Miracle-dz/UniFAR-FTUs huggingface dataset:
Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 ± 3.5 and 35.7 ± 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUCbile/AUCVH ratio in TI of 1770 (1640–11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ± 0.06; TII, 0.46 ± 0.13) and increased the AUCVP and AUCVH by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.
Permeation rates of penicillins indicate that Escherichia coli porins function principally as nonspecific channels

Significance Porin channels in the outer membrane of Gram-negative bacteria were originally thought to be nonspecific channels that discriminate among solutes only by their gross physicochemical properties, such as size, hydrophobicity, and charge. Since the discovery of the ampicillin-binding site inside one porin channel, however, such “specific” interactions are hypothesized to play significant roles especially for the permeation of drugs. We show, by the careful examination of influx and efflux of ampicillin and benzylpenicillin, that the original nonspecific model is still valid and that it is misleading to overemphasize the role of specific binding sites. Small, hydrophilic compounds such as β-lactams diffuse across the outer membrane of Gram-negative bacteria through porin channels, which were originally thought to be nonspecific channels devoid of any specificity. However, since the discovery of an ampicillin-binding site within the OmpF channel in 2002, much attention has been focused on the potential specificity of the channel, where the binding site was assumed either to facilitate or to retard the penetration of β-lactams. Since the earlier studies on porin permeability were done without the knowledge of the contribution of multidrug efflux pumps in the overall flux process across the cell envelope, in this study we have carefully studied both the porin permeability and active efflux of ampicillin and benzylpenicillin. We found that the influx occurs apparently by a spontaneous passive diffusion without any indication of specific binding within the concentration range relevant to the antibiotic action of these drugs, and that the higher permeability for ampicillin is totally as expected from the gross property of this drug as a zwitterionic compound. The active efflux by AcrAB was more effective for benzylpenicillin due to the stronger affinity and high degree of positive cooperativity. Our data now give a complete quantitative picture of the influx, efflux, and periplasmic degradation (catalyzed by AmpC β-lactamase) of these two compounds, and correlate closely with the susceptibility of Escherichia coli strains used here, thus validating not only our model but also the parameters obtained in this study.
[Expression and clinical significance of Toll-like receptors in human renal carcinoma cell 786-0 and normal renal cell HK-2].

OBJECTIVE To investigate the expression of toll-like receptors (TLR1-TLR10) in human renal carcinoma cell 786-0 and normal renal cell HK-2 and discuss the significance of TLRs in the development of renal carcinoma. METHODS Human renal carcinoma cell 786-0 (experimental group) and normal renal cell HK-2 (control group) were cultured. The expression of TLR1-TLR10 was detected by real-time fluorogenic quantitative PCR (FQ-PCR). RESULTS The FQ-PCR analysis demonstrated that 786-0 cell line and HK-2 cell line expressed TLR1-TLR6 and TLR8-TLR10 mRNA. Yet neither had an expression of TLR7. Moreover, the expression levels of TLR1, TLR2, TLR4, TLR5, TLR6, TLR8 and TLR10 in the experimental group were significantly higher than those in HK-2 cell line [(4.40 ± 0.19) × 10(-2), (1.77 ± 0.24) × 10(-2), (5.03 ± 0.62) × 10(-2), (3.93 ± 0.86) × 10(-2), (6.11 ± 0.48) × 10(-2), (1.89 ± 0.47) × 10(-2), (2.84 ± 0.57) × 10(-2) vs (0.84 ± 0.27) × 10(-2), (0.40 ± 0.04) × 10(-2), (0.95 ± 0.73) × 10(-2), (0.56 ± 0.25) × 10(-2), (0.49 ± 0.16) × 10(-2), (0.20 ± 0.07) × 10(-2), (0.27 ± 0.08) × 10(-2), P < 0.01]. There was no significant change in the expressions of TLR3 and TLR9 between 786-0 and HK-2 cell line (P > 0.05). CONCLUSION The expressions of TLR1, TLR2, TLR4, TLR5, TLR6, TLR8 and TLR10 are significantly higher in 786-0 cell line than those in HK-2 cell line. They may play key roles in the development of renal carcinoma.
The Role of the Plasminogen System in Bone Resorption In Vitro

The plasminogen/plasmin proteolytic cascade plays an important role in extracellular matrix remodeling. The presence of the two plasminogen activators (PAs), tissue‐type plasminogen activator (tPA), and urokinase‐type plasminogen activator (uPA), and their inhibitor type 1 (PAI‐1) in bone cells, suggests a role in one or more aspects of bone resorption such as osteoclast formation, mineral dissolution, and degradation of the organic matrix. These different processes were assayed in vitro using cells derived from mice with either tPA (tPA−/−), uPA (uPA−/−), PAI‐1 (PAI‐1−/−) inactivation or with a combined inactivation (tPA−/−:uPA−/−) and compared with wild‐type mice (WT). First, osteoclast formation, assessed by investigating the number and characteristics of tartrate‐resistant acid phosphatase–positive multinucleated cells formed in cocultures of primary osteoblasts and bone marrow cells treated with 1α,25‐dihydroxyvitamin D3, was not different between the different cell types. Second, dentine resorption, an assay for osteoclast activity, was not affected by the combined deficiency of both tPA and uPA. Finally, the ability to degrade nonmineralized bone‐like matrix was however, significantly reduced in tPA−/−:uPA−/− cells compared with WT cells (28.1 ± 0.6%, n = 6 vs. 56.4 ± 3.1%, n = 6, respectively, p < 0.0001). Surprisingly, collagen proteolysis by bone cells was not dependent on the presence of plasmin as suggested by degradation assays performed on type I3H‐collagen films. Taken together, these data suggest that the plasminogen activator/plasmin system is not required for osteoclast formation, nor for the resorption of the mineral phase, but is involved in the removal of noncollagenous proteins present in the nonmineralized bone matrix.
Diagnosis and management of lipoprotein abnormalities.

Abnormal lipid and lipoprotein cholesterol values have been defined as a low-density lipoprotein (LDL) cholesterol (C) value of 160 mg/dL (4.1 mmol/L) or greater, a high-density lipoprotein (HDL) C value less than 40 mg/dL (1.0 mmol/L), triglycerides (TG) 150 mg/dL (1.7 mmol/L) or greater, and a lipoprotein (a) (Lp(a)) of 30 mg/dl or greater. Such values all increase coronary heart disease (CHD) risk. The National Cholesterol Education Program Adult Treatment Panel III guidelines continue to focus on optimizing LDL-C values (established as < 100 mg/dL or 2.6 mmol/L), especially in those with established CHD, diabetes, or a 10-year CHD risk over 20%. Dietary saturated fat (< 7% of calories) and cholesterol (< 200 mg/day) restriction, and the use of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the mainstays of treatment in this regard. Such treatment substantially reduces CHD risk. Severe hypertriglyceridemia (> 1000 mg/dL or 11.0 mmol/L) is associated with pancreatitis, and fat restriction, control of glucose, and fibrate therapy are indicated in such patients. Niacin is currently the most effective agent for lowering Lp(a) and raising HDL-C. Current recommendations for treatment by diet and drugs are outlined.
Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand

Protein tyrosine phosphorylation and dephosphorylation have been implicated in the growth and functional responses of hematopoietic cells. Recent studies have identified a novel protein tyrosine phosphatase, termed hematopoietic cell phosphatase (HCP) or PTP1C, that is predominantly expressed in hematopoietic cells. HCP encodes a cytoplasmic phosphatase that contains two src homology 2 (SH2) domains. Since SH2 domains have been shown to target the association of signal-transducing molecules with activated growth factor receptors containing intrinsic protein kinase activity, we assessed the association of HCP with two hematopoietic growth factor receptors, c-Kit and c-Fms. The results demonstrate that HCP transiently associates with ligand-activated c-Kit but not c-Fms and that this association occurs through the SH2 domains. In both colony-stimulating factor 1- and stem cell factor-stimulated cells, there is a marginal increase in tyrosine phosphorylation of HCP. Lastly, HCP can dephosphorylate autophosphorylated c-Kit and c-Fms in in vitro reactions. The potential role of HCP in stem cell factor signal transduction is discussed.
Effect of the Increase in the Height of Lumbar Disc Space on Facet Joint Articulation Area in Sagittal Plane

Study Design. Computerized tomography (CT) of the lumbar spine cadaveric specimens was used to evaluate the effect of increasing the height of the disc space in the lumbar spine to the facet joint articulation in the sagittal plane. Objective. To show how the facet joint articulation is affected by increasing the height of the disc space in the lumbar spine. Summary of Background Data. The Charité Artificial Disc (DePuy Spine, Inc., Raynham, MA) was successful in relieving low back pain in the majority of patients, yet there was still a significant number of patients who did not obtain pain relief, or their pain even worsened. The etiology of their pain is still not known. To our knowledge, no study has addressed the effect on the facet joints when the disc height is increased. Methods. CT images passing through the center of the L3–S1 facet joints (sagittal plane) were obtained from 15 cadaveric lumbar spine specimens. The articulation overlap of facet joints in sagittal plane from the L3 to S1 was measured. A 1-mm incremental increase to a total 5 mm in disc space height was performed to simulate the changes seen in disc replacement. The change in the facet joint articulation overlap in sagittal plane at normal and each displacement was then measured. There were 5 lumbar spine specimens dissected to validate the technique and standardize the measurements. Mean, percentages, and standard deviation values were calculated for all measured dimensions. Results. No significant difference was found between the measurements on CT and gross specimens (P > 0.05). In 15 specimens, the mean facet joint articulation overlap on the sagittal plane was: 16.29 ± 1.20 mm (left) and 16.22 ± 1.16 (right) at the L3–L4 level; 17.81 ± 1.18 mm (left) and 17.74 ± 1.18 mm (right) at the L4–L5 level; and 18.18 ± 1.18 mm (left) and 18.23 ± 1.15 mm (right) at the L5–S1 level. There is no significant difference between the measured values on left and right sides (P > 0.05). Each 1-mm incremental increase in disc space at the L3–L4 level translated to a decrease in the facet joint articulation overlap in the sagittal plane by 6%, and the mean facet joint space increased 0.4 mm. At the L4–L5 level, the articulation overlap decreased by 6%, and the facet joint space increased 0.5 mm. At the L5–S1 level, the articulation overlap decreased by 4%, and the facet joint space increased 0.7 mm. Conclusions. There is a significant decrease of the facet joint articulation overlap in sagittal plane and an increase in the facet joint space following an increase in the lumbar disc space. The inappropriate increase of the height of disc space will result in facet joint subluxation.
A Single Preoperative Dose of Gabapentin (800 Milligrams) Does Not Augment Postoperative Analgesia in Patients Given Interscalene Brachial Plexus Blocks for Arthroscopic Shoulder Surgery

BACKGROUND: Inadequate analgesia is common after shoulder arthroscopy. Both interscalene blocks and gabapentin are effective methods of pain management under various circumstances. We tested the hypothesis that gabapentin augments postoperative analgesia provided by interscalene brachial plexus block in patients having ambulatory arthroscopic shoulder surgery. METHODS: Sixty patients were randomly assigned to receive oral gabapentin, 800 mg, or placebo 2 h before surgery. An interscalene brachial plexus block with 0.3 mL/kg of 0.5% ropivacaine was performed. General anesthesia was maintained with sevoflurane and included a single 1-&mgr;g/kg dose of remifentanil. Postoperative analgesia was initially provided with morphine and subsequently with ketoprofene (150 mg orally twice daily) and a combination of 400 mg acetaminophen and 30 mg dextropropoxyphene as needed. Pain scores, analgesic requirements, and side effects were assessed in the ambulatory unit and at home for 48 h. RESULTS: Emergence from general anesthesia was similar in both groups. There were no significant differences in pain scores, first postoperative request for analgesia, or oral analgesic consumption. The incidence of side effects was comparable in both groups, except that headaches were less frequent in the gabapentin group. CONCLUSION: A single preoperative dose of gabapentin (800 mg) does not augment postoperative analgesia in patients given interscalene brachial plexus blocks for arthroscopic shoulder surgery.
Erythrocyte Signal Transduction Pathways, their Oxygenation Dependence and Functional Significance

