Incidence du coeur pulmonaire aigu et de la thrombose veineuse profonde dans l'embolie pulmonaire aiguë [Incidence of acute cor pulmonale and deep venous thrombosis in acute pulmonary embolism]

OBJECTIVE: Ultrasounds are a useful tool when looking for indirect evidence in favor of pulmonary embolism. The aim of this study was to determine the incidence of acute cor pulmonale and deep venous thrombosis revealed by ultrasonographic techniques in a population of patients presenting with pulmonary embolism. METHODS: 96 consecutive patients with a mean (+/- SD) age of 65 +/- 15 years, admitted to our hospital for pulmonary embolism were included in this study. The diagnosis of pulmonary embolism was made either by spiral computed tomography or selective pulmonary angiography. Each patient subsequently underwent both trans-thoracic echocardiography and venous ultrasonography. The diagnostic criterion used for defining acute cor pulmonale by echocardiography was the right to left ventricular end-diastolic area ratio over (or equal to) 0.6. Diagnosis of deep venous thrombosis was supported by the visualization of thrombi or vein incompressibility and/or the absence of venous flow or loss of flow variability by venous ultrasonography. RESULTS: Using ultrasounds, an acute cor pulmonale was found in 63% of our patients while 79% were found to have deep venous thrombosis and 92% of the patients had either acute cor pulmonale or deep venous thrombosis or both. All of the patients with proximal pulmonary embolism had acute cor pulmonale and/or deep venous thrombosis. The presence of acute cor pulmonale on echocardiography was significantly higher in patients with proximal pulmonary embolism (p < 0.0001). CONCLUSION: This study emphasizes the potential value of ultrasonographic techniques in the diagnosis of acute pulmonary embolism.

High-dose intravenous immunoglobulin treatment and cerebral vasospasm : a possible mechanism of ischemic encephalopathy?

A 46-year-old woman with a severe polyradiculoneuropathy treated with high-dose intravenous immunoglobulin (IVIg) presented an encephalopathy with increased blood flow velocities of the middle cerebral arteries (MCAs) detected by transcranial Doppler (TCD) studies. The similitude between this observation and another case recently reported of a patient suffering from Guillain-Barré syndrome (GBS) and cerebral blood flow abnormalities after IVIg treatment prompted us to investigate the responsibility of the IVIg therapy in the genesis of these blood flow alterations. We studied therefore by TCD 10 consecutive patients who underwent this treatment for different reasons. In 1 case we observed an asymptomatic, spontaneously reversible increase in the blood flow velocities of the MCAs consistent with a vasospasm and occurring 3-10 days after completion of the therapy. Stroke and ischemic encephalopathy have been reported as possible complications of IVIg treatment. In the case under discussion, clinical events appeared shortly after the administration of the IVIg therapy and responded favorably to a treatment with nimodipine. Other etiopathogenic mechanisms, in particular a CNS vasculopathic process related to the GBS itself, have to be considered as well. Further studies, with a larger number of patients, are therefore needed to evaluate the underlying mechanisms of blood flow abnormalities occurring sometimes in GBS patients after IVIg treatment.

Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains.

Sleep deprivation (SD) results in increased electroencephalographic (EEG) delta power during subsequent non-rapid eye movement sleep (NREMS) and is associated with changes in the expression of circadian clock-related genes in the cerebral cortex. The increase of NREMS delta power as a function of previous wake duration varies among inbred mouse strains. We sought to determine whether SD-dependent changes in circadian clock gene expression parallel this strain difference described previously at the EEG level. The effects of enforced wakefulness of incremental durations of up to 6 h on the expression of circadian clock genes (bmal1, clock, cry1, cry2, csnk1epsilon, npas2, per1, and per2) were assessed in AKR/J, C57BL/6J, and DBA/2J mice, three strains that exhibit distinct EEG responses to SD. Cortical expression of clock genes subsequent to SD was proportional to the increase in delta power that occurs in inbred strains: the strain that exhibits the most robust EEG response to SD (AKR/J) exhibited dramatic increases in expression of bmal1, clock, cry2, csnkIepsilon, and npas2, whereas the strain with the least robust response to SD (DBA/2) exhibited either no change or a decrease in expression of these genes and cry1. The effect of SD on circadian clock gene expression was maintained in mice in which both of the cryptochrome genes were genetically inactivated. cry1 and cry2 appear to be redundant in sleep regulation as elimination of either of these genes did not result in a significant deficit in sleep homeostasis. These data demonstrate transcriptional regulatory correlates to previously described strain differences at the EEG level and raise the possibility that genetic differences underlying circadian clock gene expression may drive the EEG differences among these strains.

