Serum adiponectin and progranulin levels are associated with gallstone disease.

BACKGROUND/AIM: Aberrant adipokine serum concentrations are associated with a variety of obesity-related diseases. This study was designed to investigate the putative role of the adipokines adiponectin, chemerin, progranulin, vaspin, fibroblast growth factor 21 (FGF21) and adipocyte fatty acid binding protein (AFABP) in gallstone disease. METHODS: Serum levels of adiponectin, chemerin, progranulin, vaspin, FGF21 and AFABP of 189 gallstone patients and 833 healthy controls were measured by enzyme-linked immunosorbent assays. RESULTS: Increased adiponectin levels were nominally associated with lower gallstone risk in women (p=0.036, odds ratio (OR) 0.47, 95% confidence interval (CI) [0.23; 0.95]). Furthermore progranulin serum concentrations in men were significantly elevated in gallstone carriers in comparison to controls (p=0.012, OR 6.1, 95% CI [1.5; 24.9]). Serum levels of chemerin, vaspin, FGF21 and AFABP did not differ between controls and subjects with gallstones. CONCLUSION: Our data further support a protective effect of adiponectin on gallstone risk and suggest a role of progranulin in the pathophysiology of cholelithiasis. Nevertheless, longitudinal data and functional analyses would be required to assess the pathogenetic link between gallstone formation and adipokine serum levels.

[Complications of liver cirrhosis]. / Komplikationen der Leberzirrhose.

The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with ß-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation.

[Hormonal and metabolic functions of the small intestine]. / Hormonale und metabolische Funktionen des Dünndarms.

The small intestine exhibits numerous hormonal and metabolic functions. These are mediated by enteroendocrine cells that are expressed in addition to enterocytes in the mucosa of the small intestine. The release of cholecystokinin causes the secretion of pancreatic enzymes and a contraction of the gallbladder. Recently, a hormonal regulation of gallbladder filling was confirmed. This is mediated by the hormone FGF15/19 which is secreted by enterocytes of the terminal ileum following induction of its expression by bile acids. In addition, FGF15/19 reduces synthesis of bile acids and fatty acids and inhibits gluconeogenesis. Ghrelin is the only intestinal hormone that increases food intake. Contrary, a number of hormones such as cholecystokinin and glucagon-like peptide are expressed in the small intestine and mediate satiation. Knowledge of the intestinal hormones and their functions is important for the full understanding of metabolic control and provides targets for innovative therapy of several diseases such as diabetes type 2, non-alcoholic steatohepatitis and obesity.

[A 32-year-old patient with diarrhoea and acute kidney failure]. / 32-jähriger Patient mit Durchfall und akutem Nierenversagen.

A 32-year-old male patient presented in the emergency department of our hospital with acute vomiting and diarrhoea. He reported occasional non-severe diarrhoea over several years in the past. Furthermore, at the time of presentation the patient had had anuria for several days. A prerenal and postrenal origin of the renal failure was excluded. A renal biopsy was performed and histopathological examination displayed findings consistent with a haemolytic-uraemic syndrome but no signs of glomerulonephritis. MRI examination of the small bowel revealed inflammatory alterations typical for Crohn's disease, even without histological verification. We describe haemolytic-waemic syndrome as manifestation of Crohn's disease for the first time.

Mapping cholesterol gallstone susceptibility (Lith) genes in inbred mice.

The individual risk for developing cholesterol gallstones in response to specific environmental factors is determined by complex genetics involving multiple genes. In this review, we introduce inbred mice as a model to localise and identify the murine genes that harbour cholesterol gallstone susceptibility alleles (Lith genes). These genes are associated with increased risk of gallstone formation when mice are fed a lithogenic diet containing cholesterol and cholic acid. We summarise the steps involved in localising the chromosomal regions that harbour Lith genes, focusing particularly on the initial step known as quantitative trait locus mapping, which employs breeding crosses of gallstone-susceptible and gallstone-resistant inbred mouse strains. Subsequent steps to narrow the chromosomal regions of the quantitative trait loci and identify the underlying Lith genes are outlined, with particular reference to the examples of Lith1 and Lith2, the first discovered quantitative trait loci associated with murine cholesterol cholelithiasis. We have now reported five quantitative trait loci for murine cholelithogenesis, which are officially named Lith1 through Lith5. Once the genes underlying these quantitative trait loci and other chromosomal loci from ongoing mouse crosses are identified and confirmed, the 'road-map' for discovery of orthologous human LITH genes will be available and, thereafter, their putative roles in cholesterol gallstone formation can be tested in selected human populations.

