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Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

Background Severe aortic stenosis (AS) is associated with left ventricular (LV) pressure overload that leads to myocardial remodelling and inflammatory processes. Interleukin 6 (IL6) is secreted by leukocytes as an early response to infection and tissue damage as well as high senisitve C-reactive Protein (hsCRP), which is subsequent in the same pathway. Several studies have suggested an association of elevated serum levels with a higher risk of cardiovascular events. GDF-15 and MR-proADM are also associated with inflammatory processes in cardiovascular diseases and are predictors for adverse events and mortality in patients with AS. The aim of the present study was to evaluate their potential prognostic value regarding the patients all-cause mortality. Methods A total of 92 consecutive patients (mean age: 80,8 [±5,3] years) undergoing TAVI were included in this study. TAVI was performed according to standard clinical practice. Venous blood samples for biomarker analysis were collected prior to and 6 months after TAVI, these were processed immediately and frozen at −80°C until the assay was performed. Safety events, physiological- and echocardiographical parameters, were assessed at the baseline and the 6-month follow-up. Furthermore, we compiled the all-cause mortality of our patients after two years. Results TAVI was performed successfully in all patients. During the two-year follow-up period 24 patients met the endpoint of all-cause mortality. At baseline, serum levels of the inflammatory biomarkers were significantly higher in patients who died within the follow-up period, when compared to survivors (IL6:14,450pg/ml [IQR:7,550; 42,150] vs. 4,200pg/ml [IQR:2,515; 13,875],p=0,0004; hsCRP:5,360 mg/l [IQR:2,248; 26,790] vs. 2,900mg/l [IQR:1,208; 8,210],p=0,022); MR-proADM:1,347nmol/l [IQR:1,038–1,678] vs. 0,922nmol/l [IQR:0,706; 1,202],p=0,0003 and GDF-15:2770,0pg/ml [IQR:2401,0; 3701,0] vs. 1675,2pg/ml [IQR:1141,6; 2524,4],p=0,001). The area under the curve was 0,767 for IL-6, 0,665 for hsCRP, 0,735 for MR-proADM and 0,735 for GDF-15. In addition, there was a significant decrease of IL-6 (baseline: 4,200pg/ml [IQR:2,525; 13,875] vs. 6FU:2,600pg/ml [IQR:1,500; 7,000],p Conclusions In the present study there was a significant decrease of inflammatory biomarkers after TAVI in high risk patients with severe aortic stenosis and good clinical outcome. In this regard, IL-6, hsCRP, MR-proADM and GDF-15 were predictors of all-cause mortality in patients, who underwent TAVI. Funding Acknowledgement Type of funding sources: None.

International audience; Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so-called bile infarcts that correspond to Charcot-Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon-based imaging of BDL mice was performed with fluorescent bile salts (BS) and non-BS organic anion analogues. Key findings were followed up by matrix-assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1-3 days after BDL, BS concentrations in bile increased and single-cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a "domino effect" of further death events of neighboring hepatocytes. Bile infarcts provided a trans-epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS-overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in. (Hepatology 2019;69:666-683). SEE EDITORIAL ON PAGE 473 R ecently, the concept of an ascending patho-physiology of cholestatic liver disease has been proposed, whereby lesions start in large or small bile ducts followed by the involvement of upstream structures, such as the bile canalicular network and liver parenchyma. (1) Our knowledge of the responses of the biliary tree to cholestasis stems mainly from studies in rodents after bile duct ligation

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 μm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

Sepsis in the early stage is a common disease in emergency medicine, and rapid diagnosis is essential. Our aim was to compare pathogen diagnosis using blood cultures (BC) and the multiplex polymerase chain reaction (PCR) test.Methods. At total of 211 patients admitted to the multidisciplinary emergency department of our university hospital between 2006 and 2009 with suspected severe infection from any origin were studied. Blood samples for BC (aerobic and anaerobic) and multiplex PCR were taken for identification of infectious microorganisms immediately after hospital admission. Results of the BC and PCR correlated with procalcitonin concentration (PCT) and clinical diagnosis of sepsis (≥2 positive SIRS criteria) as well as with severity of disease at admission and with clinical outcome measures.Results of the BC were available in 200 patients (94.8%) and PCR were available in 119 patients (56.3%), respectively. In total, 87 BC (43.5%) were positive and identified 94 pathogens. In 45 positive PCRs, 47 pathogens (37.8%) were found. Identical results were obtained in 81.4%. In addition, BC identified 9 Gram-positive and 3 Gram-negative bacteria, while PCR added 5 Gram-negative pathogens. Coagulase-negative staphylococci were detected in blood cultures only (n=20, 21.3%), whereas PCR identified significantly more Gram-negative bacteria than BC. In patients with positive PCR results, the PCT level was significantly higher than in patients with negative PCR (15.0±23.3 vs. 8.8±32.8 ng/ml, p0.001). This difference was not observed for BC (10.6±25.7 vs. 11.6±44.9 ng/ml, p=0.075). The APACHE II score correlated with PCR (19.2±9.1 vs. 15.8±8.9, p0.05) and was also higher in positive BC (18.7±8.7 vs. 14.4±8.0, p0.01). Positive PCR and BC were correlated with negative clinical outcomes (e.g., transfer to ICU, mechanical ventilation, renal replacement therapy, death).In patients admitted with suspected severe infection, a high percentage of positive BC and PCR were observed. Positive findings in the PCR correlate with elevated levels of PCT and high APACHE II scores.

