The Impact of Head Position on Neurological and Histopathological Outcome Following Controlled Automated Reperfusion of the Whole Body (CARL) in a Pig Model.

Introduction: Based on extracorporeal circulation, targeted reperfusion strategies have been developed to improve survival and neurologic recovery in refractory cardiac arrest: Controlled Automated Reperfusion of the whoLe Body (CARL). Furthermore, animal and human cadaver studies have shown beneficial effects on cerebral pressure due to head elevation during conventional cardiopulmonary resuscitation. Our aim was to evaluate the impact of head elevation on survival, neurologic recovery and histopathologic outcome in addition to CARL in an animal model. Methods: After 20 min of ventricular fibrillation, 46 domestic pigs underwent CARL, including high, pulsatile extracorporeal blood flow, pH-stat acid-base management, priming with a colloid, mannitol and citrate, targeted oxygen, carbon dioxide and blood pressure management, rapid cooling and slow rewarming. N = 25 were head-up (HUP) during CARL, and N = 21 were supine (SUP). After weaning from ECC, the pigs were extubated and followed up in the animal care facility for up to seven days. Neuronal density was evaluated in neurohistopathology. Results: More animals in the HUP group survived and achieved a favorable neurological recovery, 21/25 (84%) versus 6/21 (29%) in the SUP group. Head positioning was an independent factor in neurologically favorable survival (p < 0.00012). Neurohistopathology showed no significant structural differences between HUP and SUP. Distinct, partly transient clinical neurologic deficits were blindness and ataxia. Conclusions: Head elevation during CARL after 20 min of cardiac arrest independently improved survival and neurologic outcome in pigs. Clinical follow-up revealed transient neurologic deficits potentially attributable to functions localized in the posterior perfusion area, whereas histopathologic findings did not show corresponding differences between the groups. A possible explanation of our findings may be venous congestion and edema as modifiable contributing factors of neurologic injury following prolonged cardiac arrest.

The endocannabinoid system in humans: significant associations between anandamide, brain function during reward feedback and a personality measure of reward dependence.

Preclinical evidence indicates that the endocannabinoid system is involved in neural responses to reward. This study aimed to investigate associations between basal serum concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) with brain functional reward processing. Additionally, a personality measure of reward dependence was obtained. Brain functional data were obtained of 30 right-handed adults by conducting fMRI at 3 Tesla using a reward paradigm. Reward dependence was obtained using the subscale reward dependence of the Tridimensional Personality Questionnaire (TPQ). Basal concentrations of AEA and 2-AG were determined in serum. Analyzing the fMRI data, for AEA and 2-AG ANCOVAs were calculated using a full factorial model, with condition (reward > control, loss > control) and concentrations for AEA and 2-AG as factors. Regression analyses were conducted for AEA and 2-AG on TPQ-RD scores. A whole-brain analysis showed a significant interaction effect of AEA concentration by condition (positive vs. negative) within the putamen (x = 26, y = 16, z = -8, F13.51, TFCE(1, 54) = 771.68, k = 70, PFWE = 0.044) resulting from a positive association of basal AEA concentrations and putamen activity to rewarding stimuli, while this association was absent in the loss condition. AEA concentrations were significantly negatively correlated with TPQ reward dependence scores (rspearman = -0.56, P = 0.001). These results show that circulating AEA may modulate brain activation during reward feedback and that the personality measure reward dependence is correlated with AEA concentrations in healthy human volunteers. Future research is needed to further characterize the nature of the lipids' influence on reward processing, the impact on reward anticipation and outcome, and on vulnerability for psychiatric disorders.

Microenvironmental stromal cells abrogate NF-κB inhibitor-induced apoptosis in chronic lymphocytic leukemia.

Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) is known to play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). Several NF-κB inhibitors were shown to successfully induce apoptosis of CLL cells in vitro Since the microenvironment is known to be crucial for the survival of CLL cells, herein, we tested whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). Microenvironmental support was mimicked by co-culturing CLL cells with bone marrow-derived stromal cell lines (HS-5 and M2-10B4). NF-κB inhibition by DHMEQ in CLL cells could be confirmed in both the monoculture and co-culture setting. In line with previous reports, NF-κB inhibition induced apoptosis in the monoculture setting by activating the intrinsic apoptotic pathway resulting in poly (ADP-ribose) polymerase (PARP)-cleavage; however, it was unable to induce apoptosis in leukemic cells co-cultured with stromal cells. Similarly, small interfering ribonucleic acid (siRNA)-mediated RELA downregulation induced apoptosis of CLL cells cultured alone, but not in the presence of supportive stromal cells. B-cell activating factor (BAFF) was identified as a microenvironmental messenger potentially protecting the leukemic cells from NF-κB inhibition-induced apoptosis. Finally, we show improved sensitivity of stroma-supported CLL cells to NF-κB inhibition when combining the NF-κB inhibitor with the SYK inhibitor R406 or the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, agents known to inhibit the stroma-leukemia crosstalk. We conclude that NF-κB inhibitors are not promising as monotherapies in CLL, but may represent attractive therapeutic partners for ibrutinib and R406.

Twenty minutes of normothermic cardiac arrest in a pig model: the role of short-term hypothermia for neurological outcome.

INTRODUCTION: Cardiopulmonary resuscitation restores circulation, but with inconsistent blood-flow and pressures. Our recent approach using an extracorporeal life support system, named "controlled integrated resuscitation device" (CIRD), may lead to improved survival and neurological recovery after cardiac arrest (CA). The basic idea is to provide a reperfusion tailored to the individual patient by control of the conditions of reperfusion and the composition of the reperfusate. Hypothermia is one aspect of this concept. Here, we investigated the role of immediate short-term blood cooling after experimental CA and its influence on survival and neurological recovery. METHODS: Twenty-one pigs were exposed to 20 minutes of normothermic CA. Afterwards, CIRD was immediately started for 60 minutes in all animals and the heart was converted to a sinus rhythm. The pigs either received normothermic reperfusion (37°C, n=11) or the temperature was maintained at 32°C for the first 30 minutes (n=10). Thermometric, hemodynamic and serologic data were collected during the experiment. After weaning from CIRD, neurological recovery was assessed daily by a species-specific neurological deficit score (NDS; 0: normal; 500: brain death). RESULTS: One pig in each group could not be successfully resuscitated. Due to severe neurological deficits, only 6/11 animals in the normothermic group finished the observation time of seven days with an NDS of 37±34. In the hypothermic group, all nine surviving animals reached day seven with an NDS of 16±13. Analogous to the lower NDS, animals in the hypothermic group also showed lower neuron-specific enolase end values as a marker of brain injury. CONCLUSIONS: Within this experimental setting, immediate moderate and short-term hypothermia after CA improves survival and seems to result in statistically non-significant better neurological recovery.

A behavioural syndrome, but less evidence for a relationship with cognitive traits in a spatial orientation context.

BACKGROUND: Animals show consistent individual behavioural differences in many species. Further, behavioural traits (personality traits) form behavioural syndromes, characterised by correlations between different behaviours. Mechanisms maintaining these correlations could be constrained due to underlying relationships with cognitive traits. There is growing evidence for the non-independence of animal personality and general cognitive abilities in animals, but so far, studies on the direction of the relationship between them revealed contradictory results. Still, it is hypothesised that individuals may exhibit consistent learning and decision styles. Fast behavioural types (consistently bolder and more active individuals) are expected to show faster learning styles. Slow behavioural types in contrast are assumed to learn slower but more accurately. This can be caused by a speed-accuracy trade-off that individuals face during decision making. We measured the repeatability of three personality and four spatial cognitive traits in adult Eurasian harvest mice (Micromys minutus). We analysed correlations among personality traits (behavioural syndrome). We further investigated the relationships between personality and spatial cognitive traits as a first step exploring the potential connection between personality and cognition in this species. RESULTS: Our results showed that exploration, activity and boldness were repeatable in adult mice. Spatial recognition measured in a Y Maze was also significantly repeatable, as well as spatial learning performance and decision speed. We found no repeatability of decision accuracy. Harvest mice showed a behavioural syndrome as we observed strong positive correlations between personality traits. The speed-accuracy trade-off was not apparent within, nor between individuals. Nevertheless, we found weak evidence for a relationship between personality and spatial cognitive traits as fast behavioural types learned a spatial orientation task faster than slow types, and shyer harvest mice made decisions quicker than bolder mice. CONCLUSIONS: Given these correlations, our data provided some first insights into the relationship between personality and spatial cognitive traits in harvest mice and will hopefully stimulate more studies in this field.