Multivalvular surgery for infective endocarditis.

The short and the long-term results of our experience with 25 consecutive patients who underwent multivalvular surgery for infective endocarditis are analysed. Preoperatively, 20/25 (80%) patients were in New York Heart Association (NYHA) stage III or IV, and 2/25 (8%) patients were in cardiogenic shock. All the diseased valves were replaced with mechanical bileaflet prosthesis except seven mitral valves and one tricuspid valve, which could be repaired. Major postoperative complications occurred in 3/25 (12%) patients: a fatal cerebral haemorrhage, a reversible cerebellar syndrome and an intractable heart failure, which required transplantation. During a mean follow-up of 4.7 years (range 6 months to 16.8 years), 7/25 (28%) patients suffered from valve-related complications: five bleedings (one died), one embolic event and one prosthetic valve thrombosis. The actuarial freedom of valve-related event at 10 years was 61.8 +/- 12.4%. There was no prosthetic endocarditis. At follow-up, 20/21 (95%) survivors were in NYHA stage I or II. Long-term outcome in our patient population operated on for multivalvular endocarditis, is satisfactory with no recurrent infection and excellent functional results.

The risk of subsequent cancer and arterial cardiovascular events in patients with superficial vein thrombosis in the legs.

Although it has been clearly demonstrated that venous thromboembolism is associated with an increased risk of subsequent overt cancer and arterial cardiovascular events in comparison with control populations, whether this association also applies to patients with isolated (ie, without concomitant involvement of the deep vein system) superficial vein thrombosis (SVT) in the legs is unknown. In 737 consecutive patients with isolated SVT not involving the sapheno-femoral junction, we conducted a retrospective investigation to assess the rate of cancer and that of arterial cardiovascular events occurring during follow-up. The event rates were compared with those occurring in 1438 controls having comparable characteristics. Both cases and controls were followed-up for an average period of 26 ± 8 months (range, 3-45). Malignancy was diagnosed in 26 cases (3.5%) and 56 controls (3.9%), leading to a hazard ratio of 0.86 (95% confidence interval, 0.55%-1.35%). Arterial cardiovascular events occurred in 32 cases (4.3%) and 63 controls (4.4%), leading to a hazard ratio of 0.97 (95% confidence interval, 0.63%-1.50%). We conclude that the occurrence of isolated SVT in the legs does not place patients at an increased risk of malignancies or arterial cardiovascular events. Whether this conclusion also applies to patients whose thrombosis involves the sapheno-femoral junction remains to be demonstrated.

Effect of hypoxia on cerebral blood flow regulation during rest and exercise : role of cerebral oxygen delivery on performance

