Prospective randomized controlled trial comparing a novel and dedicated device with conventional endoscopic techniques for the treatment of buried bumper syndrome (with video).

BACKGROUND AND AIMS: Buried bumper syndrome (BBS) is a rare adverse event of PEG tubes. This study compared the newly developed Flamingo device (Fujifilm Medwork GmbH, Höchstadt, Germany) with conventional endoscopic techniques for BBS treatment. METHODS: This prospective, randomized controlled trial compared the Flamingo set (study group) with other endoscopic techniques (control group) for BBS treatment in 6 German hospitals. The primary endpoint was procedure time. Further outcome parameters were technical success, adverse event rate, and number and cost of devices used in each group. RESULTS: Thirty-six patients (18 in each group; mean age, 73 years; 12 women) were included in this study between March 2018 and December 2022. Median time since placement of the feeding tube was 30 months. The bumper was located in the gastric corpus in 27 patients, and the internal bumper was completely overgrown in 31 patients. The duration of the removal procedure was 17 minutes (range, 3-72) in the study group compared with 38 minutes (range, 12-111) in the control group (P = .046). The primary technical success rate was 77.8% in the study group and 55.6% in the control group (P = .157), whereas the overall technical success rate was 100% compared with 83.3% (P = .070). Adverse events occurred in 4 patients (11.1%). CONCLUSIONS: Endoscopic removal of the buried bumper using the Flamingo device was significantly faster than that with other endoscopic techniques and showed a higher technical success rate. This device may become the endoscopic treatment of choice for BBS. (Clinical trial registration number: NCT03186066.).

Health Care Workers' Sick Leave due to COVID-19 Vaccination in Context With SARS-CoV-2 Infection and Quarantine-A Multicenter Cross-Sectional Survey.

Background: Reactogenicity of coronavirus disease 2019 (COVID-19) vaccines can result in inability to work. The object of this study was to evaluate health care workers' sick leave after COVID-19 vaccination and to compare it with sick leave due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and quarantine leave. Methods: A multicenter cross-sectional survey was conducted at Regensburg University Medical Center and 10 teaching hospitals in South-East Germany from July 28 to October 15, 2021. Results: Of 2662 participants, 2309 (91.8%) were fully vaccinated without a history of SARS-CoV-2 infection. Sick leave after first/second vaccination occurred in 239 (10.4%) and 539 (23.3%) participants. In multivariable logistic regression, the adjusted odds ratio for sick leave after first/second vaccination compared with BNT162b2 was 2.26/3.72 for mRNA-1237 (95% CI, 1.28-4.01/1.99-6.96) and 27.82/0.48 for ChAdOx1-S (95% CI, 19.12-40.48/0.24-0.96). The actual median sick leave (interquartile range [IQR]) was 1 (0-2) day after any vaccination. Two hundred fifty-one participants (9.4%) reported a history of SARS-CoV-2 infection (median sick leave [IQR] 14 [10-21] days), 353 (13.3%) were quarantined at least once (median quarantine leave [IQR], 14 [10-14] days). Sick leave due to SARS-CoV-2 infection (4642 days) and quarantine leave (4710 days) accounted for 7.7 times more loss of workforce than actual sick leave after first and second vaccination (1216 days) in all fully vaccinated participants. Conclusions: Sick leave after COVID-19 vaccination is frequent and is associated with the vaccine applied. COVID-19 vaccination should reduce the much higher proportion of loss of workforce due to SARS-CoV-2 infection and quarantine.

Lipodystrophy syndrome and self-assessment of well-being and physical appearance in HIV-positive patients.

The lipodystrophy syndrome (LDS) is a growing problem in human immunodeficiency virus (HIV)-positive patients treated with highly active antiretroviral therapy (HAART). It is characterized by alterations of body composition and metabolic abnormalities. The goal of the study was to investigate attitudes toward health condition, well-being, and individual appearance in relation to LDS. Outpatients between July and October 2000 in an HIV-specialized unit at the University Hospital of Düsseldorf, Germany, underwent clinical evaluation and received a standardized written questionnaire. Of 389 patients eligible for analysis, 313 patients returned completed questionnaires (response rate, 80.5%). LDS was observed in 37.7%; the predominant manifestation was lipoatrophy of the face (32.9%). Individuals with and without LDS did not differ significantly in their attitude to the quality of their health condition and the amount of disturbance of their well-being by HIV infection. Participants with LDS felt recognizable as HIV-positive by physical appearance in 30.1%, compared to 18.3% in patients without LDS (p = 0.027). This difference became more pronounced after adjustment for gender, age, stage of disease, CD4 cell count, and duration of HAART (odds ratio, 2.04, 95%-confidence interval [CI] 1.09-3.84). In conclusion, LDS does not seem to disturb the general attitude toward health condition and well-being. However, patients presenting with lipodystrophy are about twice as likely to feel recognizable as HIV-positive by their physical appearance. LDS may thus be perceived as a characteristic mark of being HIV-positive by affected persons. A stigmatizing effect and social disadvantages may be the consequences.

Serotonin release during percutaneous radiofrequency ablation in a patient with symptomatic liver metastases of a neuroendocrine tumor.

In a patient with symptomatic liver metastases of a neuroendocrine tumor larger than 10 cm in diameter percutaneous radiofrequency ablation was performed. The ablation resulted in a significant decrease in tumor size and a good long-term improvement of symptoms. Plasma serotonin 48 hours after the ablation was approximately 10-fold lower than before. However, sequential determination of plasma serotonin during the radiofrequency ablation revealed a two-fold increase of plasma serotonin induced by the procedure. There was also an approximately three-fold increase of 5-hydroxyindol acetic acid in urine in the 24 hours following the ablation. The data show that ablation procedures in neuroendocrine tumors may induce hormone release which may be critical in patients with severe clinical symptoms.

Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liver.

AIMS: The aim of this study was to investigate the regulation of hepatic transport systems during liver regeneration. METHODS: A DNA oligonucleotide microarray was developed with probes for 400 transcripts. Data were confirmed using real-time PCR and on a functional level in the perfused rat liver. Liver homogenates were taken 3-48 h following 2/3-hepatectomy in rats and compared with sham-operated and non-operated controls. RESULTS: A more than two-fold increase or decrease of expression was obtained in 183 genes following partial hepatectomy and in 16 genes in sham-operated rats. A strong induction during liver regeneration was detected for the amino acid transporters LAT4, SN2 and sodium-dependent neutral amino acid transporter (ASCT)2, whereas amino acid transport system (ATA)2 and ATA3 expressions remained unchanged. The upregulation of ASCT2 may be responsible for the increase in sodium-dependent neutral amino acid influx important for liver cell proliferation. Expression of the osmolyte transporters Smit, TauT and Bgt1 was almost unchanged indicating that osmolytes are not involved in the cell volume increase during liver regeneration. The basolateral bile salt transporter Ntcp messenger RNA (mRNA) was significantly downregulated, whereas bile salt export pump (Bsep) and multidrug resistance protein (Mrp)2 expressions remained almost unchanged. An increased mRNA expression following partial hepatectomy was detected for organic anion transporting polypeptide (Oatp)5, Octn1, Octn2 and SGLT2. In contrast, Mrp6, Oatp 2, Oatp 3, Oatp 4 and Oatp 7 were downregulated. A five-fold upregulation at the protein level was shown for the Na(+)-K(+)-2Cl- cotransporter sodium-potassium-2-chloride cotransporter (NKCC1). CONCLUSIONS: The data show a differential regulation of hepatic transport systems during liver regeneration.

Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat.

Glutamine synthetase (GS) in the liver is restricted to a small perivenous hepatocyte population and plays an important role in the scavenging of ammonia that has escaped the periportal urea-synthesizing compartment. We examined the effect of a single intraperitoneal injection of lipopolysaccharide (LPS) in vivo on glutamine synthesis in rat liver. LPS injection induced expression of inducible nitric oxide synthase, which was maximal after 6 to 12 hours but returned toward control levels within 24 hours. Twenty-four hours after LPS injection, an approximately fivefold increase in tyrosine-nitrated proteins in liver was found, and GS protein expression was decreased by approximately 20%, whereas GS activity was lowered by 40% to 50%. GS was found to be tyrosine-nitrated in response to LPS, and immunodepletion of tyrosine-nitrated proteins decreased GS protein by approximately 50% but had no effect on GS activity. Together with the finding via mass spectrometry that peroxynitrite-induced inactivation of purified GS is associated with nitration of the active site tyrosine residue, our data suggest that tyrosine nitration critically contributes to inactivation of the enzyme. In line with GS inactivation, glutamine synthesis from ammonia (0.3 mmol/L) in perfused livers from 24-hour LPS-treated rats was decreased by approximately 50%, whereas urea synthesis was not significantly affected. In conclusion, LPS impairs hepatic ammonia detoxification by both downregulation of GS and its inactivation because of tyrosine nitration. The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis.

Combined broncho-oesophagoscopy for diagnosis of HIV-associated disorders.