BACKGROUND Vaccination rates in adolescents in Germany are not sufficient. An intervention programme, which has been launched by the community health centre in Essen, should significantly increase vaccination coverage. METHODS In 2001 the Children and Youth Health Service at the Community Health Centre in Essen implemented a specific strategy to improve vaccination rates in adolescents. Vaccination rates were determined by control of vaccination certificates of all 6 (th) graders in Essen (n=5 589). After control of vaccination records the parents got a written, individual vaccination counselling for their child as well as a referral to the paediatrician to get the missing vaccinations. After 6 months the vaccination certificates were looked at again and vaccination coverage was determined. RESULTS At the initial vaccination record control of 6 (th) graders in 2001 only 15% of the students, who presented their vaccination certificate, had an appropriate age related immunisation status. 84% of the students had had the tetanus/diphtheria and polio booster. But only 43% had been given a second measles, mumps and rubella (MMR) immunisation and only 24% had a complete hepatitis B coverage. The intervention programme (e. g., individual vaccination counselling) improved vaccination rates for hepatitis B and MMR by 16%. From 2001 to 2008 vaccination coverage in this age group could be improved from 43% to 87% for the second MMR vaccination and from 24% to 85% for hepatitis B. CONCLUSIONS A remarkable improvement in vaccination coverage in children and adolescents could be achieved by a single, individual, written vaccination reminder. As a prerequisite a good cooperation between schools/paediatricians and the health authorities is needed.

Tetrahydroxy bile acids become major biliary bile acids in Bsep(−/−) mice and Fxr(−/−) mice fed cholic acid; we characterized disposition of these novel bile acids that also occur in patients with cholestasis. We investigated mouse Mrp2 (mMrp2) and P-glycoprotein [(P-gp) mMdr1a]-mediated transport of a tetrahydroxy bile acid, 6α-OH-taurocholic acid (6α-OH-TC), and its biliary excretion in wild-type and Mrp2(−/−) mice in the presence or absence of N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), a P-gp and breast cancer resistance protein inhibitor. 6α-OH-TC was rapidly excreted into bile of wild-type mice (78% recovery); coinfusion of GF120918 had no significant effect. In Mrp2(−/−) mice, biliary excretion was decreased (52% recovery) and coinfusion of GF120918 further decreased these values (34% recovery). In wild-type, but not Mrp2(−/−), mice, 6α-OH-TC increased bile flow 2.5-fold. Membrane vesicle transport studies of 6α-OH-TC (0.05–0.75 mM) yielded saturation kinetics with a higher apparent affinity for mMrp2 (Km = 0.13 mM) than for mMdr1a (Km = 0.33 mM); mBsep transported 6α-OH-TC with positive cooperativity (Hill slope = 2.1). Human multidrug resistance-associated protein (MRP) 2 and P-gp also transported 6α-OH-TC but with positive cooperativity (Hill slope = 3.6 and 1.6, respectively). After intraileal administration, the time course of 6α-OH-TC biliary recovery was similar to that of coinfused taurocholate, implying that 6α-OH-TC can undergo enterohepatic cycling. Thus, Mrp2 plays a key role in 6α-OH-TC biliary excretion, whereas P-glycoprotein plays a secondary role; Bsep likely mediates excretion of 6α-OH-TC in the absence of Mrp2 and P-gp. In Bsep(−/−) mice, efficient synthesis of tetrahydroxy bile acids that are Mrp2 and P-gp substrates can explain the noncholestatic phenotype.

10 pages, 7 figures, 1 table, Teleosts have high olfactory sensitivity to bile salts. To assess whether this phenomenon is involved in intra-specific chemical communication alone, or is part of a more `broad range' sensitivity to bile salts produced by heterospecifics, we investigated possible differences in the odour of bile between the sexes and among different species – the eel (Anguilla anguilla), goldfish (Carassius auratus) and Mozambique tilapia (Oreochromis mossambicus) – using the electro-olfactogram (EOG). We also identified the main bile constituents by liquid chromatography and mass spectrometry. There were marked differences in olfactory response of the eel to thin-layer chromatography fractions of bile from both sexes, and mature and immature conspecifics. Smaller differences were seen in the potency of fractions of bile from male and female goldfish and tilapia. Eels, goldfish and tilapia demonstrated similar olfactory sensitivity to bile from a range of different species, with no apparent correlation between the olfactory potency of bile and a phylogenetic closeness and/or similarity of diet of the donor to the receiver. The three species were able to detect odorants in thin-layer chromatography fractions of heterospecific bile even in the absence of activity in conspecific bile. Eels, goldfish and tilapia responded to both sulphated C27 bile salts (5β-scymnol-sulphate and 5α-cyprinol sulphate) and to taurine-conjugated C24 bile salts (taurochenodeoxycholic acid, taurolithocholic acid and taurocholic acid), irrespective of whether these bile salts were present in conspecific bile. Together, these results suggest that teleosts have a broad-range olfactory sensitivity to bile salts, with potential roles in both intra-specific chemical communication and in inter-specific interactions, This work was supported by Fundação papa a Ciência e a Tecnologia (Portugal) grants POCTI/BSE/38815/2001 and POCTI/BIA-BDE/55463/2004 (funding by the European Union Fonds Social Européen de Dévelopement Régional and the Ministério da Ciência e do Ensino Superior). M.H. was a recipient of a fellowship from the Instituto Nacional de Investigación y Tecnologia Agraria y Alimentaria (Spain)