Repeatability and consistency of individual behaviour in juvenile and adult Eurasian harvest mice.

Knowledge on animal personality has provided new insights into evolutionary biology and animal ecology, as behavioural types have been shown to affect fitness. Animal personality is characterized by repeatable and consistent between-individual behavioural differences throughout time and across different situations. Behavioural repeatability within life history stages and consistency between life history stages should be checked for the independence of sex and age, as recent data have shown that males and females in some species may differ in the repeatability of behavioural traits, as well as in their consistency. We measured the repeatability and consistency of three behavioural and one cognitive traits in juvenile and adult Eurasian harvest mice (Micromys minutus). We found that exploration, activity and boldness were repeatable in juveniles and adults. Spatial recognition measured in a Y Maze was only repeatable in adult mice. Exploration, activity and boldness were consistent before and after maturation, as well as before and after first sexual contact. Data on spatial recognition provided little evidence for consistency. Further, we found some evidence for a litter effect on behaviours by comparing different linear mixed models. We concluded that harvest mice express animal personality traits as behaviours were repeatable across sexes and consistent across life history stages. The tested cognitive trait showed low repeatability and was less consistent across life history stages. Given the rising interest in individual variation in cognitive performance, and in its relationship to animal personality, we suggest that it is important to gather more data on the repeatability and consistency of cognitive traits.

Photonic sensing of arterial distension.

Most cardiovascular diseases, such as arteriosclerosis and hypertension, are directly linked to pathological changes in hemodynamics, i.e. the complex coupling of blood pressure, blood flow and arterial distension. To improve the current understanding of cardiovascular diseases and pave the way for novel cardiovascular diagnostics, innovative tools are required that measure pressure, flow, and distension waveforms with yet unattained spatiotemporal resolution. In this context, miniaturized implantable solutions for continuously measuring these parameters over the long-term are of particular interest. We present here an implantable photonic sensor system capable of sensing arterial wall movements of a few hundred microns in vivo with sub-micron resolution, a precision in the micrometer range and a temporal resolution of 10 kHz. The photonic measurement principle is based on transmission photoplethysmography with stretchable optoelectronic sensors applied directly to large systemic arteries. The presented photonic sensor system expands the toolbox of cardiovascular measurement techniques and makes these key vital parameters continuously accessible over the long-term. In the near term, this new approach offers a tool for clinical research, and as a perspective, a continuous long-term monitoring system that enables novel diagnostic methods in arteriosclerosis and hypertension research that follow the trend in quantifying cardiovascular diseases by measuring arterial stiffness and more generally analyzing pulse contours.

Preserved brain morphology after controlled automated reperfusion of the whole body following normothermic circulatory arrest time of up to 20 minutes.

OBJECTIVES: Clinical outcomes following cardiac arrest (CA) and resuscitation remain a cause for concern. The use of Controlled Automated Reperfusion of the whoLe body (CARL) confers superior neurological outcome even after extended periods of CA. We aimed at investigating clinical outcome and brain morphology preservation when employing CARL following CA periods of 20 min. METHODS: Twenty-eight pigs were allocated to four extracorporeal circulation treatment strategies; seven others served as magnetic resonance imaging (MRI) controls. In prompt cardiopulmonary resuscitation (CPR; n = 6), induced circulatory arrest was followed immediately by open cardiac massage of 15 min, thereafter by CARL for 60 min. In delayed CPR (n = 6), induced CA was maintained for 15 min, after that open cardiac massage of 10 min duration was performed prior to extracorporeal CPR (ECPR) of 60 min. Induced CA times of 15 min in the ECPR 15' group (n = 6) and CA of 20 min in the CARL 20' group (n = 10) were followed by ECPR of 60 min and CARL of 60 min, respectively, without prior CPR. Daily neurological deficit scoring (NDS) up to the seventh day, markers of cellular injury [alanine transaminase (ALT), aspartate transaminase (AST) and neuron-specific enolase (NSE)] and brain MRI were performed. RESULTS: 100% survival and normal NDSs were achieved in all animals in the prompt CPR and ECPR 15' groups. In CARL 20', nine animals survived. In contrast, only one animal in the delayed CPR group survived; three animals died within 24 h with a further two dying on Days 4 and 5, respectively. All markers of cellular injury were elevated in the delayed CPR group, ALT [38 (20.3) to 206 U/l (158.2); P = 0.0095], AST [26 (18.8) to 97 U/l (1965.8); P = 0.0095] and NSE [0.45 (0.25) to 7.95 µg/l (24.03); P = 0.0095]. In the ECPR 15' group, only NSE [0.45 (0.15) to 1.20 µg/l (2.40); P = 0.0065] remained elevated. In the CARL 20' group, differences in ALT [36 (10) to 53 U/l (20); P = 0.0005] and NSE [0.50 (0.40) to 1.5 µg/l (0.40); P < 0.0001] values were evident. T2-weighted MR images of the cerebellum [454 (28) to 495 mm2/s (55); U = 11; P = 0.0311], caudate nucleus [400 (59) to 467 mm2/s (42); U = 9; P = 0.0156], lentiform nucleus [377 (89) to 416 mm2/s (55); U = 11; P = 0.0311] and hippocampus [421 (109) to 511 mm2/s (58); U = 9; P = 0.0164] in the CARL 20' group showed higher signal intensities compared with controls. In delayed CPR, corresponding regions of interest on early apparent diffusion coefficient images showed a restricted diffusion. CONCLUSIONS: In our experimental animal model of CA, CARL results in satisfactory survival at CA periods of 20 min despite detected enzyme and morphological changes. These changes did not translate to clinical neurological deficits.

A multivariate analysis of genetic constraints to life history evolution in a wild population of red deer.

Evolutionary theory predicts that genetic constraints should be widespread, but empirical support for their existence is surprisingly rare. Commonly applied univariate and bivariate approaches to detecting genetic constraints can underestimate their prevalence, with important aspects potentially tractable only within a multivariate framework. However, multivariate genetic analyses of data from natural populations are challenging because of modest sample sizes, incomplete pedigrees, and missing data. Here we present results from a study of a comprehensive set of life history traits (juvenile survival, age at first breeding, annual fecundity, and longevity) for both males and females in a wild, pedigreed, population of red deer (Cervus elaphus). We use factor analytic modeling of the genetic variance-covariance matrix ( G: ) to reduce the dimensionality of the problem and take a multivariate approach to estimating genetic constraints. We consider a range of metrics designed to assess the effect of G: on the deflection of a predicted response to selection away from the direction of fastest adaptation and on the evolvability of the traits. We found limited support for genetic constraint through genetic covariances between traits, both within sex and between sexes. We discuss these results with respect to other recent findings and to the problems of estimating these parameters for natural populations.

Magnetic sensor for arterial distension and blood pressure monitoring.

A novel sensor for measuring arterial distension, pulse and pressure waveform is developed and evaluated. The system consists of a magnetic sensor which is applied and fixed to arterial vessels without any blood vessel constriction, hence avoiding stenosis. The measurement principle could be validated by in vitro experiments on silicone tubes, and by in vivo experiments in an animal model, thereby indicating the non-linear viscoelastic characteristics of real blood vessels. The sensor is capable to provide absolute measurements of the dynamically varying arterial diameter. By calibrating the sensor, a long-term monitoring system for continuously measuring blood pressure and other cardiovascular parameters could be developed based on the method described. This will improve diagnostics for high risk patients and enable a better, specific treatment.

Mapping of sheep sensory cortex with a novel microelectrocorticography grid.

Microelectrocorticography (µECoG) provides insights into the cortical organization with high temporal and spatial resolution desirable for better understanding of neural information processing. Here we evaluated the use of µECoG for detailed cortical recording of somatosensory evoked potentials (SEPs) in an ovine model. The approach to the cortex was planned using an MRI-based 3D model of the sheep's brain. We describe a minimally extended surgical procedure allowing placement of two different µECoG grids on the somatosensory cortex. With this small craniotomy, the frontal sinus was kept intact, thus keeping the surgical site sterile and making this approach suitable for chronic implantations. We evaluated the procedure for chronic implantation of an encapsulated µECoG recording system. During acute and chronic recordings, significant SEP responses in the triangle between the ansate, diagonal, and coronal sulcus were identified in all animals. Stimulation of the nose, upper lip, lower lip, and chin caused a somatotopic lateral-to-medial, ipsilateral response pattern. With repetitive recordings of SEPs, this somatotopic pattern was reliably recorded for up to 16 weeks. The findings of this study confirm the previously postulated ipsilateral, somatotopic organization of the sheep's sensory cortex. High gamma band activity was spatially most specific in the comparison of different frequency components of the somatosensory evoked response. This study provides a basis for further acute and chronic investigations of the sheep's sensory cortex by characterizing its exact position, its functional properties, and the surgical approach with respect to macroanatomical landmarks.

