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Keywords Disorders of the nervous system, Neuropsychiatric disorder Acuteliverfailure; Brain edema, Encephalopathy; Glutamine;Hypothermia;Organic osmolytes
Brain edema and encephalopathy are severe central nervous system complications of acuteliverfailure (ALF). Brain edema frequently results in increased intracranial pressure leading to death by brain herniation. Despite several decades of investigation, the precise mechanisms responsible for brain edema in ALF are not completely understood. Both biochemical and spectroscopic studies suggest that reductions of osmosensitive substances such as myo- inositol  and  and taurine  are compensatory mechanisms to reduce the increased intracellular osmolarity caused by increased brain concentrations of glutamine  and  in both human and experimental liverfailure. However, these findings occur both in ALF and chronicliverfailure whereas brain edema sufficient to cause increased intracranial pressure occurs primarily in ALF.
possible that these studies describe two different stages of the disease; generalized vasodilation in the initial stage and vasoconstriction of the regional vascular beds in the later stages possibly due to the effect of activation of the neurohormonal system. This hypothesis will need to be tested in future studies.
Furthermore, our data indicate that the pathophysiological basis of renal dysfunction in this model of ALF is different from hepatorenal syndrome (HRS) seen in patients with chronicliverfailure. We found a significant reduction in creatinine clearance indicating a reduction in glomerular filtration rate (GFR), despite no change in renal plasma flow (RPF). There was no biochemical evidence of an acute tubular dysfunction in pigs with ALF. Although the urine osmolality was lower, osmolal excretion was not significantly different from shams, owing to differences in urine output. As GFR is the product of RPF and the filtration fraction, a decrease in GFR must have been caused by a decreased glomerular filtration fraction. Filtration fraction is determined by the filtration coefficient and glomerular filtration pressure . Unfortunately, our data did not allow us to explore these mechanisms in greater detail. The results of our study showing no significant effects of M-MARS on the systemic haemodynamics and renal function are at variance with the previous observations in patients with ALF. In an open, non-randomized study of eight patients with hyperacute ALF caused by paracetamol intoxication or hepatitis B infection , MARS was found to increase MAP and decrease CI. However, the improvement in systemic haemodynamics with MARS is not a universal phenomenon, and in a recently published study on patients with acute-on-chronicliverfailure, we were not able to observe any significant improvements in systemic haemodynamics or renal function with MARS . It is possible that the lack of any observed effect of MARS on the systemic haemodynamic variables in the present study may be related to the relatively short duration of treatment. Although the present model is associated with typical clinical and biochemical features of ALF [12–15], liver ischaemia is not a common aetiology for ALF ,  and the animals were studied within a rather short time frame. These facts should be borne in mind when data are
Recent studies have investigated the role of Molecular Adsorbents Recirculating System (MARS) in liverfailure (12– 14). This is an extracorporeal device (15–17) utilizing albumin dialysis with hemofiltration/dialysis to remove albumin-bound toxins (18) that accumulate in liverfailure and thus may improve/prevent associated cerebral, renal, and circulatory disturbances (12, 19). One consistent observation with its use in patients with liverfailure has been an improvement of hepatic encephalopathy (12–14, 20). However, most of the data pertain to patients with acute decompensation of chronicliver disease, and the effect of MARS therapy on cerebral status in ALF remains unclear. A porcine model of ALF induced by hepatic devascularization has been developed and validated (21–24) and shows the characteristic rise of ICP, with a concomitant increase in blood ammonia and hyperdynamic vasodilated
attenuation of systemic oxidative stress after treatment with allopurinol (inhibitor of the oxidant enzyme XO). These results suggest that ammonia and systemic oxidative stress act together in the pathogenesis of brain edema in CLF. It has previously been demonstrated that ammonia neurotoxicity leads to oxidative stress and subsequently to brain edema (astrocyte swelling) . However it must be noted that these studies involved acute ammonia intoxication models (in vitro and in vivo). First, cultured astrocytes acutely exposed to ammonia (1, 5, and 10 mM) showed an increase in ROS levels  and cell swelling . Moreover, naïve rats injected with an acute dose of ammonia (12 mmol/kg injected intraperitoneally) , as well as rats with acuteliverfailure  and , displayed severe HE along with increased oxidative stress in brain. In our study, chronic hyperammonemia and CSF ammonia levels present in PCA rats (125–250 μM; lower than brain ammonia concentrations found in animal models of acuteliverfailure: 1–5 mM  and ) do not stimulate severe HE or oxidative stress in brain (or in circulation).