Erythrocytes play a key role in human and vertebrate metabolism. Tissue O2 supply is regulated by both hemoglobin (Hb)-O2 affinity and erythrocyte rheology, a key determinant of tissue perfusion. Oxygenation-deoxygenation transitions of Hb may lead to re-organization of the cytoskeleton and signalling pathways activation/deactivation in an O2-dependent manner. Deoxygenated Hb binds to the cytoplasmic domain of the anion exchanger band 3, which is anchored to the cytoskeleton, and is considered a major mechanism underlying the oxygenation-dependence of several erythrocyte functions. This work discusses the multiple modes of Hb-cytoskeleton interactions. In addition, it reviews the effects of Mg2+, 2,3-diphosphoglycerate, NO, shear stress and Ca2+, all factors accompanying the oxygenation-deoxygenation cycle in circulating red cells. Due to the extensive literature on the subject, the data discussed here, pertain mainly to human erythrocytes whose O2 affinity is modulated by 2,3-diphosphoglycerate, ectothermic vertebrate erythrocytes that use ATP, and to bird erythrocytes that use inositol pentaphosphate.
Calcium dependence of depolarization‐induced suppression of inhibition in rat hippocampal CA1 pyramidal neurons

1 We made whole‐cell recordings from CA1 pyramidal cells in the rat hippocampal slice preparation to study the calcium (Ca2+) dependence of depolarization‐induced suppression of inhibition (DSI). DSI is a retrograde signalling process in which voltage‐dependent Ca2+ influx into a pyramidal cell leads to a transient decrease in the release of GABA from interneurons. 2 To investigate the Ca2+ dependence of DSI without altering extracellular divalent cations, we varied the type and amount of Ca2+ chelator (EGTA or BAPTA) in the recording pipette (keeping the chelator: Ca2+ ratio constant). Evoked inhibitory postsynaptic currents (IPSCs) were induced in the presence of antagonists of ionotropic glutamate receptors. DSI was induced by depolarizing voltage steps, lasting from 0·025 to 5 s, to 0 mV. 3 DSI was directly dependent on the duration of the voltage step used to induce it, from threshold up to a maximal value of IPSC suppression, whether EGTA or BAPTA was used, and whether their concentrations were 0·1, 0·5 or 2 mM. For instance, a voltage step lasting 1·37 s produced half‐maximal DSI with 2 mM BAPTA, but with 0·1 mM BAPTA, half‐maximal DSI was achieved with a step lasting 0·186 s. Peak DSI was the same in all cases, and DSI was blocked with either 10 mM EGTA or BAPTA in the pipette. Bath application of carbachol could overcome the block of DSI by 10 mM EGTA but not by 10 mM BAPTA. 4 We calculated that a voltage step lasting ≈100 ms would be necessary to activate half‐maximal DSI in the absence of exogenous Ca2+ buffers. 5 Log‐log plots of calculated total Ca2+ influx, estimated from time integrals of Ca2+ currents, versus DSI yielded a straight line with a slope of ≈1, and increasing extracellular [Ca2+] from 2·5 to 5 mM did not change the slope. 6 The time course of decay of DSI was well described by an exponential function with a time constant of ≈20 s and was not affected by changes in either concentration or type of Ca2+ buffer. 7 The data suggest that, in its Ca2+ dependence, DSI more closely resembles the slow release of neuropeptides and hormones than it does the process of fast release of many neurotransmitters.
Modification of Atrial Natriuretic Peptide Receptor Expression in the Rat Inner Ear

