Epidemiology of primary biliary cholangitis in Italy: Evidence from a real-world database

BackgroundPrimary biliary cholangitis is an autoimmune disease affecting the interlobular bile ducts. Limited information is available on its epidemiology and treatment in Italy.AimsTo describe primary biliary cholangitis epidemiology and investigate treatment patterns for Italian patients with this disease.MethodsElectronic medical records from 900 general practitioners (part of the QuintilesIMS™ Longitudinal Patient Databases) were examined. Demographics were compared with those from the Italian National Institute of Statistics dataset. The International Classification of Diseases, Ninth Revision, biliary cirrhosis code 571.6 was used for diagnosis, and data on comorbidities, concomitant medications, medical examinations, specialist referrals, and treatments were collected.ResultsThis dataset was representative of the Italian population. Point prevalence of primary biliary cholangitis was calculated as 27.90 per 100,000 and incidence as 5.31 per 100,000 inhabitants/year. Some associations between the disease and comorbidities were sex specific. The most common laboratory assays requested were for liver enzymes, and the majority of patients were not referred to a specialist. Ursodeoxycholic acid was the most common therapy.ConclusionThis can be used as a benchmark for monitoring and identifying unmet needs to improve treatment in Italy.     

Plasma-free eicosapentaenoic acid/arachidonic acid ratio: a possible new coronary risk factor

Seventy-six effort angina patients who had typical angina on exertion documented by treadmill stress test with evidence of ischemic ST-segment depression and 78 healthy volunteers in urban Japan were investigated in this study. Plasma free fatty acids (FFA) in both groups were determined using high-performance liquid chromatography. The relationships between the total cholesterol, high-density lipoprotein (HDL), triglycerides in plasma, and the genesis of coronary heart disease were also examined. The ratio (0.08 +/- 0.08) of eicosapentaenoic acid (EPA)/arachidonic acid (AA) in plasma FFA was significantly lower in effort angina patients than that (0.15 +/- 0.12) in healthy volunteers. The lower ratio was due to significantly lower levels of EPA in the patients than in normals. In 42% of angina patients, the ratio is below 0.03. In all age subgroups except the age 30-39 subgroup, the ratio of EPA/AA was significantly lower in patients than in normals, when divided into four subgroups by using a 10-year age interval. Though the total cholesterol and triglycerides were not significantly different between the two groups, HDL was significantly lower and total cholesterol/HDL ratio was significantly higher in effort angina patients than in healthy volunteers. However, there was no correlation between EPA/AA ratio and HDL in individuals in either group. From these results, it could be concluded that lower EPA/AA ratio is a new coronary risk indicator other than HDL.     

Pharmacologic Properties of the Swelling-Induced Chloride Current of Dog Atrial Myocytes

Pharmacology of Swelling-Induced Chloride Current. Introduction: Swelling-induced chloride currents may contribute to cardiac electrical activity and cell volume regulation. Identification of selective Mockers would aid in understanding the functional contribution(s) of this current.
Methods and Results: Dog atrial cells were used to investigate the pharmacologic properties of the swelling-induced chloride current. Whole cell patch clamp was used. Swelling-induced chloride current was activated by osmotic stress. Initially, the chloride selectivity and calcium independence of the swelling-induced current in dog atrial cells was demonstrated. Subsequently, a number of putative chloride channel blockers were examined. Anthracene-9-earboxylic acid (1mM) and dideoxyforskolin (1000 μ) and extracellular cAMP (5mM) were found to partially inhibit the swelling-induced chloride current (∼50%, 80%, and 10% inhibition, respectively). Niflumic acid (100 μ), nitrophenylpropylamino benzoate (NPPB; 10 to 40 μ), and (+) 2-[(2-cydopentyl-6,7-dichloro-2,3-dihydro-2-melhyl-1-oxy-1H-inden-5-yl)oxy] acetic acid (indanyloxyacetic acid; IAA-94; 100 μ) could fully inhibit the swelling-induced chloride current without decreasing cell size. DIDS (100 μ) and dinitrostilbene disulfonic acid (DNDS;5 mM) fully inhibited outward currents but only partially inhibited inward current.
Conclusions: Niflumic acid, IAA-94, and NPPB were identified as full blockers of cardiac swelling-induced chloride current. Nonspecific effects were identified for each of the full blockers. Experiments that use these agents as functional antagonists should be carefully designed and interpreted with caution.     