Additional pathogenic factors such as inflammation have demonstrated to play a role in the exacerbation of ICP in ALF , however inflammatory cells (microglia) were not very prominent in the brains of pigs with ALF. This may be obvious since we have previously shown that systemic inflammatory markers are not raised in this model following 6 h of ALF . Therefore we were able to demonstrate severe ultrastructural changes in the brain without any induction of inflammatory cells. This is clinically relevant as inflammation is believed to play a major role in patients with acute-on-chronic and ALF patients suffering from high grade HE [28,29]. Furthermore, the results of our study suggest inflammation does not play an important role in the development of brain edema and intracranial hypertension in ALF.
It was previously suggested that brain edema in hyperammonemic syndromes such as ALF is the consequence of increased intracellular accumulation of glutamine by the astrocyte.4 In favor of this hypothesis were reports of increased intracranial pressure in primates infused with ammonia26 and of increased brain glutamine
concentrations in both human29 and experimental27 and 28 ALF. Moreover, brain edema because of ammonia infusions was partially prevented by pretreatment with methionine sulfoximine (MSO), a potent inhibitor of glutamine synthetase.4 and 31 However, MSO treatment may exert multiple effects. For example, MSO also induces massive efflux of glutamine from astrocytes in cultures.32 In addition, brain glutamine accumulation also occurs in chronicliverfailure, a condition not normally associated with brain edema or its clinical consequences.4 and 33 Therefore, despite several experimental data supporting glutamine as accumulating osmolyte in HE, whether or not glutamine accumulation is a major cause for the development of brain edema in ALF is uncertain.33 Results of the present study confirm an increase in brain glutamine in ALF rats. However, mild hypothermia sufficient to abolish brain edema in these animals did not prevent either the increase in brain glutamine concentration or its de novo synthesis from glucose in astrocytes (i.e., de novo synthesis via the astrocytic enzymes pyruvate carboxylase and glutamine synthetase). A limited capacity of glutamine synthetase was also concluded by Deutz et al.,19 who demonstrated a faster increase of brain ammonia compared with glutamine and by Bosman et al.,34 who observed, after an initial increase of extracellular glutamine during mild HE, a subsequent decrease during severe HE. Direct demonstration of a lack of correlation between the grade of hepatic encephalopathy and glutamine synthetase activity was initially reported by Kanamori et al.35 using in vivo 1 H MRS in a hyperammonemic rat model. Moreover,
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determined with an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). All RNA samples presented a RIN (RNA Integrity Number) between 7 to 9. (ii) RNA labeling, hybridization, and detection: 20 µg of total mouse liver RNA sample were first subjected to chemiluminescence RT labeling (Applied Biosystems Chemiluminescent RT labeling kit, Foster City, CA, USA). Digoxigenin-labeled cDNAs were then hybridized and detected according to the supplied protocols (Applied Biosystems Chemiluminescence Detection kit, Foster City, CA, USA). A total of 12 independent experiments were performed for the two different biological conditions (PB/HA and PB/Saline groups). (iii) Transcriptome Data Analysis: Applied Biosystems Expression Array System Software v1.1.1 was used to acquire the chemiluminescence and the fluorescence images and to perform primary data analysis. In addition, we renormalized the resulting data according to the logarithmic signal median, once more, after having removed the probes for which the Applied Biosystems Software has set flags equal to or greater than 2 12 , indicating compromised or failed measurements, and signals from control spots.
disruption of DEPTOR and activation of mTORC1 and S6K1. Our in vivo and in vitro data is the first to indicate that inhibition of mTORC1 by DEPTOR counteracts the ability of ethanol to stimulate SREBP-1-dependent lipogenesis. The present study identifies a novel functional connection between DEPTOR and SREBP-1 in hepatocytes at multiple levels. First, our critical finding with high clinical significance is that hepatic DEPTOR levels inversely correlate with SREBP-1 activity in patients with ALD, suggesting that individuals with lower levels of DEPTOR may be predisposed to the deleterious consequence of excess alcohol consumption. Conversely, DEPTOR-dependent inhibition of mTORC1 is sufficient to eliminate the proteolytic processing, nuclear translocation, and transcriptional activity of SREBP-1 in chronic-binge ethanol-fed mice, the mouse model that nearly resembles the pathological features of human ALD (10). Second, recent studies show that mTORC1 directly phosphorylates lipin 1, the key enzyme for diacylglycerol synthesis, and promotes nuclear exclusion and cytoplasmic accumulation of lipin 1, and mTORC1 inhibition decreases SREBP-1 processing in a lipin 1-dependent fashion (26). As demonstrated in animals treated with rapamycin, mTORC1 is necessary for the cytoplasmic accumulation of lipin 1 and nuclear translocation of SREBP-1 in response to alcohol feeding. The regulation of SREBP-1 by DEPTOR is further supported by our findings that exogenous expression of DEPTOR reduces the cytoplasmic abundance of lipin 1 and renders mice insensitive to alcohol-induced SREBP-1 processing. Third, it has been shown that constitutive activation of mTORC1 by TSC1/2 loss promotes SREBP-1 processing in cultured cells, and this effect is inhibited by S6K1 knockdown (27). The data presented here show that the beneficial effects of hepatic overexpression of DN-S6K1 on fatty liver could be explained by the downregulation of SREBP-1 processing, suggesting that DEPTOR reduces SREBP-1 activity possibly by repressing S6K1. Interestingly, alcohol-mediated stimulation of lipin 1 acts through a S6K1-independent mechanism. Finally, because the effect of mTORC1 inhibition on SREBP-1 in ethanol-fed mice share some features seen in mice with liver- specific knockout of SCAP, the major lipid sensor that regulates SREBP-1 processing (14), we suspect that SCAP may be involved in the effect of DEPTOR on SREBP-1. Therefore, the molecular mechanisms by which DEPTOR downregulates SREBP-1 activity are more complex than originally envisioned. It is likely that DEPTOR cooperates with mTORC1 and S6K1 to control SREBP-1 processing by modulating distinct regulators.
