which technique (HG or CDS) should be preferentially utilized. Aims: To 1) compare efficacy and safety of HG and CDS techniques and 2) identify predictors of adverse events. Methods: Consecutive jaundiced patients with distal malignant biliary obstruction

who had a failed ERCP and underwent EUS-BD (CDS or HG) at 7 tertiary centers (2 US, 1 European, 4 Asian) were included. Patients were excluded if they had proximal malignant biliary strictures (<2 cm from the hilum). All operators were experts endosonographers and had performed more than 20 EUS-BD procedures. Follow-up consisted of monitoring for adverse events and repeat LFTs. Technical Nintedanib (BIBF 1120) success was defined as successful placement of stent in desired location. Clinical response was defined as at least 50% decrease in

total bilirubin at 1 week. Adverse events were graded according to the ASGE lexicon’s severity grading system. Results: A total of 150 patients (mean age 66.4 years, female 66 (44%), pancreatic cancer 72 (48%) underwent EUS-BD [CDS 61 (40.67%), HG 89 (59.33%)]. Reasons for EUS-BD was obscured ampulla by invasive cancer or previously placed enteral stent (n = 43), gastric outlet obstruction (n = 30), failed deep biliary cannulation (n = 44), altered anatomy (n = 28), and others (n = 5). EUS-guided cholangiography was successful in 97% of patients and delineated distal common bile duct stricture in all subjects. Stent placement in desired location (technical success) was achieved in 137 (91.3 %) patients (CDS 93.4%, HG 89.9%, p = 0.44) (metallic stent 122, plastic stent 15). Clinical success in patients with successfully placed biliary stents was attained in 83.3% patients in CDS group as compared to 81.8% in HG group (p = 0.82). There was no significant difference in the rate of adverse events between HG (23.6%) and CDS (16.4%), p = 0.28.

Thrombin generation assay parameters are measured with the Calibrated Automatic Thrombogram, Thrombinoscope (Maastricht, NL). Subsequent to in vitro testing is a 12-month prospective follow-up period to collect clinical data regarding inhibitor reactivity with different concentrates and examine the correlation between thrombin generation assay results and epitope specificity (Table 6). In patients with high-responding inhibitors, thrombin generation is measured before and 15 min after the Wnt inhibitor usual infusion of FVIII to determine whether

the assay is able to detect a haemostatic effect and whether the effect correlates with outcome. Patients with low-responding inhibitors who receive Kinase Inhibitor Library solubility dmso high-dose FVIII as prophylaxis are followed in the same fashion. Patients with low-responding inhibitors receiving FVIII on demand are asked to attend the hospital at minimum during a severe bleed to have their thrombin generation tested before and after infusion of the FVIII product. Preliminary in vitro results on baseline plasma samples for the first nine patients are now available. In this initial experiment,

plasma samples were spiked with each of the three FVIII concentrates at an amount calculated to mimic the clinical dose of FVIII for ITI therapy in patients with high-responding inhibitors and for prophylaxis or on demand treatment in patients with low-responding inhibitors. Plasma samples spiked with twice the clinical dose were also tested to determine whether the thrombin generation assay could detect a dose response pattern. In these first nine patients, the clinical dose of FVIII ranged from 50 to 200 IU kg−1. In view of heterogeneity in the patient population for current

inhibitor titre (1–33 BU mL−1), it was expected that measurements of thrombin generation would also be heterogeneous. To understand which thrombin generation curve parameter best distinguished FVIII concentrates, the ratio of thrombin generation pre- vs. post-spiking was examined per parameter. At a clinical dose of FVIII (Fig. 4), the ETP (AUC) showed minimal sensitivity and the peak height parameter was only marginally more sensitive. At this preliminary stage of analysis, velocity index appeared Florfenicol to be the most sensitive parameter to measure the difference in thrombin generation before and after infusion of FVIII as well as inhibitor reactivity among products. Similar, and dose-dependent, patterns were observed when spiking experiments were repeated at twice the clinical dose (i.e. up to 400 U kg−1 FVIII). The thrombin generation assay provides a more global view of thrombin generation than conventional clotting tests such as PT and APPT. Efforts to standardize the thrombin generation assay are ongoing as the pro- and anticoagulant pathways that contribute to outcome (i.e.