Concomitant blockade of P2X-receptors and ecto-nucleotidases by P2-receptor antagonists: functional consequences in rat vas deferens.

In order to assess the consequences of a concomitant blockade of P2X-receptors and ecto-nucleotidases, effects of 13 P2-receptor antagonists were investigated on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alpha,beta-MeATP) and ATP and on the removal of ATP from the incubation medium by vas deferens tissue. Increasing concentrations of all antagonists reduced and finally abolished contractions elicited by alpha,beta-MeATP (3 microM), with IC50-values ranging from 1.1 to 100 microM. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), 6-azophenyl-4-amino-5-hydroxy-naphthalene-1,3-disulphonate (NH02), 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS) and uniblue A also progressively reduced and finally abolished contractions elicited by ATP (1 mM). 8,8'-[Carbonylbis(imino-3, 1-phenylenecarbonyl-imino)]-bis-(1,3,5-naphthalenetrisulphonate ) (NF023), suramin, pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS), trypan blue and reactive blue 19, in contrast, caused only partial blockade, by 34-43% maximally; reactive blue 2 and reactive red 2 had no effect; and 6,6'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-4-amino-5-hydroxy-naphtha lene-1,3-disulphonate (NH01) and Evans blue even enhanced the response to ATP. For antagonists causing full or partial inhibition, the IC50-values against ATP were close to those against alpha,beta-MeATP. All antagonists attenuated the removal of ATP, with IC25%-values ranging from 0.8 microM to >320 microM. The results confirm the frequent combination, in one antagonist molecule, of P2-receptor blockade and blockade of ecto-nucleotidases. This dual action underlies the effect of such compounds on contractions of the vas deferens elicited by ATP which, for certain substances (e.g., suramin, reactive blue 2), can be explained by a simple model in which the antagonist simultaneously blocks the degradation of ATP and a single contraction-mediating receptor (P2X1). Several observations, however, do not conform with this model, and the existence of multiple contraction-mediating receptors for ATP or multiple, pharmacologically distinct ecto-nucleotidases has to be considered.

P2-purinoceptor antagonists: I. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by small aromatic isothiocyanato-sulphonates.

Effects of eight small aromatic isothiocyanato-sulphonates, of the aliphatic 2-isothiocyanatoethene-1-sulphonate (IES), and of the parent amines were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. The aromatic isothiocyanato-sulphonates all reduced contractions of the rat vas deferens elicited by alpha, beta-methylene ATP. The antagonism was non-competitive, with depression of the maximum of the concentration-response curve of alpha, beta-MeATP and incomplete reversibility. The IC50 values were between 11 and 54 microM. In the guinea pig taenia coli, the aromatic compounds shifted the concentration-response curve of ADP beta S to the right in a surmountable manner (one exception), and where three concentrations were tested, the Arunlakshana-Schild regression was linear and its slope did not differ from 1. The apparent Kd values were between 10 and 214 microM. The removal of ATP from the medium by vas deferens tissue was decreased by the aromatic isothiocyanates with IC25% values between 25 and 464 microM. IES and the parent amines were inactive or almost inactive (parent amines not tested on ATP breakdown). The results indicate that the isothiocyanato residue as well as the aromatic core are essential for P2-purinoceptor blockade. At the P2X-purinoceptor, potency increases with the size of the molecules but is independent of the position of the isothiocyanato and sulphonate substituents. No simple structure-activity relationship for the P2Y-purinoceptor and the ATP-degrading ecto-nucleotidases can be derived beyond the apparent lack of a major influence of the position of the substituents. 2-Isothiocyanatonaphthalene-1-sulphonate (beta-INS) seems to be interesting because of relatively high P2X-selectivity versus both the P2Y-purinoceptor and ecto-nucleotidases.

P2-purinoceptor antagonists: II. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by compounds related to Evans blue and trypan blue.