Adequate supply of oxygen to the brain is critical for maintaining normal brain function. Severe hypoxia, such as that experienced during high altitude ascent, presents a unique challenge to brain oxygen (O2) supply. During high-intensity exercise, hyperventilation-induced hypocapnia leads to cerebral vasoconstriction, followed by reductions in cerebral blood flow (CBF), oxygen delivery (DO2), and tissue oxygenation. This reduced O2 supply to the brain could potentially account for the reduced performance typically observed during exercise in severe hypoxic conditions. The aims of this thesis were to document the effect of acute and chronic exposure to hypoxia on CBF control, and to determine the role of cerebral DO2 and tissue oxygenation in limiting performance during exercise in severe hypoxia. We assessed CBF, arterial O2 content (CaO2), haemoglobin concentration ([Hb]), partial pressure of arterial O2 (PaO2), cerebrovascular CO2 reactivity, ventilatory response to CO2, cerebral autoregulation (CA), and estimated cerebral DO2 (CBF ⨉ CaO2) at sea level (SL), upon ascent to 5,260 m (ALT1), and following 16 days of acclimatisation to 5,260 m (ALT16). We found an increase in CBF despite an elevated cerebrovascular CO2 reactivity at ALT1, which coincided with a reduced CA. Meanwhile, PaO2 was greatly decreased despite increased ventilatory drive at ALT1, resulting in a concomitant decrease in CaO2. At ALT16, CBF decreased towards SL values, while cerebrovascular CO2 reactivity and ventilatory drive were further elevated. Acclimatisation increased PaO2, [Hb], and therefore CaO2 at ALT16, but these changes did not improve CA compared to ALT1. No differences were observed in cerebral DO2 across SL, ALT1, and ALT16. Our findings demonstrate that cerebral DO2 is maintained during both acute and chronic exposure to 5,260 m, due to the reciprocal changes in CBF and CaO2. We measured middle cerebral artery velocity (MCAv: index of CBF), cerebral DO2, ventilation (VE), and performance during incremental cycling to exhaustion and 15km time trial cycling in both normoxia and severe hypoxia (11% O2, normobaric), with and without added CO2 to the inspirate (CO2 breathing). We found MCAv was higher during exercise in severe hypoxia compared in normoxia, while cerebral tissue oxygenation and DO2 were reduced. CO2 breathing was effective in preventing the development of hyperventilation-induced hypocapnia during intense exercise in both normoxia and hypoxia. As a result, we were able to increase both MCAv and cerebral DO2 during exercise in hypoxia with our CO2 breathing setup. However, we concomitantly increased VE and PaO2 (and presumably respiratory work) due to the increased hypercapnic stimuli with CO2 breathing, which subsequently contributed to the cerebral DO2 increase during hypoxic exercise. While we effectively restored cerebral DO2 during exercise in hypoxia to normoxic values with CO2 breathing, we did not observe any improvement in cerebral tissue oxygenation or exercise performance. Accordingly, our findings do not support the role of reduced cerebral DO2 in limiting exercise performance in severe hypoxia. -- Un apport adéquat en oxygène au niveau du cerveau est primordial pour le maintien des fonctions cérébrales normales. L'hypoxie sévère, telle qu'expérimentée au cours d'ascensions en haute altitude, présente un défi unique pour l'apport cérébral en oxygène (O2). Lors d'exercices à haute intensité, l'hypocapnie induite par l'hyperventilation entraîne une vasoconstriction cérébrale suivie par une réduction du flux sanguin cérébral (CBF), de l'apport en oxygène (DO2), ainsi que de l'oxygénation tissulaire. Cette réduction de l'apport en O2 au cerveau pourrait potentiellement être responsable de la diminution de performance observée au cours d'exercices en condition d'hypoxie sévère. Les buts de cette thèse étaient de documenter l'effet de l'exposition aiguë et chronique à l'hypoxie sur le contrôle du CBF, ainsi que de déterminer le rôle du DO2 cérébral et de l'oxygénation tissulaire comme facteurs limitant la performance lors d'exercices en hypoxie sévère. Nous avons mesuré CBF, le contenu artériel en oxygène (CaO2), la concentration en hémoglobine ([Hb]), la pression partielle artérielle en O2 (PaO2), la réactivité cérébrovasculaire au CO2, la réponse ventilatoire au CO2, et l'autorégulation cérébrale sanguine (CA), et estimé DO2 cérébral (CBF x CaO2), au niveau de la mer (SL), au premier jour à 5.260 m (ALT1) et après seize jours d'acclimatation à 5.260 m (ALT16). Nous avons trouvé des augmentations du CBF et de la réactivité cérébrovasculaire au CO2 après une ascension à 5.260 m. Ces augmentations coïncidaient avec une réduction de l'autorégulation cérébrale. Simultanément, la PaO2 était grandement réduite, malgré l'augmentation de la ventilation (VE), résultant en une diminution de la CaO2. Après seize jours d'acclimatation à 5.260 m, le CBF revenait autour des valeurs observées au niveau de la mer, alors que la réactivité cérébrovasculaire au CO2 et la VE augmentaient par rapport à ALT1. L'acclimatation augmentait la PaO2, la concentration en hémoglobine, et donc la CaO2, mais n'améliorait pas l'autorégulation cérébrale, comparé à ALT1. Aucune différence n'était observée au niveau du DO2 cérébral entre SL, ALT1 et ALT16. Nos résultats montrent que le DO2 cérébral est maintenu constant lors d'expositions aiguë et chronique à 5.260m, ce qui s'explique par la réciprocité des variations du CBF et de la CaO2. Nous avons mesuré la vitesse d'écoulement du sang dans l'artère cérébrale moyenne (MCAv : un indice du CBF), le DO2 cérébral, la VE et la performance lors d'exercice incrémentaux jusqu'à épuisement sur cycloergomètre, ainsi que des contre-la-montres de 15 km en normoxie et en hypoxie sévère (11% O2, normobarique) ; avec ajout ou non de CO2 dans le mélange gazeux inspiré. Nous avons trouvé que MCAv était plus haute pendant l'exercice hypoxique, comparé à la normoxie alors que le DO2 cérébral était réduit. L'ajout de CO2 dans le gaz inspiré était efficace pour prévenir l'hypocapnie induite par l'hyperventilation, qui se développe à l'exercice intense, à la fois en normoxie et en hypoxie. Nous avons pu augmenter MCAv et le DO2 cérébral pendant l'exercice hypoxique, grâce à l'ajout de CO2. Cependant, nous avons augmenté la VE et la PaO2 (et probablement le travail respiratoire) à cause de l'augmentation du stimulus hypercapnique. Alors que nous avons, grâce à l'ajout de CO2, efficacement restauré le DO2 cérébral au cours de l'exercice en hypoxie à des valeurs obtenues en normoxie, nous n'avons observé aucune amélioration dans l'oxygénation du tissu cérébral ou de la performance. En conséquence, nos résultats ne soutiennent pas le rôle d'un DO2 cérébral réduit comme facteur limitant de la performance en hypoxie sévère.

Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage.

Subarachnoid haemorrhage (SAH) is a form of stroke that is associated with substantial morbidity, often as a result of cerebral ischaemia that occurs in the following days. These delayed deficits in blood flow have been traditionally attributed to cerebral vasospasm (the narrowing of large arteries), which can lead to cerebral infarction and poor neurological outcome. Data from recent studies, however, show that treatment of vasospasm in patients with SAH, using targeted medication, does not translate to better neurological outcomes, and argue against vasospasm being the sole cause of the delayed ischaemic complications. Cerebral autoregulation-a mechanism that maintains stability of cerebral blood flow in response to changes in cerebral perfusion pressure-has been reported to fail after SAH, often before vasospasm becomes apparent. Failure of autoregulation, therefore, has been implicated in development of delayed cerebral ischaemia. In this Review, we summarize current knowledge about the clinical effect of disturbed cerebral autoregulation following aneurysmal SAH, with emphasis on development of delayed cerebral ischaemia and clinical outcome, and provide a critical assessment of studies of cerebral autoregulation in SAH with respect to the method of blood-flow measurement. Better understanding of cerebral autoregulation following SAH could reveal mechanisms of blood-flow regulation that could be therapeutically targeted to improve patient outcome.

Cerebral extracellular lactate increase is predominantly non ischemic in patients with severe traumatic brain injury

Le cerveau est l'organe avec les besoins en énergie les plus élevés du corps humain, et le glucose est un substrat énergétique cérébral essentiel. Ces dernières décennies, la compréhension de la neuroénergétique a beaucoup évolué et un rôle du lactate comme substrat énergétique important a été mis en évidence, notamment suite à l'introduction du modèle de l'ANLS (astrocyte-neuron lactate shuttle). Selon celui-ci, les astrocytes convertissent le glucose en lactate par réaction de glycolyse, puis il est transporté jusqu'aux neurones qui l'utilisent comme source d'énergie à travers le cycle de Krebs. Chez l'homme, divers travaux récents ont montré que le lactate peut servir de « carburant » cérébral chez le sujet sain, après effort intense ou chez le patient diabétique. La régulation métabolique et le rôle du lactate après lésion cérébrale aiguë sont encore peu connus. Présentation de l'article Le but de ce travail a été d'étudier le métabolisme cérébral du lactate chez les patients atteints de traumatisme crânien (TCC) sévère. Nous avons émis l'hypothèse que l'augmentation du lactate cérébral chez ces patients n'était pas associée de manière prédominante à une hypoxie ou une ischémie mais plutôt à une glycolyse aérobie, et également à une perfusion cérébrale normale. L'étude a porté sur une cohorte prospective de 24 patients avec TCC sévère admis au service de médecine intensive du CHUV (centre hospitalier universitaire vaudois), monitorés par un système combinant microdialyse cérébrale (outil permettant de mesurer divers métabolites cérébraux, tels que le lactate, le pyruvate et le glucose), mesure de la pression cérébrale en oxygène et de la pression intracrânienne. Cet outil nous a permis de déterminer si l'élévation du lactate était principalement associée à une glycolyse active ou plutôt à une hypoxie. L'utilisation du CTde perfusion a permis d'évaluer la relation entre les deux patterns d'élévation du lactate (glycolytique ou hypoxique) et la perfusion cérébrale globale. Nos résultats ont montré que l'augmentation du lactate cérébral chez les patients avec TCC sévère était associée de manière prédominante à une glycolyse aérobie plutôt qu'à une hypoxie/ischémie. D'autre part, nous avons pu confirmer que les épisodes de lactate glycolytique étaient toujours associés à une perfusion cérébrale normale ou augmentée, alors que les épisodes de lactate hypoxique étaient associés à une hypoperfusion cérébrale. Conclusions et perspectives Nos résultats, qui ont permis de mieux comprendre le métabolisme cérébral du lactate chez les patients avec TCC sévère, soutiennent le concept que le lactate est produit dans des conditions aérobes et pourrait donc être utilisé comme source d'énergie par le cerveau lésé pour subvenir à des besoins augmentas. Etant donné que la dysfonction énergétique est une des probables causes de perte neuronale après traumatisme crânien, ces résultats ouvrent des perspectives thérapeutiques nouvelles après agression cérébrale chez l'homme, visant à tester un potentiel effet neuroprotecteur via l'administration de lactate exogène.

A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.

When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.

Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review.

CONTEXT: Symptomatic venous thromboembolism (VTE) after total or partial knee arthroplasty (TPKA) and after total or partial hip arthroplasty (TPHA) are proposed patient safety indicators, but its incidence prior to discharge is not defined. OBJECTIVE: To establish a literature-based estimate of symptomatic VTE event rates prior to hospital discharge in patients undergoing TPHA or TPKA. DATA SOURCES: Search of MEDLINE, EMBASE, and the Cochrane Library (1996 to 2011), supplemented by relevant articles. STUDY SELECTION: Reports of incidence of symptomatic postoperative pulmonary embolism or deep vein thrombosis (DVT) before hospital discharge in patients who received VTE prophylaxis with either a low-molecular-weight heparin or a subcutaneous factor Xa inhibitor or oral direct inhibitor of factors Xa or IIa. DATA EXTRACTION AND SYNTHESIS: Meta-analysis of randomized clinical trials and observational studies that reported rates of postoperative symptomatic VTE in patients who received recommended VTE prophylaxis after undergoing TPHA or TPKA. Data were independently extracted by 2 analysts, and pooled incidence rates of VTE, DVT, and pulmonary embolism were estimated using random-effects models. RESULTS: The analysis included 44,844 cases provided by 47 studies. The pooled rates of symptomatic postoperative VTE before hospital discharge were 1.09% (95% CI, 0.85%-1.33%) for patients undergoing TPKA and 0.53% (95% CI, 0.35%-0.70%) for those undergoing TPHA. The pooled rates of symptomatic DVT were 0.63% (95% CI, 0.47%-0.78%) for knee arthroplasty and 0.26% (95% CI, 0.14%-0.37%) for hip arthroplasty. The pooled rates for pulmonary embolism were 0.27% (95% CI, 0.16%-0.38%) for knee arthroplasty and 0.14% (95% CI, 0.07%-0.21%) for hip arthroplasty. There was significant heterogeneity for the pooled incidence rates of symptomatic postoperative VTE in TPKA studies but less heterogeneity for DVT and pulmonary embolism in TPKA studies and for VTE, DVT, and pulmonary embolism in TPHA studies. CONCLUSION: Using current VTE prophylaxis, approximately 1 in 100 patients undergoing TPKA and approximately 1 in 200 patients undergoing TPHA develops symptomatic VTE prior to hospital discharge.

