Usefulness of autotaxin for the complications of liver cirrhosis

BACKGROUND Autotaxin(ATX) has been reported as a direct biomarker for estimating the evaluation of liver fibrosis. But available data on ATX as a useful biomarker for the complications of liver cirrhosis(LC) are scant.AIM To assess the clinical usefulness of ATX for assessing the complications of LC.METHODS This multicenter, retrospective study was conducted at six locations in Japan. We include patients with LC, n = 400. The ATX level was evaluated separately in men and women because of its high level in female patients. To assess the clinical usefulness of ATX for the complications of LC, the area under the curve(AUC) of ATX assessing for the severe complications was analyzed in comparison with the model for end-stage liver disease score, albumin-bilirubin(ALBI) score, fibrosis-4 index, and aspartate aminotransferase-to-platelet ratio index.RESULTS The mean age was 68.4 ± 11.4 years, 240 patients(60.0%) were male. A total of 213(53.3%) and 187(46.8%) patients were compensated and decompensated,respectively. The numbers of patients with varix rupture, hepatic ascites, and hepatic encephalopathy were 35(8.8%), 131(32.8%), and 103(25.8%),respectively. The AUCs of ATX in men for hepatic encephalopathy, hepatic ascites, and varix ruptures were 0.853, 0.816, and 0.706, respectively. The AUCs of ATX in women for hepatic encephalopathy, hepatic ascites, and varix rupture were 0.759, 0.717, and 0.697, respectively. The AUCs of ATX in men were higher than those in women, as were all the other biomarkers used to detect encephalopathy and varix ruptures. However, for detecting ascites, the AUC of ALBI in men was more effective than using ATX.CONCLUSION ATX in men was more effective than any other biomarkers for detecting hepatic encephalopathy and varix ruptures.     

Immunohistochemistry of γ‐H2AX as a method of early detection of urinary bladder carcinogenicity in mice

Phosphorylated histone H2AX (γ‐H2AX) has been demonstrated as a DNA damage marker both in vitro and in vivo. We previously reported the effects of genotoxic carcinogens in the urinary bladder of rats by immunohistochemical analysis of γ‐H2AX using samples from 28‐day repeated‐dose tests. To evaluate the application of γ‐H2AX as a biomarker of carcinogenicity in the bladder, we examined species differences in γ‐H2AX formation in the urinary bladder of mice. Six‐week‐old male B6C3F₁ mice were treated orally with 12 chemicals for 4 weeks. Immunohistochemical analysis demonstrated that N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine, p‐cresidine and 2‐acetylaminofluorene (2‐AAF), classified as genotoxic bladder carcinogens, induced significant increases in γ‐H2AX levels in the bladder urothelium. In contrast, genotoxic (2‐nitroanisole, glycidol, N‐nitrosodiethylamine and acrylamide) and non‐genotoxic (dimethylarsinic acid and melamine) non‐bladder carcinogens did not upregulate γ‐H2AX. Importantly, 2‐nitroanisole, a potent genotoxic bladder carcinogen in rats, significantly increased the proportion of γ‐H2AX‐positive cells in rats only, reflecting differences in carcinogenicity in the urinary bladder between rats and mice. Significant upregulation of γ‐H2AX was also induced by uracil, a non‐genotoxic bladder carcinogen that may be associated with cell proliferation, as demonstrated by increased Ki67 expression. 2‐AAF caused γ‐H2AX formation mainly in the superficial layer, together with reduced and disorganized expression of uroplakin III, unlike in rats, suggesting the mouse‐specific cytotoxicity of 2‐AAF in umbrella cells. These results suggest γ‐H2AX is a useful biomarker reflecting species differences in carcinogenicity in the urinary bladder.     

Efficacy of Granulocyte and Monocyte Adsorption Apheresis for Treatment of Palmoplantar Pustulosis

Palmoplantar pustulosis (PPP) is characterized by neutrophilic pustules with erythema, which are limited to the hands and feet. Although granulocyte and monocyte adsorption apheresis (GMA) has shown remarkable effects on generalized pustular psoriasis, there are few reports of PPP treated with GMA. We treated three refractory PPP patients using GMA weekly for 5 weeks. The skin eruptions were assessed by a 5‐grade score for scales, pustules, and erythema. GMA decreased the total grade from 9 to 2 in patients 1 and 2, and from 7 to 3 in patient 3. The GMA effects were estimated to be excellent in all three patients. Pustule formation and pain disappeared in all cases. The treatment effect lasted for at least 5 months after GMA. GMA was also effective for relieving the arthralgia in one patient, but it recurred at 6 weeks. Based on these findings, GMA could be an effective therapy for refractory PPP.     

Establishment of a human nonluteinized granulosa cell line that transitions from the gonadotropin-independent to the gonadotropin-dependent status

The ovary is a complex endocrine organ responsible for steroidogenesis and folliculogenesis. Follicles consist of oocytes and two primary steroidogenic cell types, the granulosa cells, and the theca cells. Immortalized human granulosa cells are essential for researching the mechanism of steroidogenesis and folliculogenesis. We obtained granulosa cells from a 35-yr-old female and immortalized them by lentivirus-mediated transfer of several genes so as to establish a human nonluteinized granulosa cell line (HGrC1). We subsequently characterized HGrC1 and investigated its steroidogenic performance. HGrC1 expressed enzymes related to steroidogenesis, such as steroidogenic acute regulatory protein, CYP11A, aromatase, and gonadotropin receptors. Stimulation with FSH increased the mRNA levels of aromatase, which consequently induced the aromatization of androstenedione to estradiol. Activin A increased the mRNA levels of the FSH receptor, which were synergistically up-regulated with FSH stimulation. HGrC1 also expressed a series of ligands and receptors belonging to the TGF-β superfamily. A Western blot analysis showed that bone morphogenetic protein (BMP)-4, BMP-6, and BMP-7 phosphorylated small mother against decapentaplegic (Smad)1/5/8, whereas growth differentiation factor-9 phosphorylated Smad2/3. BMP-15 and anti-Müllerian hormone phosphorylated Smad1/5/8 while also weakly phosphorylating Smad2/3. These results indicate that HGrC1 may possess the characteristics of granulosa cells belonging to follicles in the early stage. HGrC1 might also be capable of displaying the growth transition from a gonadotropin-independent status to gonadotropin-dependent one.     

Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying

Background/Aims: In this crossover study, we investigated whether nizatidine, a H(2)-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. Methods: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the T(max) value using the (13)C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. Results: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and T(max) value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. Conclusion: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying.