Background & Aims: Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) improve symptoms and biochemical markers of liver injury in cholestatic liver diseases by largely unknown mechanisms. We aimed to study the mole...Background & Aims: Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) improve symptoms and biochemical markers of liver injury in cholestatic liver diseases by largely unknown mechanisms. We aimed to study the molecular mechanisms of action of these drugs in humans. Methods: Thirty otherwise healthy gallstone patients scheduled for cholestectomy were randomized to RIFA (600 mg/day for 1 week) or UDCA (1 g/day for 3 weeks) or no medication before surgery. Routine biochemistry, lipids, and surrogate markers for P450 activity (4β -hydroxy cholesterol, 4β -OH-C) and bile acid synthesis (7α -hydro-xy-4-cholesten-3-one,C-4) were measured in serum. Bile acids were analyzed in serum, urine, and bile. A wedge liver biopsy specimen was taken to study expression of hepatobiliary ABC transporters as well as detoxification enzymes and regulatory transcription factors. Results: RIFA enhanced bile acid detoxification as well as bilirubin conjugation and excretion as reflected by enhanced expression of CYP3A4, UGT1A1, and MRP2. These molec-ular effects were paralleled by decreased bilirubin and deoxycholic acid concentrations in serum and decreased lithocholic and deoxycholic acid concentrations in bile. UDCA on the other hand stimulated the expression of BSEP, MDR3, and MRP4. UDCA became the predominant bile acid after UDCA treatment and lowered the biliary cholesterol saturation index. Conclusions: RIFA enhances bile acid detoxification as well as bilirubin conjugation and export systems, whereas UDCA stimulates the expression of transporters for canalicular and basolateral bile acid export as well as the canalicular phospholipid flippase. These independent but complementary effects may justify a combination of both agents for the treatment of cholestatic liver diseases.展开更多
Objective: To validate an intracoronary Doppler ultrasound device for high intensity transient signals(HITS) detection and to assess the incidence of HITS during percutaneous coronary intervention(PCI). Methods and Re...Objective: To validate an intracoronary Doppler ultrasound device for high intensity transient signals(HITS) detection and to assess the incidence of HITS during percutaneous coronary intervention(PCI). Methods and Results: In an in vitro model, particle count and number of HITS detected by an intracoronary 0.014 inch Doppler wire were closely correlated(r=0.97, p< 0.001). In the clinical study, 32 patients(mean(SD) age 61(11) years; 23 men, nine women) with coronary artery disease were treated with balloon dilatation and stent implantation for a single vessel stenosis. In these patients HITS were detected during PCI in 84%(27 of 32). Reproducibility(r=0.99, p< 0.001) and interobserver agreement(r=0.84, p< 0.001)of HITS counts were significant. The number of HITS after stent implantation was significantly higher than after balloon dilatation(11(7) v 2(4), p< 0.001). Postprocedural coronary flow velocity reserve(CFVR) was< 2.0 in 55%(16 of 29) of all patients after balloon dilatation and< 2.0 in 23%(six of 26) after stent implantation. The number of HITS after stent implantation did not differ significantly between patients with CFVR< 2.0 and patients with CFVR ≥2.0(12(8) v 10(7), not significant). Conclusions: Embolic particles can be detected as HITS by an intracoronary Doppler ultrasound device. Coronary microembolism is often observed during PCI, especially after stent implantation. However, the incidence of HITS alone does not explain a reduced CFVR after PCI.展开更多
Twelve boys with verified diagnosis of severe attention deficit hyperactivity disorder (mean age 9.2± 2.9 years) and 12 control boys were investigated. According to the DSM IV system the patients were positive re...Twelve boys with verified diagnosis of severe attention deficit hyperactivity disorder (mean age 9.2± 2.9 years) and 12 control boys were investigated. According to the DSM IV system the patients were positive regarding all aspects. None of the patients received medication at or around the time of the investigation. The boys were asked to tap a button 128 times in a frequency that felt comfortable to them. The investigation was performed with specially designed software. There was no significant difference in the mean or median intervals between tapping, However, range and spread of the tapping intervals were significantly higher in patients with hyperactivity disorder. The results show that these children perform less rhythmically although they were allowed to choose the tapping frequency themselves. There are many possible reasons for these results, ranging from social to genetic. One of the reasons could be due to changes in the genetically codedmolecular clock. In humans there are only three genes identified that code for molecular clocks (CLOCK, PER2, BMAL1). In these genes as well as in other proteins and enzymes involved in the signaling pathway, mutations and polymorphisms have been described that lead to a decreased rhythm in motor timing.展开更多
文摘Background & Aims: Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) improve symptoms and biochemical markers of liver injury in cholestatic liver diseases by largely unknown mechanisms. We aimed to study the molecular mechanisms of action of these drugs in humans. Methods: Thirty otherwise healthy gallstone patients scheduled for cholestectomy were randomized to RIFA (600 mg/day for 1 week) or UDCA (1 g/day for 3 weeks) or no medication before surgery. Routine biochemistry, lipids, and surrogate markers for P450 activity (4β -hydroxy cholesterol, 4β -OH-C) and bile acid synthesis (7α -hydro-xy-4-cholesten-3-one,C-4) were measured in serum. Bile acids were analyzed in serum, urine, and bile. A wedge liver biopsy specimen was taken to study expression of hepatobiliary ABC transporters as well as detoxification enzymes and regulatory transcription factors. Results: RIFA enhanced bile acid detoxification as well as bilirubin conjugation and excretion as reflected by enhanced expression of CYP3A4, UGT1A1, and MRP2. These molec-ular effects were paralleled by decreased bilirubin and deoxycholic acid concentrations in serum and decreased lithocholic and deoxycholic acid concentrations in bile. UDCA on the other hand stimulated the expression of BSEP, MDR3, and MRP4. UDCA became the predominant bile acid after UDCA treatment and lowered the biliary cholesterol saturation index. Conclusions: RIFA enhances bile acid detoxification as well as bilirubin conjugation and export systems, whereas UDCA stimulates the expression of transporters for canalicular and basolateral bile acid export as well as the canalicular phospholipid flippase. These independent but complementary effects may justify a combination of both agents for the treatment of cholestatic liver diseases.
文摘Objective: To validate an intracoronary Doppler ultrasound device for high intensity transient signals(HITS) detection and to assess the incidence of HITS during percutaneous coronary intervention(PCI). Methods and Results: In an in vitro model, particle count and number of HITS detected by an intracoronary 0.014 inch Doppler wire were closely correlated(r=0.97, p< 0.001). In the clinical study, 32 patients(mean(SD) age 61(11) years; 23 men, nine women) with coronary artery disease were treated with balloon dilatation and stent implantation for a single vessel stenosis. In these patients HITS were detected during PCI in 84%(27 of 32). Reproducibility(r=0.99, p< 0.001) and interobserver agreement(r=0.84, p< 0.001)of HITS counts were significant. The number of HITS after stent implantation was significantly higher than after balloon dilatation(11(7) v 2(4), p< 0.001). Postprocedural coronary flow velocity reserve(CFVR) was< 2.0 in 55%(16 of 29) of all patients after balloon dilatation and< 2.0 in 23%(six of 26) after stent implantation. The number of HITS after stent implantation did not differ significantly between patients with CFVR< 2.0 and patients with CFVR ≥2.0(12(8) v 10(7), not significant). Conclusions: Embolic particles can be detected as HITS by an intracoronary Doppler ultrasound device. Coronary microembolism is often observed during PCI, especially after stent implantation. However, the incidence of HITS alone does not explain a reduced CFVR after PCI.
文摘Twelve boys with verified diagnosis of severe attention deficit hyperactivity disorder (mean age 9.2± 2.9 years) and 12 control boys were investigated. According to the DSM IV system the patients were positive regarding all aspects. None of the patients received medication at or around the time of the investigation. The boys were asked to tap a button 128 times in a frequency that felt comfortable to them. The investigation was performed with specially designed software. There was no significant difference in the mean or median intervals between tapping, However, range and spread of the tapping intervals were significantly higher in patients with hyperactivity disorder. The results show that these children perform less rhythmically although they were allowed to choose the tapping frequency themselves. There are many possible reasons for these results, ranging from social to genetic. One of the reasons could be due to changes in the genetically codedmolecular clock. In humans there are only three genes identified that code for molecular clocks (CLOCK, PER2, BMAL1). In these genes as well as in other proteins and enzymes involved in the signaling pathway, mutations and polymorphisms have been described that lead to a decreased rhythm in motor timing.