Effects of Evans blue and four derivatives as well as of trypan blue and four derivatives, mostly smaller fragments but two compounds with an additional ethylene bridge in the center of the molecule, were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. All compounds shifted the concentration-response curve of alpha, beta-MeATP in the rat vas deferens to the right, and most compounds increased the maximum of the curve. Each member of the Evans blue series was similar in potency to the corresponding member of the trypan blue series. Where three concentrations were tested, the Arunlakshana-Schild regression was linear, and the slope did not differ from 1. The apparent Kd values were between 0.8 and 385 microM. In the guinea-pig taenia coli, only the members of the trypan blue group were relatively potent, shifting the concentration-response curve of ADP beta S to the right in a surmountable manner. In 2 of 3 cases where three concentrations were tested, the slope of the Arunlakshana-Schild regression was lower than 1. Apparent Kd values in the trypan blue group were between 5.2 and 324 microM. The removal of ATP from the medium by vas deferens tissue was decreased mainly by the members of the Evans blue group, with IC25% values between 13 and 158 (in 1 case > 1000) microM. The results indicate that the position of the sulphonate residues at the terminal naphthalene rings of these compounds hardly influences P2X purinoceptor affinity but greatly influences P2Y affinity and ecto-nucleotidase blockade. Among active compounds, apparent purinoceptor affinity and ecto-nucleotidase blockade increase with the size of the molecules up to Evans blue and trypan blue themselves; introduction of a central ethylene bridge does not result in a further gain in potency. NH01, the desmethyl derivative of Evans blue, seems to be interesting because it is the compound with the highest P2X- versus P2Y-selectivity presently available.

P2-purinoceptor antagonists: III. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by compounds related to suramin.

Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. One compound, NF023, differed from suramin by removal of two p-methylbenzamido groups, whereas another, BSt101, differed from NF023 by additional removal of the three sulphonate residues from one of the terminal naphthalene rings. The compounds all shifted the concentration-response curve of alpha, beta-MeATP in the rat vas deferens to the right and simultaneously increased the maximum of the curve. Where three concentrations were tested, the Arunlakshana-Schild regression was linear, and the slope did not differ from 1. The apparent Kd values were between 1 and 3672 microM. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADP beta S to the right in a parallel manner, but in the one case where three concentrations were tested, the slope of the Arunlakshana-Schild regression was lower than 1. Apparent Kd values were between 10 and 786 microM. The removal of ATP from the medium by vas deferens tissue was decreased only by suramin, NF023 and BSt101, with IC25% values between 170 and 590 microM.

[The effect of starch sources barley, corn and potatoes and their ration proportions on nutrient digestibility and energy utilization in ruminants. 2. Fractions of ruminally and postruminally digested nutrients in cattle]. / Einfluss der Stärkeherkünfte Gerste, Mais und Kartoffeln und ihrer Rationsanteile auf die Nährstoffverdaulichkeit und die Energieverwertung bei Wiederkäuern. 2. Mitteilung--Anteile an ruminal und postruminal verdauten Nährstoffen beim Rind.

The investigations of this paper are part of a complex research project to develop energetic feed evaluation within the Net Energy Fat System. The aim was to obtain new results to estimate the relation between place as well as kind of nutrient digestion and energetic utilization of rations in cattle. The ruminal nutrient digestibility was measured in adult oxen on feeding level 1.7 by means of duodenal reentrant cannula for 9 rations including the starch sources barley, maize and potatoes and with their energy parts of 50, 25 and 10%. The intake of starch ranged from 484 to 2573 g/animal.d and the amounts of ruminal and postruminal digested starch from 444 to 2336 as well as 10 to 284 g/animal.d. For the organic matter, starch, water soluble carbohydrates and N free residual substances high relative parts of ruminal digested from apparent digested nutrients were measured with values between 78 and 88, 83 and 98, 93 and 97 as well as 88 and 100% respectively.

[Comparative studies of the parameters of rumen fermentation and the digestibility of feed rations in cattle and sheep. 1. Parameters of rumen fermentation]. / Ergebnisse aus vergleichenden untersuchungen von Parametern der Pansenfermentation und zur Verdaulichkeit von Futterrationen bei Rind und Schaf. 1. Mitteilung--Parameter der Pansenfermentation.

The results from 283 studies of rumen liquid, taken by means of oesophagus probe, from different species of cattle (ox, cow, male and female young cattle) and sheep (adult wether) are compared. In the rumen liquid the parts of volatile fatty acids (VFA), total VFA content, pH value and the content of NH3 and urea were analysed. In the cattle's rumen liquid the part of acetic acid is on average 2 Mol-% and the content of total VFA up to 28 mmol/l (middle of the cow--sheep comparisons) higher than in that of wether. The contents of NH3 and urea are lower in cattle than in wether. Relations between the amount of difference of characteristic rumen fluid numbers of cattle and sheep and the crude fibre content of the rations, the live weight of the young cattle and the nutrition level are considered.