NorUDCA (24-norursodeoxycholic acid), the C-23-homolog of ursodeoxycholic acid (UDCA), showed remarkable therapeutic effects in cholestatic Mdr2 (Abcb4) (multidrug resistance protein 2/ATP-binding cassette b4) knockout mice with sclerosing/fibrosing cholangitis. In contrast to UDCA, norUDCA is inefficiently conjugated in human and rodent liver, and conjugation has been discussed as a key step for the anticholestatic action of UDCA in cholestasis. We compared the choleretic, anticholestatic, and antiapoptotic properties of unconjugated and taurine-conjugated UDCA (C-24) and norUDCA (C-23) in isolated perfused rat liver (IPRL) and in natrium/taurocholate cotransporting polypeptide (Ntcp)-transfected human hepatoma (HepG2) cells. Taurolithocholic acid (TLCA) was used to induce a predominantly hepatocellular cholestasis in IPRL. Bile flow was determined gravimetrically; bile acids determined by gas chromatography and liquid chromatography/tandem mass spectrometry; the Mrp2 model substrate, 2,4-dinitrophenyl-S-glutathione (GS-DNP) was determined spectrophotometrically; and apoptosis was determined imtnunocytochemically. The choleretic effect of C-23-bile acids was comparable to their C-24-homologs in IPRL. In contrast, TnorUDCA, but not norUDCA antagonized the cholestatic effect of TLCA. Bile flow (percent of controls) was 8% with TLCA-induced cholestasis, and unchanged by coinfusion of norUDCA (14%). However, it was increased by TnorUDCA (83%), UDCA (73%) and TUDCA (136%). Secretion of GS-DNP was markedly reduced by TLCA (5%), unimproved by norUDCA (4%) or UDCA (17%), but was improved modestly by TnorUDCA (26%) or TUDCA (58%). No apoptosis was observed in IPRL exposed to low micromolar TLCA, but equivalent antiapoptotic effects of TUDCA and TnorUDCA were observed in Ntcp-HepG2 cells exposed to TLCA. Conclusion: Conjugation is essential for the anticholestatic effect of norUDCA in a model of hepatocellular cholestasis. Combined therapy with UDCA and norUDCA may be superior to UDCA or norUDCA monotherapy in biliary disorders in which hepatocyte as well as cholangiocyte dysfunction contribute to disease progression. (HEPATOLOGY 2010;52:1758-1768)

Elsewhere in this issue Julian Walters and his colleagues report a major advance in our understanding of the pathogenesis of chronic diarrhea associated with idiopathic bile acid malabsorption.1 The story is a fascinating one and unites long standing and very recent discoveries in physiology, biochemistry, and molecular biology.

In 1991, 230 cementless total hip arthroplasties (THAs) with anatomical Stolzalpe-Buchner-Graf (SBG) stems were implanted in 230 patients at our hospital. Patients were examined retrospectively and consecutively 15 years after the operations.In total, 118 patients were available for follow-up (average 12.8 +/- 3.8 years postoperatively), with 44 examined clinically/radiologically at our hospital and 74 interviewed by telephone. Five THAs needed revision (stem explantation), three for aseptic loosening. Average patient age at the time of surgery was 61 years (27-91 years). For all THAs, we implanted ceramic-to-metal heads in combination with ultra-high molecular weight polyethylene inlay (ceramic/polyethylene and metal/polyethylene articulating components).The survival rate of the SBG stem was 98.13% (CI 94.32-99.39%) with aseptic loosening as the endpoint and 96.98% (CI 92.85-98.74%) with revision and stem explantation for any other reason as the endpoint. The average Harris Hip Score was 36.0 +/- 6.9 (range 22-45) preoperatively, increasing to 88.2 +/- 15.3 (30-100) for clinically evaluated patients and 80.3 +/- 11.3 (27-91) for telephone-interviewed patients at 15 years postoperatively. Osteolysis and radiolucent lines around the prosthetic stem were rarely observed (mainly at the proximal diaphysis).These follow-up results emphasize the excellent long-term outcomes associated with the SBG stem.

In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl(-) and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl(-) secretion was measured as changes in short-circuit current across voltage-clamped T(84) cell monolayers. At high concentrations (0.5-1 mM), DCA acutely stimulated Cl(-) secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10-200 microM) inhibited responses to Ca(2+) and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids - taurodeoxycholic acid, chenodeoxycholic acid and cholic acid - had similar antisecretory effects. DCA (50 microM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity.

24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2(-/-) mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr(-/-) mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO(3)(-)-output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO(3)(-)-dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO(3)(-)-output also in Cftr(-/-) mice. In Mdr2(-/-) mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA. CONCLUSION:The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO(3)(-)-rich hypercholeresis that protects the liver from cholestatic injury

An elevated concentration in the colon of the primary bile acid chenodeoxycholic acid (CDCA) or the secondary bile acid deoxycholic acid (DCA) is known to induce water secretion, causing diarrhea. We hypothesized that of the many fecal bile acids, only CDCA and DCA function as endogenous laxatives; therefore, a decrease in their proportion may be a cause of childhood functional constipation. To test this possibility, fecal bile acid composition was determined in children with functional constipation and in nonconstipated control children.Fecal samples were obtained from 207 children, 103 with functional constipation and 104 with normal bowel habits. Bile acid classes were determined by use of electrospray ionization-single ion monitoring-mass spectrometry (ESI-SIM-MS), and individual bile acids were measured by gas chromatography (GC)-MS (GC-MS). The structure of individual sulfated bile acids was obtained by use of liquid chromatography (LC)-MS (LC-MS).By ESI-SIM-MS, the proportions of DCA did not differ in constipated children (n = 73) from that in control children (n = 92), but monosulfated dihydroxy bile acids were greater (P0.05). The difference was attributable to 6 patients in the constipated group whose major fecal bile acid by LC-MS was the 3-sulfate of CDCA. Sulfation of CDCA is known to abolish its secretory activity. By GC-MS, the bile acid profile was identical in the 2 groups.In most children with functional constipation, the fecal bile acid profile seems to be normal. There is a small subset of children, however, whose dominant fecal bile acid is the 3-sulfate of CDCA, indicating a novel disturbance in bile acid metabolism. Such sulfation abolishes the secretory activity of CDCA and may contribute to constipation.