Birthweights in the Faroe Islands: possible role of isovaleric acid

A high intake of n-3 polyunsaturated fatty acids has been suggested as a factor in prolonged gestation in the population of the Faroe Islands. It is now suggested that isovaleric acid from pilot whales, a species frequently consumed in the Faroe Islands, may be the unusual dietary factor. Fatty acid data for eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) in blood lipids of Faroese and Norwegians is reviewed in terms of the type of fish eaten, apparently mostly lean white fish with DHA much greater than EPA. The popular lean fish, thus, probably provides too little EPA to produce a marked effect on human biochemistry.     

非溃疡性消化不良病人胃粘膜分泌维生素C的研究

目的：研究非溃疡性消化不良病人胃粘膜分泌维生素Ｃ（ＶｉｔＣ）的变化以及与幽门螺杆菌（Ｈｐ）感染、胃酸分泌、年龄和性别的关系。方法：用高铁还原法测定血浆和胃液中ＶｉｔＣ浓度，以１小时内ＶｉｔＣ从血液到胃液中的清除率代表胃粘膜分泌Ｖｉｔｃ的能力。结果：胃粘膜的ＶｉｔＣ分泌与Ｈｐ感染与否无关（Ｐ＞０．０５）：ＶｉｔＣ分泌与胃酸分泌呈明显正相关（ｒ＝０．８４），在给五肽胃泌素后，随着胃酸分泌的增加，ＶｉｔＣ分泌也增加：４０岁以上病人的ＶｉｔＣ分泌明显低于３９岁以下病人（Ｐ＜０．０１）。结论：胃粘膜的ＶｉｔＣ分泌不受Ｈｐ感染的影响：ＶｉｔＣ分泌与胃酸分泌明显相关；另外，ＶｉｔＣ分泌也与年龄有关，４０岁以上病人的Ｖｉｔｃ分泌明显减少，推测其胃癌发生率增高可能与ＶｉｔＣ分泌减少有关。     

Innovations in host and microbial sialic acid biosynthesis revealed by phylogenomic prediction of nonulosonic acid structure

Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of ≈1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the “unique” Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars.     

Disturbances in essential fatty acid metabolism in patients receiving long-term home parenteral nutrition

Patients receiving home total parenteral nutrition (HTPN) are at risk for the development of essential fatty acid deficiency (EFAD). This study examined the essential fatty acid status of patients on long-term HTPN for gut failure. Serum phospholipid and triglyceride fatty acids were measured in 11 patients and 10 healthy volunteers. Patients had similar levels of linoleic acid (18:2w6) in serum triglyceride fatty acids but significantly lower levels of 18:2w6 in serum phospholipids compared to controls. Although there was accumulation of Mead acid (20:3w9) in both fatty acid fractions, the ratio of 20:3w9 to arachidonic acid (20:4w6) remained less than 0.2, reflecting an adequate essential fatty acid status in these patients. There were, however, substantial increases in 20:4w6 content in both triglyceride and phospholipid fractions in serum despite the lower levels of 18:2w6 in serum phospholipids, suggesting that an accelerated hepatic conversion of 18:2w6 to 20:4w6 occurs in HTPN patients, as well as the 20-carbon members of w3 (20:3w3) and w9 (20:3w9) families. The determination of optimal parenteral fat intakes should be investigated further as important priority in patients receiving long term HTPN.     

肝硬化及非肝消化病患者胆酸,透明质酸及层粘蛋白的变化

目的:研究血清胆酸(CG)、透明质酸(HA)及层粘蛋白(LN)对肝硬化及非肝消化病的诊断意义.方法:用放射免疫法检测血清CG、HA及LN,并计算它们之间的相关系数.结果:肝硬化患者血清CG、HA及LN明显高于健康人及非肝消化病组,差别有高度显著性,HA与LN存在正相关关系.结论:联合检测CC、HA及LN对肝硬化非盯消化病具有重要的意义.     

