A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury.

AIM: Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20-HETE and prevent the initiation of AKI. METHODS: Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP-eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI. RESULTS: Ischemia induced an about eightfold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K- as well as mTORC2-dependent rephosphorylation of Akt, induced inactivation of GSK-3ß, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R-induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20-HETE and 8,9-EET levels. CONCLUSIONS: Pharmacological interventions targeting the CYP-eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP-eicosanoid formation may contribute to the risk of developing AKI in clinical settings.

Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception.

Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.

Detailing the relation between renal T2* and renal tissue pO2 using an integrated approach of parametric magnetic resonance imaging and invasive physiological measurements.

OBJECTIVES: This study was designed to detail the relation between renal T2* and renal tissue pO2 using an integrated approach that combines parametric magnetic resonance imaging (MRI) and quantitative physiological measurements (MR-PHYSIOL). MATERIALS AND METHODS: Experiments were performed in 21 male Wistar rats. In vivo modulation of renal hemodynamics and oxygenation was achieved by brief periods of aortic occlusion, hypoxia, and hyperoxia. Renal perfusion pressure (RPP), renal blood flow (RBF), local cortical and medullary tissue pO2, and blood flux were simultaneously recorded together with T2*, T2 mapping, and magnetic resonance-based kidney size measurements (MR-PHYSIOL). Magnetic resonance imaging was carried out on a 9.4-T small-animal magnetic resonance system. Relative changes in the invasive quantitative parameters were correlated with relative changes in the parameters derived from MRI using Spearman analysis and Pearson analysis. RESULTS: Changes in T2* qualitatively reflected tissue pO2 changes induced by the interventions. T2* versus pO2 Spearman rank correlations were significant for all interventions, yet quantitative translation of T2*/pO2 correlations obtained for one intervention to another intervention proved not appropriate. The closest T2*/pO2 correlation was found for hypoxia and recovery. The interlayer comparison revealed closest T2*/pO2 correlations for the outer medulla and showed that extrapolation of results obtained for one renal layer to other renal layers must be made with due caution. For T2* to RBF relation, significant Spearman correlations were deduced for all renal layers and for all interventions. T2*/RBF correlations for the cortex and outer medulla were even superior to those between T2* and tissue pO2. The closest T2*/RBF correlation occurred during hypoxia and recovery. Close correlations were observed between T2* and kidney size during hypoxia and recovery and for occlusion and recovery. In both cases, kidney size correlated well with renal vascular conductance, as did renal vascular conductance with T2*. Our findings indicate that changes in T2* qualitatively mirror changes in renal tissue pO2 but are also associated with confounding factors including vascular volume fraction and tubular volume fraction. CONCLUSIONS: Our results demonstrate that MR-PHYSIOL is instrumental to detail the link between renal tissue pO2 and T2* in vivo. Unravelling the link between regional renal T2* and tissue pO2, including the role of the T2* confounding parameters vascular and tubular volume fraction and oxy-hemoglobin dissociation curve, requires further research. These explorations are essential before the quantitative capabilities of parametric MRI can be translated from experimental research to improved clinical understanding of hemodynamics/oxygenation in kidney disorders.

Enlargement of cerebral ventricles as an early indicator of encephalomyelitis.

Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.

High temporal resolution parametric MRI monitoring of the initial ischemia/reperfusion phase in experimental acute kidney injury.

Ischemia/reperfusion (I/R) injury, a consequence of kidney hypoperfusion or temporary interruption of blood flow is a common cause of acute kidney injury (AKI). There is an unmet need to better understand the mechanisms operative during the initial phase of ischemic AKI. Non-invasive in vivo parametric magnetic resonance imaging (MRI) may elucidate spatio-temporal pathophysiological changes in the kidney by monitoring the MR relaxation parameters T2* and T2, which are known to be sensitive to blood oxygenation. The aim of our study was to establish the technical feasibility of fast continuous T2*/T2 mapping throughout renal I/R. MRI was combined with a remotely controlled I/R model and a segmentation model based semi-automated quantitative analysis. This technique enabled the detailed assessment of in vivo changes in all kidney regions during ischemia and early reperfusion. Significant changes in T2* and T2 were observed shortly after induction of renal ischemia and during the initial reperfusion phase. Our study demonstrated for the first time that continuous and high temporal resolution parametric MRI is feasible for in-vivo monitoring and characterization of I/R induced AKI in rats. This technique may help in the identification of the timeline of key events responsible for development of renal damage in hypoperfusion-induced AKI.

