Novel explanted human liver model to assess hepatic extraction, biliary excretion, and transporter function

Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug–drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (Cmax) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers. Cellular mechanisms in basic and clinical gastroenterology and hepatolog

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney’s and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the “Role of pancreas machine perfusion to increase the donor pool for beta cell replacement,” the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.</p

Seroprevalence and Risk Factors of Lyme Borreliosis in The Netherlands: A Population-Based Cross-Sectional Study

Lyme borreliosis (LB) is not notifiable in many European countries, and accurate data on the incidence are often lacking. This study aimed to determine the seroprevalence of Borrelia burgdorferi sensu lato (s.l.)-specific antibodies in the general population of The Netherlands, and to determine risk factors associated with seropositivity. Sera and questionnaires were obtained from participants (n = 5592, aged 0-88 years) enrolled in a nationwide serosurveillance study. The sera were tested for B. burgdorferi s.l.-specific IgM and IgG antibodies using ELISA and immunoblot. Seroprevalence was estimated controlling for the survey design. Risk factors for seropositivity were analyzed using a generalized linear mixed-effect model. In 2016/2017, the seroprevalence in The Netherlands was 4.4% (95% CI 3.5-5.2). Estimates were higher in men (5.7% [95% CI 4.4-7.2]) than in women (3.1% [95% CI 2.0-4.0]), and increased with age from 2.6% (95% CI 1.4-4.4) in children to 7.7% (95% CI 5.9-7.9) in 60- to 88-year-olds. The seroprevalence for B. burgdorferi s.l. in the general population in The Netherlands was comparable to rates reported in European countries. The main risk factors for seropositivity were increasing age, being male and the tick bite frequency. The dynamics of LB infection are complex and involve variables from various disciplines. This could be further elucidated using infectious disease modelling

Experimental traumatic brain injury

Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury

Evidence for Time-Dependent Glutamate-Mediated Glycolysis in Head-Injured Patients: A Microdialysis Study

In the brain, lactate is not only a marker of anaerobic glycolysis due to hypoxia/ischemia, but also a neuronal energy source which is provided by glutamate-induced astrocytic glycolysis. In the present study we wanted to investigate the relationship between glutamate release and lactate production during the entire time-course and during three time periods of microdialytic monitoring in 54 severely head injured patients. Within-subject Spearman rank correlations were calculated in each period for glutamate and lactate, for each patient and the mean of all correlation coefficients were analyzed for difference from zero by a one-sample t-test. The results show a strong overall positive relationship between glutamate and lactate. However, during the first 12 hours after injury, there was no significant correlation. Thereafter, good correlation was seen. The splitting of patients into groups with good (Glasgow Outcome Scale; GOS 0–2) and poor outcome (GOS 3–4) showed a similar strong correlation for patients with good outcome, but this was lost for patients with poor outcome. The results clearly indicate that glutamate “drives” astrocytic lactate production in head-injured patients. The contribution of glutamate to overall lactate release is thus time-dependent. During the first 12 hours after injury, factors such as hypoxia, ischemia or edema overshadowed glutamate-induced glycolysis in astrocytes. In addition, the effect of glutamate is more pronounced in patients with good outcome

Evidence for time-dependent glutamate-mediated glycolysis in head-injured patients: a microdialysis study

In the brain, lactate is not only a marker of anaerobic glycolysis due to hypoxia/ischemia, but also a neuronal energy source which is provided by glutamate-induced astrocytic glycolysis. In the present study we wanted to investigate the relationship between glutamate release and lactate production during the entire time-course and during three time periods of microdialytic monitoring in 54 severely head injured patients. Within-subject Spearman rank correlations were calculated in each period for glutamate and lactate, for each patient and the mean of all correlation coefficients were analyzed for difference from zero by a one-sample t-test. The results show a strong overall positive relationship between glutamate and lactate. However, during the first 12 hours after injury, there was no significant correlation. Thereafter, good correlation was seen. The splitting of patients into groups with good (Glasgow Outcome Scale; GOS 0-2) and poor outcome (GOS 3-4) showed a similar strong correlation for patients with good outcome, but this was lost for patients with poor outcome. The results clearly indicate that glutamate "drives" astrocytic lactate production in head-injured patients. The contribution of glutamate to overall lactate release is thus time-dependent. During the first 12 hours after injury, factors such as hypoxia, ischemia or edema overshadowed glutamate-induced glycolysis in astrocytes. In addition, the effect of glutamate is more pronounced in patients with good outcome

Cortical extracellular sodium transients after human head injury: an indicator of secondary brain damage?

Animal studies indicate that elevated extracellular sodium can increase glutamate-induced excitotoxicity. Therefore, we investigated the relationship between sodium and glutamate and the effect of changes in sodium concentrations on the outcome of head-injured patients. Thirty-four (34) patients were selected for this study and divided into a group of patients having episodes (> or = 30-min) of high sodium in dialysates (> or = 200 mM; HIGH, n = 11) and a group of patients having no such episodes (NORMAL, n = 23). Levels for sodium (226 +/- 5.7 mM), glutamate (12.53 +/- 2.2 microM) and ICP (32.2 +/- 4.0 mm Hg,) were relatively high during the high sodium episodes. Overall, mean values for glutamate, ICP and outcome did not differ amono both groups. The mean dialysate sodium concentration, however, was significantly higher in the HIGH (178 +/- 6 mM) compared to the NORMAL group (158 +/- 3 mM; p < 0.01). Spearman rank correlation between sodium and glutamate or ICP were not significant. The HIGH sodium group did not have significantly more patients with poor outcome than the NORMAL group. The results indicated sodium concentrations did not affect the outcome of head-injured patients. However, other sodium monitoring techniques are desirable to elucidate these apparent potentially major sodium transients, which we have observed in the human cortex, after severe head injury

Cortical Extracellular Sodium Transients after Human Head Injury: An Indicator of Secondary Brain Damage?

Animal studies indicate that elevated extracellular sodium can increase glutamate-induced excitotoxicity. Therefore, we investigated the relationship between sodium and glutamate and the effect of changes in sodium concentrations on the outcome of head-injured patients. Thirty-four (34) patients were selected for this study and divided into a group of patients having episodes (≥;30-min) of high sodium in dialysates (≥200 mM; HIGH, n = 11) and a group of patients having no such episodes (NORMAL, n = 23). Levels for sodium (226 ± 5.7 mM), glutamate (12.53 ± 2.2 μM) and ICP (32.2 ± 4.0 mm Hg,) were relatively high during the high sodium episodes. Overall, mean values for glutamate, ICP and outcome did not differ amono both groups. The mean dialysate sodium concentration, however, was significantly higher in the HIGH (178 ± 6 mM) compared to the NORMAL group (158 ± 3mM; p < 0.01). Spearman rank correlation between sodium and glutamate or ICP were not significant. The HIGH sodium group did not have significantly more patients with poor outcome than the NORMAL group. The results indicated sodium concentrations did not affect the outcome of head-injured patients. However, other sodium monitoring techniques are desirable to elucidate these apparent potentially major sodium transients, which we have observed in the human cortex, after severe head injury