9-顺维甲酸诱导的肺癌细胞RXRs受体转录水平的变化

目的：检测用9-cis-RA处理前后肺腺癌细胞株PG和A549维甲酸受体RXR。不同时相的表达变化。方法：将两细胞株分别分为9-cis-RA组和对照组，应用细胞计数方法统计每组各时相细胞数，相对定量RT-PCR方法检测组加药前后RXRS各亚型在不同时相的表达变化。结果：加入9-cis-RA后，PG和A549细胞RXRS mRNA转录水平检测结果显示：（1）RXRγ在两细胞株中均有一定水平的基础转录，而RXRα、RXRβ均无基础转录。（2）应用1uM 9-cis-RA后，两细胞株的RXRγ有短暂增高，其余受体转录无明显变化。结论：RXRγ可能参与介导9-cis-RA对两细胞株的诱导分化和凋亡作用。     

Effects of ascorbic and dehydroascorbic acid on the multiplication of tumor ascites cells in vitro

Summary The effects of AA and DHA on ATP C⁺ cell multiplication in vitro were studied by measuring incorporation of ³H thymidine into DNA. The results obtained demonstrate that both AA and DHA have the same effects: they favor cell multiplication at low doses and inhibit it at high doses. Experiments carried out with serial doses of both these substances revealed that AA is more efficient in determining both stimulating and inhibiting effects. The lesser efficiency of DHA may be attributed to its limited stability in culture medium. Studies on the effect of high doses of AA and DHA added to the culture medium in single or fractionated doses revealed that fractionated administration is more efficient in inhibiting cell multiplication than single administration.Abbreviations AA ascorbic acid - DHA dehydroascorbic acid - ATP C⁺ ascites tumor Perugia in Balb C⁺ mice - GSH reduced glutathione     

软脂酸和花生四烯酸对人肝细胞瘤细胞株细胞葡萄糖摄取的影响

脂肪酸对人肝细胞瘤细胞株(HepG2)细胞葡萄糖摄取研究显示，高浓度的软脂酸可通过抑制HepG2细胞胰岛素受体和葡萄糖转运子2的表达抑制胰岛素刺激的葡萄糖摄取；花生四烯酸可通过类似机制刺激葡萄糖摄取，部分阻断软脂酸的作用。     

Ileal absorption of bile acids in patients with chronic cholestasis

The effect of cholestasis on ileal bile acid absorption is controversial in animal models (up-or down-regulation) and unknown in humans. We therefore studied values of the selena homotaurocholic acid (SeHCAT) test before and after long-term administration (>3 months, 13–15 mg/kg/day) of ursodeoxycholic acid (UDCA) in 27 patients with chronic cholestatic liver diseases (24 women, 3 men; mean age, 50 years; 24 primary biliary cirrhosis, 2 secondary biliary cirrhosis, 2 others). The control group consisted of 14 healthy volunteers. Seven-day SeHCAT percentage retention was identical in the 12 untreated cholestatic patients (serum bilirubin, 75 ± 42 µmol/L, alkaline phosphatase, 4.2 ± 1.0N; mean ± SEM) and in the control group (43.6 ± 2.9 and 43.8 ± 4.2%, respectively). In the 22 patients treated by UDCA for 38 ± 8 months, SeHCAT percentage retention was 20.3 ± 3.0%. In the seven patients with the SeHCAT test done before and after UDCA treatment (16 ± 5 months), SeHCAT percentage retention decreased significantly under UDCA therapy (42.0 ± 4.4 vs 19.4 ± 4.1%; P < 0.02). We conclude that, in patients with chronic cholestasis (1) SeHCAT percentage retention is not altered—taken together with the known defect of biliary excretion, this lack of increase in SeHCAT percentage retention argues against up-regulation of bile acid ileal transport; and (2) UDCA treatment induces a decrease in the SeHCAT percentage retention—this effect may be related primarily to a decreased bile acid ileal absorption.     

Regional Postprandial Differences in pH Within the Stomach and Gastroesophageal Junction

Our objective was to determine regional differences in intragastric pH after different types of meals. Ten normal subjects underwent 27-hr esophagogastric pH monitoring using a four-probe pH catheter. Meals were a spicy lunch, a high-fat dinner, and a typical bland breakfast. The fatty dinner had the highest postprandial buffering effect, elevating proximal and mid/distal gastric pH to 4.9 ± 0.4 and 4.0 ± 0.4, respectively, significantly (P< 0.05) higher compared to 4.2 ± 0.3 and 3.0 ± 0.4 for the spicy lunch and 3.0 ± 0.3 and 2.5 ± 0.8 for the breakfast. The buffering effect of the high-volume fatty meal to pH > 4 was also longer (150 min) compared to that of the spicy lunch (45 min) and the bland breakfast, which did not increase gastric pH to > 4 at any time. Proximal gastric acid pockets were seen between 15 and 90 min postprandially. These were located 3.4 ± 0.8 cm below the proximal LES border, extending for a length of 2.3 ± 0.8 cm, with a drop in mean pH from 4.7 ± 0.4 to 1.5 ± 0.9. Acid pockets were seen equally after the spicy lunch and fatty dinner but less frequently after the bland breakfast. We conclude that a high-volume fatty meal has the highest buffering effect on gastric pH compared to a spicy lunch or a bland breakfast. Buffering effects of meals are significantly higher in the proximal than in the mid/distal stomach. Despite the intragastric buffering effect of meals, focal areas of acidity were observed in the region of the cardia–gastroesophageal junction during the postprandial period.     

Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids

Animal studies suggest that increased consumption of the long-chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, can protect against the development of obesity in animals exposed to an obesogenic diet and reduce body fat when already obese. There is also evidence that increased intakes of these fatty acids can reduce body fat in humans, but human studies are relatively few and have generally been conducted over short time periods with small sample sizes, making it difficult to draw definitive conclusions. Reported reductions in body fat may result from appetite-suppressing effects, adipocyte apoptosis and changes of gene expression in skeletal muscle, heart, liver, intestine and adipose tissues that suppress fat deposition and increase fat oxidation and energy expenditure. We conclude that increased intakes of long-chain omega-3 fatty acids may improve body composition, but longer-term human studies are needed to confirm efficacy and determine whether increasing omega-3 intakes might be an effective strategy to combat obesity.     

口服支链氨基酸治疗肝硬化低蛋白血症多中心总结

为验证口服支链氨基酸治疗肝硬化低蛋白血症的疗效,将149例患者随机分为两组,A组口服支链氨基酸,B组口服复方氨基酸胶囊,疗程9周。结果表明:A组血清白蛋白水平由治疗前(32.25±3.11)g/dl升高到(37.61±5.13)g/dl(P<0.05);B组血清白蛋白由治疗前(32.12±2.04)g/dl升高到(36.64±4.66)g/dl(P<0.05),两组对比,支链氨基酸组血清白蛋白升幅明显高于对照组。两组均未发生严重不良反应。因此,支链氨基酸是一种安全有效的提升肝病患者白蛋白水平的药品。     

Arabidopsis lipins mediate eukaryotic pathway of lipid metabolism and cope critically with phosphate starvation

Phosphate is an essential nutrient for plant viability. It is well-established that phosphate starvation triggers membrane lipid remodeling, a process that converts significant portion of phospholipids to non-phosphorus-containing galactolipids. This remodeling is mediated by either phospholipase C (PLC) or phospholipase D (PLD) in combination with phosphatidate phosphatase (PAP). Two PLC genes, NPC4 and NPC5, and PLD genes, PLDζ1 and PLDζ2, are shown to be involved in the remodeling. However, gene knockout studies show that none of them plays decisive roles in the remodeling. Thus, although this phenomenon is widely observed among plants, the key enzyme(s) responsible for the lipid remodeling in a whole plant body is unknown; therefore, the physiological significance of this conversion process has remained to be elucidated. We herein focused on PAP as a key enzyme for this adaptation, and identified Arabidopsis lipin homologs, AtPAH1 and AtPAH2, that encode the PAPs involved in galactolipid biosynthesis. Double mutant pah1pah2 plants had decreased phosphatidic acid hydrolysis, thus affecting the eukaryotic pathway of galactolipid synthesis. Upon phosphate starvation, pah1pah2 plants were severely impaired in growth and membrane lipid remodeling. These results indicate that PAH1 and PAH2 are the PAP responsible for the eukaryotic pathway of galactolipid synthesis, and the membrane lipid remodeling mediated by these two enzymes is an essential adaptation mechanism to cope with phosphate starvation.     

Hepatoprotection in ethinylestradiol-treated rats is provided by tauroursodeoxycholic acid,but not by ursodeoxycholic acid*