The aim of the study was to characterize the value of combined endoscopy of tracheobronchial tree and oesophagus within 1 session for diagnosis of HIV-associated disorders. Hospitalized HIV-positive patients who underwent combined flexible broncho-oesophagoscopies between 1999 and 2002 in 2 units for infectious diseases were studied retrospectively. 54 HIV patients were analysed; 89% were at stage CDC C, 79% were male, mean age was 40 y. Bronchoscopy led to a diagnosis in 57.4% (95% CI 43.2-70.8). In 40.7%, these were AIDS-defining events (ADE) and 16.7% were general disorders (GD). Oesophagoscopy was diagnostic in 46.3% (95% CI 32.6-60.4). In 35.2% these were ADE, and 11.1% were GD. Patients with pathological oesophagoscopy had a significantly lower CD4 cell count and a higher viral load. There was no association of pathological bronchoscopy with pathological oesophagoscopy regarding ADE. No severe complication was recorded. It is concluded that combined flexible broncho-oesophagoscopy is a valuable and safe method for the diagnosis of HIV-associated disorders. The diagnostic output is highest in patients with advanced disease. A pathological finding in oesophagoscopy cannot be predicted by the presence of bronchoscopic abnormalities. Prospective studies are necessary to confirm these results.

Involvement of the Src family kinase yes in bile salt-induced apoptosis.

BACKGROUND AND AIMS: Hydrophobic bile acids induce CD95 (Fas, APO-1)-dependent hepatocyte apoptosis, which involves epidermal growth factor receptor (EGFR)-catalyzed CD95 tyrosine phosphorylation. The mechanisms underlying bile salt-induced EGFR activation remain unclear. METHODS: Bile acid-induced EGFR activation was studied in 24-hour cultured rat hepatocytes and perfused rat liver. RESULTS: The proapoptotic bile salts taurolithocholate-3-sulfate (TLCS), glycochenodesoxycholate (GCDC) and taurochenodeoxycholate (TCDC), but not taurocholate (TC), activate within 1 minute the Src kinase family member Yes, followed by an association of Yes with EGFR and subsequent EGFR activation. EGFR phosphorylation by TLCS involves tyrosines 845 and 1173 but not 1045. Yes/EGFR association and EGFR activation were sensitive to inhibition by SU6656 but not by PP-2. cAMP had no effect on TLCS and GCDC-induced Yes activation but induced Ser/Thr phosphorylation of Yes and prevented Yes/EGFR association and subsequent EGFR activation. Both SU6656 and cAMP had no effect on bile salt-induced c-Jun N-terminal kinase activation, but blocked bile salt-induced CD95 tyrosine phosphorylation, membrane trafficking of CD95, formation of the death-inducing signaling complex, and apoptosis. In 4-day cultured hepatocytes, knockdown of either Yes or EGFR strongly attenuated bile salt-induced CD95 activation and apoptosis. CONCLUSIONS: The data identify the Src kinase Yes as an upstream target of proapoptotic bile acids, which triggers EGFR activation, subsequent CD95 tyrosine phosphorylation, and apoptosis. The antiapoptotic effect of cAMP involves a protein kinase A-dependent inhibition of Yes/EGFR association, thereby preventing EGFR activation, which is required for CD95 activation.

Taurine supplementation induces multidrug resistance protein 2 and bile salt export pump expression in rats and prevents endotoxin-induced cholestasis.

The effect of oral taurine supplementation on endotoxin-induced cholestasis was investigated in rat liver. At 12h following lipopolysaccharide (LPS) injection (4mg/kg body weight i.p.) bile flow and bromosulfophthalein (BSP) and taurocholate (TC) excretion were determined in the perfused liver and the expression of the canalicular transporters multidrug resistance protein 2 (Mrp2) and bile salt export pump (Bsep) was analyzed. Injection of LPS induced a significant decrease of bile flow ( 2.2+/-0.2 microl/g liver wet weight/min vs 3.3+/-0.1 microl/g liver wet weight in controls), biliary BSP excretion (10.8+/-2.2 nmol/g/min vs 21.0+/-3.8 nmol/g/min), and biliary TC excretion (114+/-23 nmol/g/min vs 228+/-8 nmol/g/min). These effects were due to transporter retrieval from the canalicular membrane and downregulation of Mrp2 and Bsep expression. In taurine-supplemented rats bile flow was 30% higher than that in untreated rats and the expression of Mrp2 and Bsep protein was increased two- to threefold. In taurine-supplemented rats there was no significant reduction of bile flow or of BSP and TC excretion at 12h following LPS injection. This protective effect of taurine was due to higher Mrp2 and Bsep protein levels compared to nonsupplemented LPS-treated rats, whereas relative Mrp2 retrieval from the canalicular membrane induced by LPS was not significantly different. LPS-induced tumor necrosis factor alpha and interleukin-1beta release were lower in taurine-fed rats; however, downregulation of Mrp2 and Bsep expression by LPS was delayed but not prevented. The data show that oral supplementation of taurine induces Mrp2 and Bsep expression and may prevent LPS-induced cholestasis.

Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis.