An implantable optical blood pressure sensor based on pulse transit time.

An implantable sensor system for long-term monitoring of blood pressure is realized by taking advantage of the correlation between pulse transit time and blood pressure. The highly integrated implantable sensor module, fabricated using MEMS technologies, uses 8 light emitting diodes (LEDs) and a photodetector on chip level. The sensor is applied to large blood vessels, such as the carotid or femoral arteries, and allows extravascular measurement of highly-resolved photoplethysmograms. In addition, spectrophotometric approaches allow measurement of hemoglobin derivatives. For the calibration of blood pressure measurements, the sensor system has been successfully implemented in animal models.

Arterial input function measurements for bolus tracking perfusion imaging in the brain.

Imaging of cerebral perfusion by tracking the first passage of an exogenous paramagnetic contrast agent (termed dynamic susceptibility contrast, MRI) has been used in the clinical practice for about a decade. However, the primary goal of dynamic susceptibility contrast MRI to directly quantify the local cerebral blood flow remains elusive. The major challenge of dynamic susceptibility contrast MRI is to measure the contrast inflow to the brain, i.e., the arterial input function. The measurement is complicated by the limited dynamic range of MRI pulse sequences that are optimized for a good contrast in brain tissue but are suboptimal for a much higher tracer concentration in arterial blood. In this work, we suggest a novel method for direct arterial input function quantification. The arterial input function is measured in the carotid arteries with a dedicated plug-in to the conventional pulse sequence to enable resolution of T(2) on the order of a millisecond. The new technique is compatible with the clinical measurement protocols. Applied to the pig model (N = 13), the method demonstrates robustness of the arterial input function measurement. The cardiac output and cerebral blood volume, obtained without adjustable parameters, agree well with positron emission tomography measurements and values found in the literature.

Arterial strain measurement by implantable capacitive sensor without vessel constriction.

Cardiovascular disease caused 32.8% of deaths in the United States in 2008 [1]. The most important medical parameter is the arterial blood pressure. The origin of high or low blood pressure can mostly be found in the vessel compliance. With the presented implantable sensor, we are able to directly measure strain of arteries, as an indicator of arteriosclerosis. The sensor is designed as a cuff with integrated capacitive structures and is wrapped around arteries. With a new and innovative locking method, we could show that the system does not affect the arteries. This is demonstrated by theory as well as experimental in vivo investigations. Biocompatibility tests, confirmed by histological cuts and MRI measurements, showed that no stenosis, allergic reactions or inflammation occurs. The sensor shows excellent linear behavior with respect to stress and strain.

Determination of vessel wall dynamics by optical microsensors.

Spectralphotometric measurement methods as, for example, pulse oximetry are established approaches for extracorporeal determination of blood constituents. We measure the dynamics of the arterial distension intracorporeally thus extending the scope of the method substantially. A miniaturized opto-electronic sensor is attached directly to larger arteries without harming the vessel. The transmitted light through the arteries shows a linear correlation with the pulsatile expansion in theory as well as in experiments. Intra-arterial blood pressure also shows a linear interrelationship with the optical signal. Measurements of blood vessel wall dynamics has great potential to quantify arteriosclerosis by this new and innovative approach.

The novel immunoregulatory molecule FGL2: a potential biomarker for severity of chronic hepatitis C virus infection.

