The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug–drug interactions. Predicting potential ...interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
Hepatocyte transplantation (HcTx) has proven to be a safe procedure, although the functional results have been unsatisfactory, probably due to insufficient engraftment or a loss of transplanted mass ...or function. In this study, we investigate whether hepatocytes in contact with blood induce an inflammatory reaction leading to, similar to what happens in clinical islet transplantation, an instant blood-mediated inflammatory reaction (IBMIR) resulting in an early loss of transplanted cells.
By using an experimental model that mimics the portal vein blood flow, we could study different parameters reflecting the effects on the innate immunity elicited by hepatocytes in contact with ABO-matched human blood.
We report that all aspects of the IBMIR such as platelet and granulocyte consumption, coagulation, and complement activation were demonstrated. Addition of various specific inhibitors of coagulation allowed us to clearly delineate the various stages of the hepatocyte-triggered IBMIR and show that the reaction was triggered by tissue factor. Analysis of a case of clinical HcTx showed that hepatocyte-induced IBMIR also occurs in vivo. Both the inflammatory and the coagulation aspects were controlled by low-molecular-weight dextran sulfate.
Isolated hepatocytes in contact with blood induce the IBMIR in vitro, and there are indications that these events are also relevant in vivo. According to these findings, HcTx would benefit from controlling a wider range of signals from the innate immune system.
The mesenteric hemodynamic response to circulatory shock is characteristic and profound; this vasoconstrictive response disproportionately affects both the mesenteric organs and the organism as a ...whole. Vasoconstriction of post-capillary mesenteric venules and veins, mediated largely by the alpha-adrenergic receptors of the sympathetic nervous system, can effect an "autotransfusion" of up to 30% of the total circulating blood volume, supporting cardiac filling pressures ("preload"), and thereby sustaining cardiac output at virtually no cost in nutrient flow to the mesenteric organs. Under conditions of decreased cardiac output caused by cardiogenic or hypovolemic shock, selective vasoconstriction of the afferent mesenteric arterioles serves to sustain total systemic vascular resistance ("afterload"), thereby maintaining systemic arterial pressure and sustaining the perfusion of non-mesenteric organs at the expense of mesenteric organ perfusion (Cannon's "flight or fight" response). This markedly disproportionate response of the mesenteric resistance vessels is largely independent of the sympathetic nervous system and variably related to vasopressin, but mediated primarily by the renin-angiotensin axis. The extreme of this response can lead to gastric stress erosions, nonocclusive mesenteric ischemia, ischemic colitis, ischemic hepatitis, ischemic cholecystitis, and/or ischemic pancreatitis. Septic shock can produce decreased or increased mesenteric perfusion, but is characterized by an increased oxygen consumption that exceeds the capacity of mesenteric oxygen delivery, resulting in net ischemia and consequent tissue injury. Mesenteric organ injury from ischemia/reperfusion due to any form of shock can lead to a triggering of systemic inflammatory response syndrome, and ultimately to multiple organ dysfunction syndrome. The mesenteric vasculature is therefore a major target and a primary determinant of the systemic response to circulatory shock.
Current management of gastric cancer Haglund, Ulf H.; Wallner, Bengt
Journal of Gastrointestinal Surgery,
11/2004, Volume:
8, Issue:
7
Book Review, Journal Article
Right Hemihepatectomy Haglund, Ulf H.; Norén, Agneta; Urdzik, Jozef ...
Journal of gastrointestinal surgery,
07/2008, Volume:
12, Issue:
7
Journal Article
Peer reviewed
A right hemihepatectomy is frequently required for surgical removal of colorectal liver metastases. Today, this procedure can be performed quite safely provided the remaining liver is free from ...significant disease including steatohepatitis due to prolonged cytostatic treatment. Standard surgical techniques for liver resection are described in surgical textbooks. However, each center has developed its own modifications of important details. In this paper, we describe our technique to resect the right liver lobe using conventional surgical techniques as well as a vascular stapler and an ultrasonic dissector. This technique has proven to be quite safe, and blood loss is most often not significant despite we do not routinely apply the Pringle’s manoeuvre during the division of the liver parenchyma.