Two hours following the onset of liver devascularization (pre-MARS treatment), a significant increase in extracellular brain ammonia was observed in pigs with ALF compared with sham-operated control pigs (Fig. 1A). Extracellular ammonia continued to rise in pigs with ALF, whereas this rise was attenuated at T = 6 hours following a 4-hour treatment with MARS (P < 0.01; Fig. 1A). Transforming the data into percent increase (from T = 0 in each group), an earlier attenuation with MARS was observed, as early as 2 hours following MARS treatment (at T = 4–6; Fig. 1B). To emphasize the effect of MARS on extracellular ammonia, the percent change in extracellular brain ammonia was calculated from T = 2 hours (start of the MARS treatment) until T = 6 hours (end of the MARS treatment), as shown in Fig. 1C. Using all 6 times from all 3 groups, a significant correlation was calculated between percent change in extracellular ammonia and percent change in ICP (r 2 = 0.511, P < 0.001; Fig. 1D).
2 Cardiologie et maladies vasculaires,
hôpital européen Georges‑Pompidou (HEGP), Paris, France
3 Chirurgie cardiaque et vasculaire, HDZ, Bad Oeynhausen, Allemagne Introduction: The ratio of early diastolic transmittal flow velocity to tissue Doppler mitral annular early diastolic velocity, E/e′, and pulmo‑ nary capillary wedge pressure (PCWP) have been shown to be correla‑ ted. The validity of E/e’ for predicting PCWP in DESHF patients was recently challenged, but the influence of inotropes was not taken into account, despite the reported influence of these drugs on left ventricu‑ lar relaxation properties. We investigated the impact of inotropes on the accuracy of E/e’ ratio as a surrogate for PCWP in acute decompen‑ sated end‑stage systolic heart failure (DESHF) patients.
Résultats : Durant une période de 12 mois, sur 309 patients admis 280 patients ont pu être étudiés. Parmi ces patients, 13 cardiomyopa- thies de Tako-Tsubo ont été identifiées (4.6 %). La majorité était mise en évidence dès l ’admission (84.6 %) mais 2 (15.4 %) sont survenues 3 jours après l ’entrée du patient dépistées devant une dégradation hémodynamique ou respiratoire. Le sexe féminin était prédominant (69.2 %) et l ’âge moyen était de 62.9 (+/- 13.5) ans. Les pathologies pulmonaires représentaient le facteur déclenchant le plus fréquent (46.2 %) de Tako-Tsubo. Un terrain d ’immunodépression et d’hépato- pathie était plus retrouvé dans le Tako-Tsubo que dans le reste de la population (respectivement 53.8 % contre 24.0 % avec p=0.023, et 23.1 % contre 5.6 % avec p=0.043). Les antécédents de cancer et d ’in- suffisance respiratoire chronique étaient fréquemment rencontrés dans le Tako-Tsubo (respectivement 30.8 % mais sans différence avec le reste de la population. Le score SAPS II (New Simplified Acute Phy- siology Score) moyen des Tako-Tsubo était de 57.5 (+/- 20.5). Leur fraction d ’éjection ventriculaire gauche moyenne était de 25.0 % [22.5 – 38.5]. La présence d’un état de choc était plus importante parmi la population de Tako-Tsubo que dans le reste de la population (69.2 % contre 36.0 %, p=0.02). De même, la nécessité d ’une ventilation, invasive ou non invasive, était plus importante dans la population de Tako-Tsubo (92.3 % contre 62.9 %, p=0.036). Deux (15.4 %) ont eu recours à une épuration extra-rénale. Cinq (38.5 %) ont présenté une arythmie supra-ventriculaire. Un patient (7.7 %) a été admis pour mort subite récupérée compliquant une arythmie ventriculaire. Un autre (7.7 %) a présenté une insuffisance mitrale moyenne liée à la présence d ’un gradient intra-ventriculaire gauche. Quatre patients (30.8 %) sont décédés.