BACKGROUND & AIMS: This report describes the use of a novel sensitive and specific ELISA for the measurement of human fibrinogen-like protein 2 (FGL2/fibroleukin), a novel effector of natural regulatory T (Treg) cells, to predict the course of chronic hepatitis C viral infection (HCV). METHODS: Plasma levels of FGL2 were measured in HCV patients and compared to healthy controls and to patients with alcoholic liver disease. RESULTS: FGL2 levels were significantly higher in HCV patients (84.3+/-89.1 ng/ml, n=80) compared to healthy controls (36.4+/-21.9 ng/ml, n=30, p<0.001), to a subset of patients who cleared HCV following anti-viral treatment (16.6+/-19.7 ng/ml, n=32, p<0.001), and to patients with inactive alcoholic liver disease (18.8+/-17.4 ng/ml, n=24, p<0.001). Among HCV patients, plasma levels of FGL2 correlated significantly with the stage of fibrosis (p=0.001) and were significantly higher in patients with cirrhosis (164.1+121.8 ng/ml, n=60) compared to non-cirrhotics (57.7+/-52.8 ng/ml, n=20, p=0.001). Genotype 1 patients had significantly higher levels of FGL2 (98.1+/-100.3 ng/ml, n=60) compared to patients with genotype 2/3 (41.5+/-38.6 ng/ml, n=20, p=0.0008). Patients with genotype 2/3 had FGL2 levels similar to healthy controls (41.5+/-38.6 vs. 36.41+/-21.9 ng/ml, p=ns). Infiltrating lymphocytes in liver biopsies of HCV patients were positive for either FGL2 or FoxP3 (a marker of Treg cells) or expressed both markers. CONCLUSIONS: This report documents the development of a sensitive ELISA for measurement of plasma levels of FGL2 an effector Treg cells, which correlates with the severity of HCV infection.

Inhaled carbon monoxide prevents acute kidney injury in pigs after cardiopulmonary bypass by inducing a heat shock response.

BACKGROUND: Cardiopulmonary bypass (CPB) may be associated with acute kidney injury (AKI). Inhaled carbon monoxide (CO) is cyto- and organ-protective. We hypothesized that pretreatment with inhaled CO prevents CPB-associated AKI. METHODS: Pigs (n = 38) were nonrandomly assigned to SHAM, standard CPB, pretreatment with inhaled CO (250 ppm, 1 hour) before SHAM or CPB, to pretreatment with quercetin (an inhibitor of the heat shock response), and to pretreatment with SnPPIX (an inhibitor of endogenously derived CO), before CO inhalation and CPB. The primary outcome variables were markers of AKI (urea, uric acid, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor-alpha), which were determined 120 minutes after CPB. Secondary outcome variables were heat shock protein (HSP)-70 and heme oxygenase-1 protein expressions as indicators of CO-mediated heat shock response. RESULTS: Pretreatment with inhaled CO attenuated (all P < 0.001) CPB-associated, (1) increases in serum concentrations of cystatin C (64 +/- 14 vs 28 +/- 9 ng/mL), neutrophil gelatinase-associated lipocalin (391 +/- 65 vs 183 +/- 56 ng/mL), renal tumor necrosis factor-alpha (450 +/- 73 vs 179 +/- 110 pg/mL), and interleukin-6 (483 +/- 102 vs 125 +/- 67 pg/mL); (2) increase in renal caspase-3 activity (550 +/- 66 vs 259 +/- 52 relative fluorescent units); and (3) histological evidence of AKI. These effects were accompanied by activation of HSP-70 (196 +/- 64 vs 554 +/- 149 ng/mL, P < 0.001). Pretreatment with the heat shock response inhibitor quercetin counteracted the CO-associated biochemical and histological renoprotective effects (all P < 0.001), whereas the heme oxygenase inhibitor SnPPIX only partially counteracted the CO-associated renoprotection and the activation of the heat shock response. CONCLUSIONS: CO treatment before CPB was associated with evidence of renoprotection, demonstrated by fewer histological injuries and decreased cystatin C concentrations. The findings that the antiinflammatory and antiapoptotic effects of CO were accompanied by activation of HSP-70, which in turn were reversed by quercetin, suggest that renoprotection by pretreatment with inhaled CO before CPB is mediated by activation of the renal heat shock response.

Successful resuscitation after prolonged periods of cardiac arrest: a new field in cardiac surgery.