Hypothesis: The purpose of this animal study was to confirm the presence of all three atrial natriuretic peptide (ANP) receptor subtypes in the rat inner ear and compare the expression of each receptor after inner ear injectionof ANP, phosphate-buffered saline, or a solution containing ANP incubated with anti-ANP antibody (to block upregulation). Background: Receptors for ANP and related compounds have been localized in the inner ear of animals and humans. A previous study at this institution demonstrated the ability to up-regulate the expression of the three ANP receptors (ANP-A, ANP-B, ANP-C) in response to round window injection of ANP in the rat inner ear. Methods: After surgical exposure, the round window of female Lewis rats was injected with various concentrations of ANP, ANP plus anti-ANP antibody, or control. Animals were killed 24 hours after injection, inner ear tissues were harvested and homogenized, and RNA was isolated for reverse-transcription polymerase chain reaction. Results: Electrophoresis showed the presence of all three receptor subtypes with exposure to phosphate-buffered saline. Expression was significantly higher 24 hours after injection with the two concentrations of ANP. This increase was partially blocked with increasing relative concentrations of anti-ANP antibody. Conclusions: These findings confirm the presence and responsiveness of ANP receptors in the rat inner ear. The ability to block up-regulation with the antibody provides a potential new research tool for manipulating the function of this hormone system in experimental models and, ultimately, in understanding the mechanisms of fluid homeostasis in the inner ear.
A comparison of McGrath and Macintosh laryngoscopes in novice users: a manikin study

Direct laryngoscopy using the Macintosh laryngoscope is a difficult skill to acquire. Videolaryngoscopy is a widely accepted airway management technique that may be easier for novices to learn. We compared the McGrath® videolaryngoscope and Macintosh laryngoscope by studying the performance of 25 medical students with no previous experience of performing tracheal intubation using an easy intubation scenario in a manikin. The order of device use was randomised for each student. After brief instruction each participant performed eight tracheal intubations with one device and then eight tracheal intubations with the other laryngoscope. Novices achieved a higher overall rate of successful tracheal intubation, avoided oesophageal intubation and produced less dental trauma when using the McGrath. The view at laryngoscopy was significantly better with the McGrath. Intubation times were similar for both laryngoscopes and became shorter with practice. There was no difference in participants’ rating of overall ease of use for each laryngoscope.
Global financial reporting convergence: A study of the adoption of International Financial Reporting Standards by the Swedish accountancy profession

International Financial Reporting Standards (IFRS) is a financial reporting standard for listed corporations in more than half of the world’s countries. This wide adoption combined with its influence on accounting in countries that have not formally adopted it makes IFRS a remarkable case of far-reaching convergence. This paper develops a framework that integrates institutional theory and political economy and employs a discourse analytical approach to address the issue of why the Swedish accountancy profession came to accept and adopt IFRS. The analysis covers the professional debates regarding the measurement of the value of assets and liabilities in the main professional journal over the nearly two decades in which IFRS was gradually integrated into the local accounting standards on a voluntary basis prior to its formal adoption. The analysis emphasizes the combination of a pervasive international development discourse that stresses the significance of financial markets developing into a sense of inevitability and an elite portion of the accountancy profession with a vested interest in change. IFRS can be seen as a strategic professionalization project for the elite members of the accountancy profession which, combined with financial interests, led to its endorsement of the changes and alignment with forces of financialization.
A static and dynamic visual debugger for malware analysis

The number of viruses and malware has grown dramatically over the last few years, and this number is expected to grow in all likelihood. Due to the increasing amount of malicious software circulated over the Internet, it is almost impossible to reverse engineering all binary executable software line by line as it is very challenging and time consuming. In order to provide immediate security solutions and reduce the amount of time on understanding malicious portion consisted in viruses, Trojans and other general security flow, a comprehensive design of visual debugger is introduced in this paper. The research involves with the reverse engineering of binary executable by transforming a stream of bytes that constitutes the program into a corresponding sequence of machine instructions. Both static and dynamic debugger will be developed and interacted with a graph visualization system to visualize the parse instructions of a targeted executable file in execution flow graph. With the intention of improving the effectiveness, graph visualization is developed to accelerate the analysis progress. We reconstruct the targeted program's control flow and broke it into smaller regions. Fragment of malicious instructions can be easily determined via the control flow graph information.