BACKGROUND AND OBJECTIVE Nearly 50% of adults in Germany have no measurable antibody protection against diphtheria, even though most of them will have been vaccinated against it in their childhood. We investigated how vaccination should be performed in this situation to provide lasting protection. MATERIAL AND METHODS 100 adults (53 men, 47 women; mean age 27.7 [19-54] years) whose last diphtheria vaccination had been at least 10 years previously, were injected up to three times with customary commercial monovalent diphtheria vaccine for adults (5 IU toxoid/0.5 ml), at intervals of 4-8 weeks. Each time, before and 4-8 weeks after the latest injection, the antitoxin level was determined by cell-culture neutralization test. RESULTS Before the vaccination 30 of the 100 subjects had protection against diphtheria (antitoxin level > 0.1 IU/ml), 24 had "basic immunity" (0.01 to < 0.1 IU/ml), and 46 no measurable protection (< 0.01 IU/ml). After the first booster the protection threshold had not been reached in seven of the 100, all of them women. The main determinant for the pre- and post-vaccination antitoxin level was the interval since the last vaccination. In addition, women had significantly lower pre- and postvaccination levels than men. But after the second and third booster the antitoxin level of the seven women had risen to above the protection threshold, while the geometric mean of the whole collective had fallen, despite further boosters. It was 0.015 IU/ml before vaccination, 1.156 IU/ml after the first booster, 0.924 IU/ml after the second, and 0.952 after the third. CONCLUSION Those adults who were last vaccinated against diphtheria more than 20 years ago should have two booster shots, more than 8 weeks apart, so that the highest possible and most lasting antitoxin level can be achieved. Women in particular should have at least two booster shots, as their antitoxin response tends to be less than that of men.

Insbesondere Beschaftigte im Gesundheitsdienst und in Laboratorien sind dem Risiko berufsbedingter Infektionen ausgesetzt, aber auch das Personal in der Kinderbetreuung, in der Lebensmittelproduktion, im Forst- und Landwirtschaftsbereich sowie Beschaftigte in der Abfallentsorgung und in der Abwasserbehandlung. EG-Richtlinien sowie nationale deutsche Verordnungen und Empfehlungen dienen dem Zweck der Gefahrdungsbeurteilung, des Risikomanagements und der Pravention von Infektionen. In diesem Beitrag wird die derzeit ubliche Biostoffklassifikation vorgestellt. Seropravalenzdaten aus verschiedenen Bereichen des Arbeitslebens illustrieren das jeweilige Gefahrdungspotenzial. Abschliesend werden technische, organisatorische, personliche und immunologische Praventionsmasnahmen vorgestellt und diskutiert.

PURPOSE The present study examines the differences of radiological diagnosis of lumbar prolaps with quantitative and morphological criteria. Advantages and disadvantages of both methods were analysed. METHOD Concerning the "Deutsche Wirbelsaulenstudie" (DWS) 286 male and 278 female patients between 25 and 70 years of age undergoing clinical or ambulant therapy for radicular symptoms and the diagnosis of a lumbar prolaps in CT and/or MRT were integrated into our study. Actual MRT and CT pictures of the patients' lumbar spine were analysed by an independent radiologist (primary radiologist). Radiological diagnosis was concerned with quantitative and morphological criteria. Radiological images of 100 selected patients were reexamined by another radiologist (secondary radiologist). On the basis of these results, the interobserver reliability (kappa) was calculated. RESULTS In 95.2% of all segments a prolaps was seen with quantitative and morphological criteria, in 4.5% a prolaps was analysed with quantitative and in 0.3% a prolaps was seen with morphological criteria. The radiological diagnosis of prolaps by quantitative criteria was confirmed by the operative findings. Many prolapses with lateral localisation were seen in these cases. Therefore radiological diagnosis on the basis of morphological criteria could be difficult. For both radiological methods similar interobserver reliabilities were calculated. To sum up both radiological methods are even equivalent. It is also possible to graduate the diagnosis with quantitative criteria. Detrimental effects of quantitative criteria could be difficulties in measurement with non-digital images. CONCLUSION Besides several recommendations in the international literature on the radiological analysis of prolaps with morphological criteria, diagnosis with quantitative criteria is also an effective method.

Fasting levels of cholic acid conjugates were determined by radioimmunoassay in the serum of 24 patients with extensively documented Gilbert's syndrome and in 98 healthy controls without unconjugated hyperbilirubinemia. The Gilbert's syndrome patients studied included all three subtypes, as determined from studies of the plasma disappearance kinetics of sulf obromophthalein and indocyanine green. Although patients with structural liver disease severe enough to produce hyperbilirubinemia almost invariably have elevated fasting serum levels of cholic acid conjugates, values were normal in each of the Gilbert's syndrome patients, including patients with metabolic abnormalities in sulfobromophthalein and indocyanine green transport. It is concluded that the measurement of fasting serum levels of cholic acid conjugates is a useful adjunct to the diagnosis of Gilbert's syndrome.

A dose-response study was performed with three doses of colestipol, using postprandial serum bile acid levels to assess bile acid sequestering activity in 40 volunteers with asymptomatic hyperlipidaemia. Subjects who entered the study had total serum cholesterol concentrations greater than 220 mg/dl and triglyceride concentrations less than 200 mg/dl. They were randomly assigned to one of four parallel treatment groups: (a) placebo b.d., (b) colestipol (as Colestid hydrochloride granules) 2.5 g b.d., (c) colestipol 5 g b.d., and (d) colestipol 7.5 g b.d. Subjects were maintained on a constant repeating solid diet throughout the 6-day study period, and colestipol was ingested 30 min before breakfast and dinner. No drug was administered on Days 1-3; baseline (pre-treatment) serum bile acid concentration profiles were determined on Day 3. The above treatments were given on Days 4-6, and total serum bile acid concentrations were determined at 30- or 60-min intervals for 10 h on Days 4 and 6. Serum bile acids were measured using a bioluminescence procedure which enzymically measures total 3 alpha hydroxy bile acids. Serum bile acid concentrations were significantly decreased from the pretreatment period by 5.0 and 7.5 g/day as compared to 2.5 g/day or placebo. Differences from the pre-treatment period in the area under the serum bile acid time curve revealed the same trends in the data as analysis of percentage difference (Day 6 vs pre-treatment period) in serum bile acid concentrations. These results indicate that postprandial serum bile acid concentrations are influenced by colestipol in a dose-related manner, with doses of 5 and 7.5 g b.d. having a significantly greater effect than 2.5 g b.d. The dose of 7.5 g b.d. had an identical effect on serum bile acid patterns as a dose of 5.0 g t.d.s., which was previously reported. Our findings also show that changes in serum bile acid concentrations may be used to follow the immediate effects of bile acid sequestration in hypercholes terolaemic subjects, and that the bioluminescence enzyme technique is sufficiently sensitive to detect such changes.