[Effect of the starch sources barley, corn, potatoes and their ration fractions on the nutrient digestibility and energy utilization in ruminants. 1. Comparative studies of nutrient digestibility in cattle and sheep]. / Einfluss der Stärkeherkünfte Gerste, Mais, Kartoffeln und ihrer Rationsanteile auf die Nährstoffverdaulichkeit und Energieverwertung bei Wiederkäuern. 1. Mitteilung--Vergleichende Untersuchungen zur Nährstoffverdaulichkeit bei Rind und Schaf.

Rations with energy parts of 50, 25 and 10% from barley, maize and potatoes were investigated comparatively by means of total metabolism experiments with oxen with a view to arriving at a more precise estimation equation of net energy fat for cattle. Parallel to the investigations with oxen the energy and nutrients digestibility of the rations in wethers was measured. The crude fibre content of the rations ranged from 166 to 271 g and the starch content from 69 to 330 g/kg DM. The daily starch intake of the oxen ranged from 575 to 2739 g on nutrition level (NL) 1.7 and from 365 to 1804 g on NL 1.1. The energy digestibility of the rations in oxen with energy parts of 50% barley, maize and potatoes was on average 73.5, 73.9 and 75.3%, of the rations with energy parts of 25% on average 72.2, 71.6 and 72.4% and of the rations with energy parts of 10% on average 68.8, 69.5 and 69.8%. The digestibility of energy and nutrients in cattle and sheep was in good agreement excepted crude protein and crude fat; these were digested 4-5%-units lower from cattle than from sheep. The increase of the nutrition level by one unit lowered the digestibility of rations with energy parts of 50 and 25% from concentrates in cattle about 3-6 units and of rations with energy parts of 10% from concentrates about one %-unit. Information about rumen physiological data is given comparatively between cattle and sheep.

[The energetic utilization of rations with dried concentrates, potatoes, sugar beets, apple pectin and cane sugar by growing, intact and ileorectostomized swine. 1. Results in swine with ileorectal anastomoses]. / Untersuchungen zur energetischen Verwertung von Rationen mit Trockenkonzentraten, Kartoffeln, Zuckerrüben, Apfelpektin und Rohrzucker durch wachsende, intakte und ileorektostomierte Schweine. 1. Mitteilung. Ergebnisse an Schweinen mit Ileo-Rektal Anastomosen.

Rations with dried feedstuffs and rations with between 30 and 50% raw potatoes in the dry matter as well as steamed potatoes and sugar beets, sucrose and apple pectin were tested in measurings of the total metabolism in growing pigs with ileo-rectal anastomoses. The prececal digestibility of the energy of the rations ranged between 42% (rations with raw potatoes) and 79% (rations with sucrose). The digestibility of the rations with a 50% quota of steamed potatoes was better by 30%--units than that of rations with raw potatoes. In addition to crude nutrient digestibility, data are given on the digestibility of starch, water soluble carbohydrates and pectin. The wide variation in the N retention of 6-25 g/animal.day can only be partly connected with energy retention. Urine energy amounted to between 2.5 and 5% of gross energy. The average utilization of metabolizable energy amounted to 69.4%. A connection is to be seen with the value of energy maintenance requirement of 646 kJ retention energy/kg LW0.62.d.

[Energetic utilization of sugar beets, dried shreds, sucrose and apple pectin by growing swine. 1. Study overview and composition and digestibility of feed and rations]. / Untersuchungen zur energetischen Verwertung von Zuckerrüben, Trockenschnitzeln, Rohrzucker und Apfelpektin durch wachsende Schweine. 1. Mitteilung. Versuchsübersicht sowie Zusammensetzung und Verdaulichkeit der Futtermittel und Rationen.

Total metabolism experiments with a basic ration were carried out over two measuring periods and with a basic ration plus supplements of raw sugar beets, steamed sugar beets, dried sugar beet pulp, sucrose and apple pectin resp. with 4 pigs per test group and 4 test groups (LW 40-135 kg). Live weight gain was approximately equal after the feeding of raw and steamed sugar beets. It amounted to 650 g/animal and day in the first experimental period and to 715 g in the second. After feeding dried sugar beet pulp as supplement the corresponding weight gain was 525 and 565 g/animal and day. In the course of the ontogenetic development up to a live weight of about 70 kg an increase of digestibility could be observed. Adaptation cannot be excluded. This question will be pursued in the following experiments, so that consequences for energetic feed evaluation have to be postponed. For both raw and steamed sugar beets the digestibility of the organic matter was 88%, of NFE 95% and of water soluble carbohydrates 95%.

Methodological studies on the formation of CO2 and volatile fatty acids in porcine ileo-chyme and faeces.