Abstract Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been suggested as potential treatments for drug-induced cholestasis. It was therefore decided to study the effects of administration of UDCA or TUDCA on individual serum bile acid concentrations, conventional liver tests and associated hepatic ultrastructural changes in ethinylestradiol-treated (EE) rats (5 mg/kg per day). Control rats were treated s.c. with propylene glycol. EE-treated rats were randomly assigned to receive daily i.p. injections of placebo, TUDCA or UDCA. Four rats in each group were treated for 4 consecutive days, and a second four for 14 days. After 4 days of treatment, the serum levels of cholic acid and taurocholic acid were significantly increased in EE-treated rats. None of the conventional liver tests were significantly different among the four groups. After 14 days of treatment the serum levels of cholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, bilirubin, alkaline phosphatase and gamma glutamyltransferase were significantly raised in EE and EE plus UDCA treated rats. EE plus TUDCA treated rats, however, had no significant changes in these individual serum bile acids or conventional liver tests. The ultrastructure of livers from EE plus TUDCA treated rats was similar to those of controls. On the other hand, EE and EE plus UDCA rats both showed a significant reduction in sinusoidal microvilli. These results show that treatment of rats for 4 days with EE induces significant rises in the serum concentrations of two individual bile acids and that TUDCA protects against this. On treatment over 14 days TUDCA provides protection against changes in several biochemical liver tests as well as ultrastructural hepatoprotection. Treatment with UDCA, however, afforded no such protection.     

Tauroursodeoxycholic acid enhances phagocytosis of the cultured rat Kupffer cell

BACKGROUND: Ursodeoxycholic acid is used in the treatment of acute and chronic intrahepatic cholestasis because it ameliorates cholestasis and protects hepatocytes. However, few studies have examined the effect of bile acids on the function of Kupffer cells. METHODS: The effect of various bile acids on cultured rat Kupffer cells was studied in terms of phagocytic activity in response to latex particles and morphological alterations. Video-enhanced differential interference contrast microscopy was used. RESULTS: Taurochenodeoxycholic acid and taurodeoxycholic acid reduced the number of latex particles incorporated into Kupffer cells, but taurocholic and tauroursodeoxycholic acids enhanced phagocytosis of latex particles. Inhibition of phagocytosis by taurochenodeoxycholic acid or taurodeoxycholic acid was essentially dose dependent. Tauroursodeoxycholic acid also enhanced phagocytosis by Kupffer cells in which phagocytosis had been reduced by pretreatment with taurochenodeoxycholic acid or taurodeoxycholic acid. Incorporated latex particles had a distinct translocation speed of 0.084+/-0.024 microm/s (mean maximum speed+/-SD); the speed was in the same range with tauroursodeoxycholic acid treatment. Tauroursodeoxycholic acid induced a 56% expansion of cytoplasm, associated with increased ruffling and movement of intracellular organelles. CONCLUSIONS: These observations suggest that tauroursodeoxycholic acid enhances membrane trafficking without changing translocation speed.     

Relationships of Fatty Acids,Delta-5 Desaturase Activity,and Lipid Profiles in Men with Acute Coronary Syndrome

Aims: We evaluated the relationship between the ratios of eicosapentaenoic acid and arachidonic acid (EPA/AA), docosahexaenoic acid (DHA)/AA, and delta-5 desaturase activity (D5D) and atherogenic lipid profiles (ALP) and coronary atherosclerosis.Methods: Polyunsaturated fatty acids (PUFA) and ALP were assessed in 436 men with the first episode of acute coronary syndrome (ACS) not take any lipid-lowering drugs. D5D was estimated as the ratio of AA to dihomogamma-linolenic acid (DGLA). These biomarkers were compared between the lower and higher levels of EPA/AA (0.41) or DHA/AA (0.93) according to the levels in Japanese general population. The thrombolysis in myocardial infarction flow (TIMI) grade of the culprit coronary artery was visually estimated during the initial angiography.Results: Approximately 70% of patients had low EPA/AA or DHA/AA. Serum levels of LDL-cholesterol, apolipoprotein B (apoB), and remnant lipoprotein cholesterol (RL-C) were significantly higher in the low EPA/AA or DHA/AA groups, while those of triglycerides and malondialdehyde-modified LDL (MDA-LDL) were significantly higher in the low EPA/AA group alone. The levels of EPA, EPA/AA, DHA/AA, and HbA1c increased and those of DGLA and apoA1 decreased with increasing number of stenotic vessels. Patients with three stenotic coronary vessels or TIMI grade ≥ 1 had significantly higher EPA levels compared with the others. The levels of LDL-cholesterol, non-HDL-cholesterol, triglycerides, small dense LDL-cholesterol, RL-C, MDA-LDL, apoB, and apoE decreased progressively and those of EPA, DHA, EPA/AA and HDL-cholesterol increased as D5D increased.Conclusions: The EPA/AA is a superior risk marker than DHA/AA in term of correlation with ALP in ACS patients.