Biliary secretion in health and disease is reviewed. The powerful techniques of molecular biology have enabled cloning of the transporters involved in biliary secretion and the enterohepatic circulation of bile acids. This, in turn has permitted elucidation of their function as well as their regulation by nuclear receptors. Bile acid secretion is required for efficient lipid absorption, and bile acids also possess powerful direct and indirect antimicrobial functions in the small intestine. The enterohepatic circulation results from efficient ileal absorption, and is highly regulated at two sites. In the hepatocyte, biosynthesis of bile acids is regulated in negative feedback manner by the nuclear receptor FXR as well as by cytokines and by a peptide (FGF-19) liberated by bile acids from the ileal enterocyte. In the ileal enterocyte, bile acid reclamation is regulated in negative feedback manner by FXR and other nuclear receptors. The bile salt export pump (BSEP) mediates uphill canalicular bile acid secretion. Inborn defects in its function cause intrahepatic cholestasis in infants; inhibition of its function by drugs causes hepatotoxicity. Bile acid therapy is based on correction of bile acid deficiency by supplemental bile acids or displacement in which a noncytotoxic bile acid (ursodeoxycholic acid, ursodiol, UDCA) is administered and dilutes out the endogenous cytotoxic bile acids. Administration of primary bile acids may be lifesaving in inborn defects of bile acid biosynthesis. A synthetic bile acid, norUDCA is absorbed by the biliary ductules after secretion and cures the peribiliary fibrosis occurring in the MDR2-/- mouse which lacks biliary phospholipid.

The aim was to develop a method for quantification of hepatobiliary uptake and secretion of conjugated bile acids using PET and the (11)C-labeled conjugated bile acid analog [N-methyl-(11)C]cholylsarcosine ((11)C-CSar).METHODS: Six pigs (13 experiments) underwent dynamic (11)C-CSar PET of the liver with measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal and hepatic venous blood. In three pigs (seven experiments) bile was collected from a catheter in the common hepatic duct (CHD). PET data were analyzed by a two-tissue compartmental model with calculation of rate constants for transport of (11)C-CSar between blood, hepatocytes and intra- and extra-hepatic bile ducts. PET results were validated against invasive blood and bile measurements.RESULTS: Directly measured secretion rate of (11)C-CSar into bile was equal to removal rate from blood at steady state. Hepatocytes accordingly did not accumulate bile acids but simply facilitated transport of bile acids from blood into bile against a measured concentration gradient of 4,000 from blood to bile. In experiments with catheter in CHD, rate constant for secretion of (11)C-CSar from hepatocytes into bile was 25% of that in experiments without a catheter (P < 0.05) which we interpreted as mild cholestasis caused by the catheter. The catheter caused an increased backflux of (11)C-CSar from hepatocytes to blood and hepatic blood flow was 25% higher than in experiment without catheter. The capacity of the overall transport of (11)C-CSar from blood into bile, as quantified by intrinsic clearance, was significantly lower in experiments with catheter than in pigs without catheter (P < 0.001). PET and blood measurements correlated significantly (P < 0.05).CONCLUSION: In vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic (11)C-CSar PET.

Progressive familial intrahepatic cholestasis type 1 (PFIC1, Byler disease, OMIM 211600) is a severe inherited liver disease caused by mutations in ATP8B1. ATP8B1 is a member of the type 4 subfamily of P-type ATPases, which are phospholipid flippases. PFIC1 patients generally develop end-stage liver disease before the second decade of life. The disease is characterized by impaired biliary bile salt excretion, but the mechanism whereby impaired ATP8B1 function results in cholestasis is unclear. In a mouse model for PFIC1, we observed decreased resistance of the hepatocanalicular membrane to hydrophobic bile salts as evidenced by enhanced biliary recovery of phosphatidylserine, cholesterol, and ectoenzymes. In liver specimens from PFIC1 patients, but not in those from control subjects, ectoenzyme expression at the canalicular membrane was markedly deficient. In isolated mouse livers Atp8b1 deficiency impaired the transport of hydrophobic bile salts into bile. In conclusion, our study shows that Atp8b1 deficiency causes loss of canalicular phospholipid membrane asymmetry that in turn renders the canalicular membrane less resistant toward hydrophobic bile salts. The loss of phospholipid asymmetry may subsequently impair bile salt transport and cause cholestasis.

Experiments were performed in 2 volunteers to define the biotransformation and physiological properties of norursodeoxycholic acid (norUDCA), the C(23) (C(24)-nor) homolog of UDCA. To complement the in vivo studies, the biotransformation of norUDCA ex vivo using precision-cut human liver slices was also characterized. In the human studies, both a tracer dose given intravenously and a physiological dose (7.9 mmol, 3.0 g) given orally were excreted equally in bile and urine. By chromatography and mass spectrometry, the dominant biotransformation product of norUDCA in bile and urine was the C-23 ester glucuronide. Little N-acyl amidation (with glycine or taurine) occurred. The oral dose induced a sustained bicarbonate-rich hypercholeresis, with total bile flow averaging 20 mu L/kg/min, a rate extrapolating to 2 L/d. The increased bile flow was attributed to cholehepatic shunting of norUDCA as well to the lack of micelles in bile. Phospholipid and cholesterol secretion relative to bile acid secretion decreased during secretion of norUDCA and its metabolites, presumably also because of the absence of micelles in canalicular bile. When incubated with human liver slices, norUDCA was glucuronidated, whereas UDCA was conjugated with glycine or taurine. In conclusion, in humans, norUDCA is glucuronidated rather than amidated. In humans, but not animals, there is considerable renal elimination of the C-23 ester glucuronide, the dominant metabolite. NorUDCA ingestion induces a bicarbonaterich hypercholeresis and evokes less phospholipid and cholesterol secretion into bile than UDCA. Molecules that undergo cholehepatic shunting should be powerful choleretics in humans.