As part of digestibility and energy metabolism studies in intact and ileorectostomized growing pigs model experiments were carried out on sampling techniques and the influence of storage conditions on CO2 and volatile fatty acid production in chyme. Results on the formation of CO2 and VFA in chyme and faeces are given. They indicate that chyme from the small intestine can be subjected to bacterial and enzymatic changes outside the animals and therefore must be stored in a cool place. In the chyme of IRA animals with closed colon descendens (end-to-end anastomosis) significantly reduced VFA contents were found in comparison to animals with open colon descendens (end-to-side anastomosis).

[The energy preservation requirement of growing pigs of different sexes fed normal and high protein diets. 4. Determination of parameters in the blood for estimating metabolic status]. / Untersuchungen zum Energieerhaltungsbedarf wachsender Schweine verschiedenen Geschlechts bei normalen und hohen Proteingaben. 4. Mitteilung. Bestimmung von Kennwerten im Blut zur Beurteilung der Stoffwechsellage.

In connection with experiments for the ascertainment of energy and nutrient metabolization in castrated pigs, sows and boars over the complete fattening period and with alternating maintenance and growth feeding as well as the inclusion of an extreme protein supply level, blood parameters were studied of 3 animals per variant in order to recognize possible deviations in the metabolism and to be able to better assess the results of the measurements of energy metabolism. The results of the determination of the content of glucose, insulin, ketoses, ammonia, urea and amino acids in the blood are announced, the results of glucose elimination contained in the intravenous glucose tolerance test are depicted as tolerance curves. As a result, there was to be seen, arranged according to animal categories, a ranking of the glucose elimination rate of castrated pigs greater than sows greater than boars. The same sequence was observed with regard to insulin secretion, which corresponds to the blood sugar level. On the whole, the results of the blood tests do not show critical states of the metabolism hat can lead to an influentiation of energy metabolism.

[The energy preservation requirements of growing pigs of different sexes fed normal and high protein diets. 5. Comparison with the results obtained from castrated pigs, sows and boars]. / Untersuchungen zum Engergieerhaltungsbedarf wachsender Schweine verschiedenen Geschlechts bei normalen und hohen Proteingaben. 5. Mitteilung. Vergleich der an Kastraten, Sauen und Ebern erhaltenen Ergebnisse.

In one experiment each with castrated pigs, sows and boars (hybrid pigs of line 150), two groups of six animals received rations containing 17 and 45% crude protein resp. over the complete test period from 35 to 130 kg (castrated pigs), 150 kg (sows), 170 kg live weight (boars) and passed alternatively through a total of 60 metabolism periods on growth and 48 on maintenance level. There were significant differences between the 3 categories of animals with regard to energy maintenance requirement in the relation of 100:105:110 for castrated pigs less than sows less than boars. In contrast to the estimated values derived from previous studies for energetic maintenance requirement of 650 kJ/kg LW0.62.d the measured values for all 3 animal categories are by approximately 50% higher. The protein content did not have an influence on the maintenance requirement of metabolizable energy of the animals. The utilization of metabolizable energy of the two rations for body energy retention corresponds to the expectations with regard to its dependence on nutrients. The requirement of metabolizable energy for protein and fat retention is 1.7:1.0. The energy content of the weight gain of boars was, on average, 85% of that of castrated pigs and sows. The studies of blood parameters did not show any deviations in the parameters tested.

[The energy requirement of heifers. 4. Comparison of the digestibility and rumen physiologic parameters in heifers and full-grown sheep]. / Untersuchungen zum Energiebedarf weiblicher Jungrinder. 4. Mitteilung. Vergleich der Verdaulichkeit und pansenphysiologischer Kennwerte bei weiblichen Jungrindern und ausgewachsenen Schafen.

In 159 comparative studies with fully grown sheep and heifers of the digestibility and of rumen physiologic values at a variation of the feed ration in the crude fibre content between 112 and 318 g, in the crude protein content between 94 and 194 g and in the content of nitrogen free extractive between 484 and 641 g/kg DM is provided that the digestibility of energy in heifers was, on average, 4 digestibility units lower than in sheep. The corresponding values for the digestibility of crude protein and crude fibre are 12 and 3.5 digestibility units. Due to the lower methane energy excretion of the heifers the difference at the level of metabolizable energy is reduced to 1.5% of the gross energy. The level of the differences in digestibility is influenced by the development of the young cattle and the composition of the rations. In young cattle of the live weight range between 100 and 150 kg the digestibility of the energy is 6-8 units lower than in sheep. A higher crude fibre content in the ration diminishes the difference in the digestibility of energy and the nutrients between the two animal species.