(1) Oxaliplatin-based chemotherapy for colorectal cancer liver metastasis is associated with sinusoidal injury of liver parenchyma. The effects of oxaliplatin-induced liver injury on the protein ...level remain unknown. (2) Protein expression in liver tissue was analyzed-from eight patients treated with FOLFOX (combination of fluorouracil, leucovorin, and oxaliplatin) and seven controls-by label-free liquid chromatography mass spectrometry. Recursive feature elimination-support vector machine and Welch
-test were used to identify classifying and relevantly changed proteins, respectively. Resulting proteins were analyzed for associations with gene ontology categories and pathways. (3) A total of 5891 proteins were detected. A set of 184 (3.1%) proteins classified the groups with a 20% error rate, but relevant change was observed only in 55 (0.9%) proteins. The classifying proteins were associated with changes in DNA replication (
< 0.05) through upregulation of the minichromosome maintenance complex and with the innate immune response (
< 0.05). The importance of DNA replication changes was supported by the results of Welch
-test (
< 0.05). (4) Six weeks after FOLFOX treatment, less than 1% of identified proteins showed changes in expression associated with DNA replication, cell cycle entry, and innate immune response. We hypothesize that the changes remain after recovery from FOLFOX treatment injury.
Abstract Introduction A single-center nonrandomized clinical trial was performed to assess the safety and efficacy of IRE ablation of liver tumors in humans. Methods 38 malignant liver tumors on 30 ...patients were treated with IRE between September 2011 and September 2014. Treatment was with curative intent, and the diagnoses were colorectal cancer with liver metastases (CRLM) (n = 23), hepatocellular carcinoma (HCC) (n = 8) and other metastasis (n = 7). Patients were selected when surgery, radiofrequency ablation (RFA) or microwave ablation (MWA) was not an option, and when they met inclusion criteria (tumor size < 3 cm, 1–2 tumors). Patients were followed-up at 1 and 6 months with a contrast-enhanced computed tomography (CE-CT), and contrast-enhanced ultrasound (CE-US) at 3 months. Results Ablation success was defined as no evidence of residual tumor in the ablated area as confirmed by CE-CT and CE-US. At 3 months ablation success was 78.9%, and 65.8% at 6 months. There was no statistically significant difference between tumor volume (<5 cm3 vs >5 cm3 , p = 0.518), and between diagnosis (CRLM vs HCC, p = 0.084) in terms of local recurrence. Complications were classified according to the standardized grading system of Society of Interventional Radiology (SIR). A minor complication occurred in six patients (20%), one patient (3.3%) suffered from a major complication (bile duct dilatation and stricture of the portal vein and bile duct). No mortalities occurred at 30 days. Conclusions IRE appears to be a safe treatment modality for a selected group of patients with liver tumors and offers high local tumor control at 3 and 6 months.
Objectives
On the basis of a systematic review, we aimed to establish the cost and drivers of cost and/or resource use of intra- and perioperative complications occurring as a result of selected ...major surgical procedures, as well as to understand the relationship between costs and severity of complication and, consequently, the economic burden they represent. We also assessed the clinical and economic methodologies used to derive costs and resource use across the studies with a view to providing guidance on reporting standards for these studies.
Methods
We searched EMBASE, MEDLINE and Econlit (from 2002 to 2012) for study publications including resource use/cost data relating to surgical complications.
Results
We identified 38 relevant studies on pancreatic (
n
= 14), urologic (
n
= 4), gynaecological (
n
= 6), thoracic (
n
= 13) and hepatic surgery (
n
= 1). All studies showed that complications lead to higher resource use and hospital costs compared with surgical procedures without complications. Costs depend on type of complication and complication severity, and are driven primarily by prolonged hospitalisation. There was considerable heterogeneity between studies with regard to patient populations, outcomes and procedures, as well as a lack of consistency and transparency of reporting of costs/resource use. Complication severity grading systems were used infrequently.
Conclusions
The overall conclusions of included studies are consistent: complications represent an important economic burden for health care providers. We conclude that more accurate and consistent data collection is required to serve as input for good-quality economic analyses, which in turn can inform hospital decisions on cost-efficient allocation of their limited resources.
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