Acromegalic patients treated with octreotide have prolonged colonic transit, increased bacterial formation, and subsequent absorption of deoxycholic acid that is indicated by an increased proportion of deoxycholic acid in plasma bile acids. Enrichment of deoxycholic acid in the circulating bile acid pool leads to supersaturated bile and cholesterol gall stones. Thomas and colleagues,1 in this issue of Gut , extend previous work from the laboratory of R Hermon Dowling by showing that acromegalic patients treated with octreotide have an increase in faecal anaerobic bacteria that convert cholic acid, the major primary bile acid in humans, to deoxycholic acid, the major secondary bile acid (see page 630) . The paper also confirms previous reports from the Dowling laboratory2,3 that octreotide treatment increases colonic transit time in acromegalic patients. In addition, the paper of Thomas et al shows that octreotide treatment results in enrichment of deoxycholic acid in fasting state plasma bile acids. The present paper is the 11th and could well be the last in a series of papers spanning more than a decade from the Dowling laboratory that have dealt with the pathogenesis of gall stones in acromegalic patients treated with octreotide, a potent somatostatin agonist. Octreotide is a synthetic peptide whose amide bonds are resistant to hydrolysis by plasma peptidases, thus resulting in its having a much longer duration of action than that of somatostatin.4 In acromegalic patients, octreotide administration suppresses the release of growth hormone and insulin growth factor by the pituitary and results in clinical improvement.5 The initial paper in this series showed that such patients have an increased prevalence of gall stones.6 The gall stones were shown to be rich in cholesterol7 and, as would be expected, bile was found to be supersaturated in cholesterol8 and to …

AIM To test the efficacy of cholylsarcosine (synthetic conjugated bile acid) and ox bile extracts (mixture of natural conjugated bile acids) on fat absorption, diarrhea, and nutritional state in four short bowel syndrome (SBS) patients with a residual colon not requiring parenteral alimentation. METHODS The effect of cholylsarcosine (2 g/meal) on steatorrhea and diarrhea was examined in short-term balance studies with a constant fat intake in all four patients. The effect of continuous cholylsarcosine ingestion on nutritional state was assessed by changes in body weight in three patients. In two patients, the effects of cholylsarcosine were compared with those of ox bile extracts. Because of the low incidence rate of SBS this is not a controlled study. RESULTS In balance studies, cholylsarcosine increased fat absorption from 65.5 to 94.5 g/day (a 44 % increment), an energy gain of 261 kcal/d. Fecal weight increased by 26 %. In two patients natural conjugated bile acids also reduced steatorrhea, but greatly increased diarrhea. As outpatients consuming an unrestricted diet and ingesting cholylsarcosine, three patients gained weight at an average rate of 0.9 kg/week without worsening of diarrheal symptoms. CONCLUSIONS Cholylsarcosine is efficacious and safe for enhancing fat absorption and nutritional status in short bowel syndrome patients with residual colon. Natural conjugated bile acids improve steatorrhea to a smaller extent and greatly worsen diarrhea.

Background: Patients with short bowel syndrome (SBS) have steatorrhea, in part because of bile acid malabsorption that causes decreased bile acid secretion into the duodenum and consequent fat maldigestion. In SBS patients with colon in continuity, luminal calcium forms calcium fatty acid soaps rather than precipitating as insoluble calcium oxalate. Soluble oxalate is hyperabsorbed by the colon leading to hyperoxaluria and an increased risk for renal calcium oxalate stones and deposits. The authors hypothesized that oral ingestion of conjugated bile acids would increase fat absorption and thereby decrease calcium fatty acid soap formation and oxalate hyperabsorption. Methods: The effect of conjugated bile acid replacement therapy (9 g/d) on fecal fat excretion and urine oxalate excretion was measured in an appropriate patient, utilizing the metabolic balance technique. The effects of chronic bile acid replacement therapy on oxalate excretion and nutritional status also were measured in a 3-month outpatient study. Results: Natural conjugated bile acid replacement therapy reduced fecal fat excretion from 119 to 79 g/d (Δ40 g/d), and urinary oxalate excretion from 87 to 64 mg/d (966 to 710 μmol/d; Δ23 mg/d). Cholylsarcosine, a synthetic conjugated bile acid, had similar but less powerful effects. During a 3-month outpatient trial of natural conjugated bile acids (9 g/d), urine oxalate decreased to normal levels (27 mg/d) in association with weight gain, decreased hunger, and decreased hyperphagia. Conclusion: Conjugated bile acid replacement therapy reduced fecal fat excretion, reduced urinary oxalate excretion, and improved nutritional status in a patient with SBS with colon in continuity, hyperoxaluria, and oxalate nephrolithiasis. Am J Kidney Dis 41:230-237. © 2003 by the National Kidney Foundation, Inc.