Mapping the structural core of human cerebral cortex.

Structurally segregated and functionally specialized regions of the human cerebral cortex are interconnected by a dense network of cortico-cortical axonal pathways. By using diffusion spectrum imaging, we noninvasively mapped these pathways within and across cortical hemispheres in individual human participants. An analysis of the resulting large-scale structural brain networks reveals a structural core within posterior medial and parietal cerebral cortex, as well as several distinct temporal and frontal modules. Brain regions within the structural core share high degree, strength, and betweenness centrality, and they constitute connector hubs that link all major structural modules. The structural core contains brain regions that form the posterior components of the human default network. Looking both within and outside of core regions, we observed a substantial correspondence between structural connectivity and resting-state functional connectivity measured in the same participants. The spatial and topological centrality of the core within cortex suggests an important role in functional integration.

Ictal cerebral positron emission tomography (PET) in focal status epilepticus.

The diagnosis of focal status epilepticus (SE) can be challenging, particularly when clinical manifestations leave doubts about its nature, and electroencephalography (EEG) is not conclusive. This work addresses the utility of ictal (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) in focal SE, which was performed in eight patients in whom SE was finally diagnosed. Clinical, MRI and EEG data were reviewed. (18)F-FDG-PET proved useful: (1) to establish the diagnosis of focal SE, when clinical elements were equivocal or the EEG did not show clear-cut epileptiform abnormalities; (2) to delineate the epileptogenic area in view of possible resective surgery; and (3) when clinical features, MRI and EEG were incongruent regarding the origin of SE. We suggest that ictal (18)F-FDG-PET may represent a valuable diagnostic tool in selected patients with focal SE or frequent focal seizures.

Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.

Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of the present work was thus to analyse how the genes of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), allowing creatine synthesis, as well as of the creatine transporter SLC6A8, allowing creatine uptake into cells, are regulated in rat brain cells under NH4+ exposure. Reaggregated brain cell three-dimensional cultures exposed to NH4Cl were used as an experimental model of hyperammonemia in the developing central nervous system (CNS). We show here that NH4+ exposure differentially alters AGAT, GAMT and SLC6A8 regulation, in terms of both gene expression and protein activity, in a cell type-specific manner. In particular, we demonstrate that NH4+ exposure decreases both creatine and its synthesis intermediate, guanidinoacetate, in brain cells, probably through the inhibition of AGAT enzymatic activity. Our work also suggests that oligodendrocytes are major actors in the brain in terms of creatine synthesis, trafficking and uptake, which might be affected by hyperammonemia. Finally, we show that NH4+ exposure induces SLC6A8 in astrocytes. This suggests that hyperammonemia increases blood-brain barrier permeability for creatine. This is normally limited due to the absence of SLC6A8 from the astrocyte feet lining microcapillary endothelial cells, and thus creatine supplementation may protect the developing CNS of hyperammonemic patients.