BACKGROUND & AIMS: Stimulation of canalicular secretion by tauroursodeoxycholate (TUDC) involves dual activation of p38 mitogen-activated protein kinase (p38(MAPK)) and extracellular signal-regulated kinase (ERK). This study investigates the sensing and upstream signaling events of TUDC-induced choleresis. METHODS: TUDC and hypo-osmolarity effects on protein kinase activities and taurocholate excretion were studied in perfused rat liver. RESULTS: TUDC induced a rapid activation of focal adhesion kinase (FAK) and Src, as shown by an increase in Y418 phosphorylation and a decrease in Y529 phosphorylation of Src. Inhibition of Src by PP-2 abolished the TUDC-induced activation of p38(MAPK) but not of FAK and ERKs. An integrin-inhibitory peptide with an RGD motif blocked TUDC-induced FAK, Src, ERK, and p38(MAPK) activation, suggesting that integrin signaling toward FAK/Src is required for TUDC-induced MAPK activation. The RGD peptide and PP-2 also abolished the stimulation of taurocholate excretion in perfused rat liver in response to TUDC. Integrin-dependent Src activation was also identified as an upstream event in hypo-osmotic signaling toward MAPKs and choleresis. CONCLUSIONS: TUDC-induced stimulation of canalicular taurocholate excretion involves integrin sensing, FAK, and Src activation as upstream events for dual MAPK activation. Integrins may also represent one long-searched sensor for cell hydration changes in response to hypo-osmolarity.

Critical flicker frequency for quantification of low-grade hepatic encephalopathy.

Subclinical hepatic encephalopathy (SHE) is currently diagnosed by psychometric tests or neurophysiologic techniques. In view of its sociomedical relevance, simple and reproducible tests for routine diagnosis are required. This study evaluates critical flicker-frequency thresholds for quantification of low-grade hepatic encephalopathy. A total of 115 patients (92 with cirrhosis, 23 controls) were analyzed for HE severity (mental state, computerized psychometric tests), and the threshold frequencies at which light pulses are perceived as fused (fusion frequency) or flickering light (critical flicker frequency [CFF]). CFF was a highly reproducible parameter with little age, day-time, and training dependency. CFFs in cirrhotic patients without HE (HE 0) were not different from those found in noncirrhotic controls. Significantly lower CFFs were found in cirrhotic patients with subclinical or manifest HE, and the various HE groups separated from each other at a high level of significance (P <.01). By using a CFF cut-off value of 39 Hz, a 100% separation of patients with manifest HE from noncirrhotic controls and HE 0 cirrhotic patients was obtained. SHE patients separated from HE 0 cirrhotic patients with high sensitivity (55%) and specificity (100%). The HE severity-dependent differences were found in both, alcoholic and posthepatitic cirrhosis. Statistically significant correlations (P <.01) were found between CFFs and individual psychometric tests. Aggravation of preexisting HE after transjugular intrahepatic portosystemic stent shunt (TIPS) implantation was accompanied by a corresponding decrease of CFF, whereas improvement of HE increased CFF. In conclusion, CFF is a sensitive, simple, and reliable parameter for quantification of low-grade HE severity in cirrhotic patients and may be useful for the detection and monitoring of SHE.

Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver.

Bile secretion is regulated by different signaling transduction pathways including protein kinase C (PKC). However, the role of different PKC isoforms for bile formation is still controversial. This study investigates the effects of PKC isoform selective activators and inhibitors on PKC translocation, bile secretion, bile acid uptake, and subcellular transporter localization in rat liver, isolated rat hepatocytes and in HepG2 cells. In rat liver activation of Ca(2+)-dependent cPKCalpha and Ca(2+)-independent PKCepsilon by phorbol 12-myristate 13-acetate (PMA, 10nmol/liter) is associated with their translocation to the plasma membrane. PMA also induced translocation of the cloned rat PKCepsilon fused to a yellow fluorescent protein (YFP), which was transfected into HepG2 cells. In the perfused liver, PMA induced marked cholestasis. The PKC inhibitors Gö6850 (1 micromol/liter) and Gö6976 (0.2 micromol/liter), a selective inhibitor of Ca(2+)-dependent PKC isoforms, diminished the PMA effect by 50 and 60%, respectively. Thymeleatoxin (Ttx,) a selective activator of Ca(2+)-dependent cPKCs, did not translocate rat PKCepsilon-YFP transfected in HepG2 cells. However, Ttx (0.5-10 nmol/liter) induced cholestasis similar to PMA and led to a retrieval of Bsep from the canalicular membrane in rat liver while taurocholate-uptake in isolated hepatocytes was not affected. Gö6976 completely blocked the cholestatic effect of Ttx but had no effect on tauroursodeoxycholate-induced choleresis. The data identify Ca(2+)-dependent PKC isoforms as inducers of cholestasis. This is mainly due to inhibition of taurocholate excretion involving transporter retrieval from the canalicular membrane.