Cholestasis results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus. In early primary biliary cirrhosis, bile secretion continues, because of the secretory pressure of bile or because some ductules are not obstructed. With complete cholestasis, a bile acid deficiency occurs in the small intestinal lumen leading to lipid maldigestion and fat-soluble vitamin malabsorption. Bacterial proliferation, bacterial translocation to lymph nodes and endotoxemia may also occur leading to an acute phase reaction. Retention of bile acids in the hepatocyte leads to apoptosis. Accumulation of bile acids in the systemic circulation leads to pruritus, and may contribute to endothelial injury in the lungs and kidney. Early attempts to mimic hepatic excretory function by hemoperfusion over adsorbent columns were unsuccessful for a variety of reasons. Extracorporeal dialysis against albumin offers promise of a realistic albeit partial simulation of hepatic excretory function.

Purpose To direct attention to the structures of the posterior hyaloid as visualized by SD OCT, and to improve understanding of vitreo-retinal biomechanics. Methods Findings were collected from a Wetzlar study cohort of subjects who gave their informed consent to gather experience in vitreal SD OCT. In addition, OCT images were worked up retrospectively from the Mannheim pool of recordings. Exams were performed by the RS 3000 SD OCT (Nidek) or by the Spectralis SD OCT (Heidelberg engineering). Images underwent a modified processing to favour the visualization of vitreous structures. Results Observations range from a completely attached and homogeneous hyaloid with regular foveal profile at the age of 75, to premacular vitreal bursae and intravitreal lacunae, regions of low and high density within an apparently disintegrating hyaloid, intravitreal condensates and supposed cell aggregations. Various patterns of holes within the posterior limitating vitreal membrane appeared in connection with vitreo-retinal and vitreo-papillar traction of a partially detached vitreous Conclusion OCT visualization of vitreous structures contributes to our understanding of vitreal degradation and vitreo - retinal interaction. Commercial interest

Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl4) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP(+) cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl4 liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.

The TGR5 receptor (or GP-BAR1, or M-BAR) was characterized ten years ago as the first identified G-coupled protein receptor specific for bile acids. TGR5 gene expression is widely distributed, including endocrine glands, adipocytes, muscles, immune organs, spinal cord, and the enteric nervous system. The effect of TGR5 activation depends on the tissue where it is expressed and the signalling cascade that it induces. Animal studies suggest that TGR5 activation influences energy production and thereby may be involved in obesity and diabetes. TGR5 activation also influences intestinal motility. This review provides an overview of TGR5-bile acid interactions in health as well as the possible involvement of TGR5 in human disease.

Bile acid malabsorption is often present in patients after near-total proctocolectomy and ileal pouch-anal canal anastomosis, suggesting ileal dysfunction. Experiments were performed in dogs to compare bile acid absorption after a modified procedure, in which a jejunal pouch was interposed between the terminal ileum and the distal rectum, with that after a conventional ileal pouch operation. Fecal bile acid output (equivalent to hepatic bile acid biosynthesis) and composition were determined by gas chromatography/mass spectrometry in five jejunal pouch dogs and in five ileal pouch dogs more than 6 months after operation. Fecal bile acid output in the jejunal pouch dogs (mean +/- standard deviation) was 215 +/- 59 mg/day (10.1 +/- 2.7 mg/kg-day), a value similar to that obtained in the ileal pouch dogs (261 +/- 46 mg/day [12.8 +/- 3.1 mg/kg-day]; P0.05). These values were also similar to those reported by others for healthy unoperated dogs, indicating that increased bile acid biosynthesis occurring in response to bile acid malabsorption was not present. Fecal bile acids in pouch dogs were completely deconjugated and extensively 7-dehydroxylated (jejunal pouch = 90.4% dehydroxylated; ileal pouch = 88.6% +/- 6.6% dehydroxylated) and consisted predominantly of deoxycholic acid derivatives. We conclude that when either a jejunal pouch or an ileal pouch is used as a rectal substitute in dogs, an anaerobic pouch flora develops that efficiently deconjugates and dehydroxylates bile acids, rendering them membrane permeable. The resultant passive absorption of unconjugated bile acids appears to compensate for any loss of active ileal absorption of conjugated bile acids, and bile acid malabsorption does not occur.

Background: We set out to determine whether intravenously administered cholylglycylaminofluorescein (CGF), a fluorescent bile acid, would enhance the visualization of the biliary tract and bile leaks in rabbits undergoing laparoscopic cholecystectomy (LC). Methods: CGF was infused at doses of 1, 5, and 10 mg/kg b.w. Biliary recovery was determined spectrophotometrically (six rabbits). For LC (seven rabbits), a blue (fluorescein) filter was attached to the light source, and a fluorescein-emission filter was attached to the charge coupled device (CCD) camera. The biliary tract and bile leak (made by incising the gallbladder) was observed under standard and fluorescent illumination. Results: Apple-green fluorescence appeared in 2 min and persisted for 30-60 min, enhancing visualization of bile duct anatomy as well as the bile leak. Biliary recovery of CGF at 90 min was high (86-96% of the infused dose). Conclusion: In rabbits, CGF is secreted quantitatively in bile, induces biliary fluorescence, and enhances visualization of the bile ducts and bile leaks when viewed with appropriate filters

The consideration of psychomental and psychological load of employees is not part of the traditional working sphere of occupational physicians. Medical diagnostics and check-up are still regarded as the primary area of responsibility. This fact might be seen as a drawback with regard to the increasing importance of work-related psychomental load on the one hand and the actual requirements for high-quality occupational medicine on the other. The goal of a study in 64 occupational physicians in hospitals was to find out how occupational physicians estimate their own competence for dealing with psychomental problems of their clients, whether employees trust them, and which personal attitudes can be found towards the importance of work-related psychomental strain. The self-estimation of personal competence was--in contradiction to the results of former studies focusing on employees' views--surprisingly positive. A significant influence is the amount of work within the health-care sector compared to others. This might be interpreted as a selective effect and leads to the need for large-scale studies. Agreement could be found concerning the lack of chances for qualification in this sphere. Hence, further education and training in professional work with psychomental problems at the workplace has to be extended.