OBJECTIVE: Cardiopulmonary resuscitation is associated with high mortality and poor neurological recovery. Cardiopulmonary resuscitation can cause ischemia-reperfusion injury of the whole body and brain. We assessed the hypothesis that controlled reperfusion of the whole body with cardiopulmonary bypass would limit reperfusion injury after 15 minutes of normothermic cardiac arrest with better survival and neurological recovery. METHODS: Eleven pigs were exposed to normothermic ischemia for 15 minutes by inducing ventricular fibrillation, followed by cardiopulmonary resuscitation (control group, n = 4) or 60 minutes of cardiopulmonary bypass (treatment group, n = 7). Conditions of reperfusion and the reperfusate were controlled with cardiopulmonary bypass. Animals were observed for up to 7 days, and neurological assessment (Neurological Deficit Score: 0, normal; 500, brain death), magnetic resonance imaging, and brain histology were performed. RESULTS: All animals in the control group died after 20 minutes of cardiopulmonary resuscitation (n = 4). All (n = 7) survived in the treatment group. Clinically apparent neurological recovery occurred within 24 hours; 1 fully conscious pig could not walk. The Neurological Deficit Score was 98 +/- 31 in all animals (n = 7) after 24 hours and decreased to 0 after 48 hours in 4 of 5 eligible animals; 1 animal had a Neurological Deficit Score of 110 after 3 days. Brain histology revealed hypoxic and apoptotic neurons with an inconclusive correlation regarding neurological recovery. CONCLUSION: Clinically apparent neurological recovery after a period of 15 minutes of cardiac arrest occurred with cardiopulmonary bypass instead of cardiopulmonary resuscitation for reperfusing the whole body. This approach contrasts with cardiopulmonary resuscitation, in which resuscitation has been reported as successful after only 3 to 5 minutes of cardiac arrest. Cardiopulmonary bypass might be a key to improve survival and neurological recovery after cardiac arrest.

The Role of FGL2 in the Pathogenesis and Treatment of Hepatitis C Virus Infection.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide and remains the most common indication for liver transplantation. The current standard of care leads to a sustained viral response of roughly 50% of treated patients at best. Furthermore, anti-viral therapy is expensive, prolonged, and associated with serious side-effects. Evidence suggests that a poor response to treatment may be the result of a suppressed anti-viral immunity due to the presence of increased numbers and activity of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells). We and others have recently identified fibrinogen-like protein 2 (FGL2) as a putative effector of Treg cells, which accounts for their suppressive function through binding to Fc gamma receptors (FcγR). In an experimental model of fulminant viral hepatitis, our laboratory showed that increased plasma levels of FGL2 pre- and post-viral infection were predictive of susceptibility and severity of disease. Moreover, treatment with antibody to FGL2 fully protected susceptible animals from the lethality of the virus, and adoptive transfer of wild-type Treg cells into resistant fgl2-deficient animals accelerated their mortality post-infection. In patients with HCV infection, plasma levels of FGL2 and expression of FGL2 in the liver correlated with the course and severity of the disease. Collectively, these studies suggest that FGL2 may be used as a biomarker to predict disease progression in HCV patients and be a logical target for the development of novel therapeutic approaches for the treatment of patients with HCV infection.

The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis.

UNLABELLED: Fulminant viral hepatitis (FH) remains an important clinical problem in which the underlying pathogenesis is not well understood. Here, we present insight into the immunological mechanisms involved in FH caused by murine hepatitis virus strain 3 (MHV-3), indicating a critical role for CD4(+)CD25(+) regulatory T cells (Tregs) and production of the novel Treg effector molecule FGL2. Before infection with MHV-3, susceptible BALB/cJ mice had increased numbers of Tregs and expression of fgl2 messenger RNA (mRNA) and FGL2 protein compared with resistant A/J mice. After MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with increased percentage of Tregs. Treatment with anti-FGL2 antibody completely inhibited Treg activity and protected susceptible BALB/cJ mice against MHV-3-liver injury and mortality. Adoptive transfer of wild-type Tregs into resistant fgl2(-/-) mice increased their mortality caused by MHV-3 infection, whereas transfer of peritoneal exudate macrophages had no adverse effect. CONCLUSION: This study demonstrates that FGL2 is an important effector cytokine of Tregs that contributes to susceptibility to MHV-3-induced FH. The results further suggest that targeting FGL2 may lead to the development of novel treatment approaches for acute viral hepatitis infection.