Design, construction, and evaluation of a dynamic MR compatible cardiac left ventricle model.

PURPOSE: Development of magnetic resonance (MR) sequences is important to answer clinical questions and to overcome current limitations. To meet the challenges of cardiac MR, dynamic and reproducible testing conditions are required. We aimed at developing a dynamic MR-compatible cardiac left ventricle model that imitates myocardial tissue properties and simulates dynamic motion. METHODS: A dynamic left ventricle silicone model was designed to match myocardial T(1) and T(2) relaxation times. Silicone mixtures were explored to replicate T(2) values of myocardial edema. A controllable piston pump was constructed to produce pulsatile flow paradigms. They were validated against flow sensors and MR data, including SSFP-based and phase-contrast-based sequences. A dedicated software interface was developed for the control. RESULTS: Model dimensions represented cardiac left ventricle dimensions of healthy men. The range of end diastolic volumes was 85-175 ml, depending on the driven stroke volume. Stroke volume quantification for flow paradigms of 30∕60∕90∕120 ml resulted in 29.2∕57.6∕88.8∕118.4 ml by MR volumetry, 29.6∕59.9∕89.4∕119.0 ml by phase contrast measurements, and 29.9∕60.4∕91.1∕120.9 ml by flow meter revealing consistency. The system accurately replicated physiological and pathophysiological flow paradigms. The silicon model exhibited T(1) of 1002 ± 8 ms, T(2) of 58 ± 1 ms. Signal intensities (a.u.) of the ventricle model were 128 ± 23 for FGRE (vs 138 ± 17 in vivo) and 1156 ± 37 for b-SSFP (vs 991 ± 96 in vivo). T(2) of 75 ± 2 ms was achieved for the myocardial pathology. CONCLUSIONS: We developed a controllable left ventricle model resembling MR signal characteristics of human myocardium, including pathological conditions, and allowing for the replication of contraction and flow paradigms.

[Introduction of electronic monitoring increased interest for quality work. Nine-year-registration at Hjartcentrum indicates improved medical results]. / Elektronisk uppföljning okade intresset för kvalitetsarbete i Umeå. Nio ars registrering vid Hjärtcentrum visar att medicinska resultat förbättras.

Medical, administrative and economic data in a cardio-thoracic unit were followed for 9 years in an extensive monitoring system. Several changes in the practice could be observed. There was a general improvement in total quality factors seen as decreased complication rate especially in normal patients, a change in case mix towards older and more complicated patients and a decrease in the costs. The monitoring was a prerequisite for following, initiating and controlling changes. The article is published in English in Interactive Cardiovascular and Thoracic Surgery.

Improved total quality by monitoring of a cardiothoracic unit. Medical, administrative and economic data followed for 9 years.

To describe monitoring of a cardio-thoracic department from a total quality aspect point of view and to follow the development over 9 years. During the time period 1994-2002 a total of 10,828 cardio-thoracic operations were performed. Capacity, demographic, risk, quality, outcome and economic data were prospectively collected in various registries and analysed. Mean (and median) age increased from 64.2 to 65.3 (66-67). Patients above 70 years increased from 33.6 to 38.7% and above 80 from 2.9 to 5.5%. Operative mortality was unchanged over the time periods at slightly over 2%, with 1-year mortality 6-7%. Mortality for primary, elective coronary artery bypass grafting was 0.26% during the last 3 years. The rate of postoperative complications remained unchanged or decreased with few exceptions: Patients with postoperative confusion increased from 5.0 to 8.1% and patients with a need for face mask ventilation increased from 2.4 to 4.0%. Mean postoperative ventilation time was unchanged at around 22 h, whereas the median decreased from 9.5 to 5.3 h. The workload created by elderly patients was especially noticeable in the intensive care unit (ICU) as both number of postoperative deviations and ICU hours increased as a function of age. Cost per operation decreased by 11%. Total medical rationalisation was higher as salaries increased over time. Mean length of stay decreased by 3 days. Hospital staff hours per operation decreased whereas hospital staff hours per patient hour increased. Physician cost per operation was unchanged. Patient, staff and referring physician satisfaction was high. Several areas for improvement have been found. Monitoring and general feedback of total quality factors has shown itself a powerful tool to detect and follow large and subtle changes in the practice of cardio-thoracic surgery. Most followed factors show improvement in spite of an increase in mean and median age. Several areas may be defined where further development might decrease the trauma to the patient. Aiming at a total quality and patient safety system, monitoring is an essential prerequisite.