Reinforcement cages are widely used for the treatment of large acetabular bone defects. We report the case of a loosened Burch-Schneider reinforcement ring causing a recurrent macrohaematuria due to a perforation of the urinary bladder. After performing several diagnostic procedures, the patient underwent interdisciplinary revision surgery. Due to the severe destruction of the acetabular bone stock and an infection of the total hip prosthesis as confirmed by fresh frozen section, the hip prosthesis was explanted. At the last follow-up the patient was free of infect-related symptoms and was able to walk with one crutch.

Berichte uber 46 Falle nosokomialer Ubertragungen von Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) und HIV von infektiosem medizinischem Personal auf Patienten wurden zusammengestellt und analysiert. Die nosokomiale Ubertragung von HBV (40 Falle, 404 infizierte Patienten), HCV (4 Falle, 224 infizierte Patienten) und HIV (2 Falle, 7 infizierte Patienten) zeigt Parallelen auf. Die zahlenmasig umfassendsten Ubertragungsfalle (217 HCV-Infektionen durch einen Anaesthesist, 75 HBV-Ubertragungen durch einen EEG-Laborant) werden auf unzureichende Hygienemasnahmen zuruckgefuhrt (hier: i. v. Drogenkonsum). Bei Einhalten der ublichen Hygienemasnahmen besteht nur durch infektioses chirurgisches arztliches Personal ein Infektionsrisiko fur Patienten. Tatigkeitsbeschrankungen sollten nur nach Einzelfallprufung ausgesprochen werden. Haufig hat sich das betroffene Personal selbst an Patienten infiziert. Gerate und Arbeitsmethoden sollten regelmasig in Bezug auf Infektionsgefahrdung fur Personal und Patienten uberpruft werden.

In den USA (1991), Kanada (1998), im Vereinigten Konigreich (1993, 1994) und in Deutschland (1999) wurden Empfehlungen zur Durchfuhrung „gefahrgeneigter Tatigkeiten“ durch Hepatitis-B-Virus (HBV)-, Hepatitis-C-Virus (HCV)- und HIV-infektiose Personen veroffentlicht. In dieser Arbeit werden die Definitionen gefahrgeneigter Tatigkeiten, die Methoden zur Reduktion der Transmission von blutubertragenen Mikroorganismen, die Impf- und Testpolitik, die Bildung eines Expertengremiums und die Frage von Ruckschauuntersuchungen zusammengefast, die in diesen Regelungen enthalten sind.

Bile acids, amphipathic end products of cholesterol metabolism, are “good” in the infant because they enhance lipid absorption and thereby promote growth. Bile acids also induce bile flow and biliary lipid secretion. The enterohepatic circulation of bile acids is “bad” in the adult because it downregulates hepatocyte low-density lipoprotein receptor activity and thereby elevates plasma cholesterol levels. Defects in bile acid metabolism such as impaired biosynthesis or transport are “ugly” because they cause morbidity and death. New approaches for treating these defects are being developed.

Background & Aims: Dihydroxy bile acids induce a bicarbonate-rich hypercholeresis when secreted into canalicular bile in unconjugated form; the mechanism is cholehepatic shunting. The aim of this study was to identify a xenobiotic that induces hypercholeresis by a similar mechanism. Methods: Five organic acids (sulindac, ibuprofen, ketoprofen, diclofenac, and norfloxacin) were infused into rats with biliary fistulas. Biliary recovery, bile flow, and biliary bicarbonate were analyzed. Sulindac transport was further characterized using Tr − rats (deficient in mrp2 , a canalicular transporter for organic anions), the isolated perfused rat liver, and hepatocyte membrane fractions. Results: In biliary fistula rats, sulindac was recovered in bile in unconjugated form and induced hypercholeresis of canalicular origin. Other compounds underwent glucuronidation and were not hypercholeretic. In the isolated liver, sulindac had delayed biliary recovery and induced prolonged choleresis, consistent with a cholehepatic circulation. Sulindac was secreted normally in Tr − rats, indicating that its canalicular transport did not require mrp2. In the perfused liver, sulindac inhibited cholyltaurine uptake, and when coinfused with cholyltaurine, induced acute cholestasis. With both basolateral and canalicular membrane fractions, sulindac inhibited cholyltaurine transport competitively. Conclusions: Sulindac is secreted into bile in unconjugated form by a canalicular bile acid transporter and is absorbed by cholangiocytes, inducing hypercholeresis. At high flux rates, sulindac competitively inhibits canalicular bile salt transport; such inhibition may contribute to the propensity of sulindac to induce cholestasis in patients. GASTROENTEROLOGY 1999;117:962-971

Background & Aims: Although fat malabsorption in the short-bowel syndrome is caused in part by decreased bile acid secretion, bile acid replacement therapy is not used because of the belief that ingested bile acids would worsen diarrhea, outweighing the benefits of improved fat absorption. This study compared the effect of a natural conjugated bile acid mixture from ox bile with that of cholylsarcosine, a synthetic conjugated bile acid, on fat absorption and diarrhea in a patient with the short-bowel syndrome. Cholylsarcosine is resistant to bacterial metabolism and has no cathartic activity. Methods: Metabolic balance studies and a clinical trial were performed in an emaciated patient with the short-bowel syndrome and ileostomy in whom parenteral nutrition could not be used. Results: In balance studies, conjugated bile acid replacement therapy with either preparation caused fat absorption to increase by approximately 40 g/day. Calcium absorption also increased. Neither bile acid product caused a clinically significant increase in ileostomy water output. During a 4-month outpatient trial, while the patient ingested 2 g/meal natural bile acids, her weight increased from 80 to 98 lb, without side effects. Conclusions: Conjugated bile acid replacement therapy should be part of the armamentarium for the treatment of selected patients with the short-bowel syndrome. GASTROENTEROLOGY 1999;116:15-21