Materials and Methods.— Twenty-five patients with a definitive diagnosis of Selumetinib research buy SIH and 25 healthy subjects were evaluated with PC-MRI. Magnetic resonance (MR) images were acquired using a 1.5-T unit with an 8-channel head coil. Differences between SIH patients and control subjects were assessed statistically using Wilcoxon’s rank sum test, Spearman’s rho test, or Pearson’s chi-square test, as appropriate. Results.— CSF flow volumes toward

the third ventricle, CSF flow volumes toward the fourth ventricle, the absolute stroke volume, the peak systolic velocity, and the peak diastolic velocity in SIH patients were significantly smaller than those in control subjects (P < .0001). On the other hand, the net CSF flow volume (P = .9227) and the net CSF flow direction (P = .2472) for SIH patients and control subjects were not significantly different. Conclusions.— The results

obtained by CSF flow analysis were directly related find more to values of CSF opening pressure, determined by lumbar puncture, and clinical findings, such as headache scores. Thus, CSF flow analysis with PC-MRI, which has a short performance time and is non-invasive, may contribute to assessment of SIH patients. “
“(Headache 2010;50:413-419) Objective.— To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. Background.— Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and

headache disorders. Methods.— Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about very headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. Results.— A total of 220 subjects were evaluated – 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. Conclusions.— To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

The most successful therapeutic regimen is the combination of spironolactone at 100 mg/day and furosemide at 40 mg/day, and the doses are increased in a stepwise fashion, maintaining the same ratio of doses in order to maintain normal potassium Ferrostatin-1 purchase levels.[4-7] However, these titration therapies cannot be easily used due to the risk of adverse events or refractory ascites. Also, use of diuretics

is associated with several complications such as renal failure and electrolyte disorders despite beneficial drug administration. Thus, a novel, orally available diuretic has been desired to be introduced into clinical practice; however, no drug has been launched. Tolvaptan, an arginine vasopressin V2 receptor antagonist, is a diuretic agent with an aquaretic effect that promotes electrolyte-free water excretion without disrupting electrolyte balance.[8, 9] It was approved for the treatment of hyponatremia in the USA and for the treatment of hyponatremia secondary to inappropriate antidiuretic hormone syndrome in the EU.[10] In 2010, tolvaptan was approved for the treatment of volume overload in patients with heart failure in Japan.[11] Now, tolvaptan is prescribed to patients who are non-responders to conventional diuretic therapy Daporinad cost for treatment of edema due to heart failure in Japan. Thus, tolvaptan is already prescribed worldwide; therefore,

its benefits and risks due to occurrence of adverse events are well known. Therefore, tolvaptan can be prescribed in comfort when a new indication is added. This is desirable information Benzatropine in cirrhotic patients, and whole body management of hepatic edema may be possible. In this issue of Hepatology Research, Sakaida et al. conducted a multicenter, randomized, double-blinded, placebo-controlled phase 3 study to verify the efficacy and safety of tolvaptan in cirrhotic patients with edema.[12] They set the study based on the result of a previous dose-finding trial that showed significant difference in bodyweight change between tolvaptan and placebo for 7 days in participating

patients who had insufficient response to combination therapy of spironolactone and furosemide.[12] This study demonstrated that tolvaptan at 7.5 mg/day improved hepatic edema compared with placebo. Tolvaptan dose was 7.5 mg/day, and the treatment period was 7 days. The primary end-point was change in bodyweight from baseline on the final dosing day to that was considered to reflect improvement of hepatic edema. The surrogate end-point was improvement of hepatic edema status which is assumed as a total of changes in ascites, lower limb edema and pleural effusion volumes. Change in bodyweight from baseline on the final dosing day was −0.44 kg in the placebo group and −1.95 kg in the tolvaptan group. Difference between the two groups was statistically significant (−1.51 kg, P < 0.0001). Change in ascites volume, calculated by performing computed tomography (CT), was −191.8 mL in the placebo group and −492.4 mL in the tolvaptan group.