Realizing repeated quantum error correction in a distance-three surface code.

Quantum computers hold the promise of solving computational problems that are intractable using conventional methods1. For fault-tolerant operation, quantum computers must correct errors occurring owing to unavoidable decoherence and limited control accuracy2. Here we demonstrate quantum error correction using the surface code, which is known for its exceptionally high tolerance to errors3-6. Using 17 physical qubits in a superconducting circuit, we encode quantum information in a distance-three logical qubit, building on recent distance-two error-detection experiments7-9. In an error-correction cycle taking only 1.1 µs, we demonstrate the preservation of four cardinal states of the logical qubit. Repeatedly executing the cycle, we measure and decode both bit-flip and phase-flip error syndromes using a minimum-weight perfect-matching algorithm in an error-model-free approach and apply corrections in post-processing. We find a low logical error probability of 3% per cycle when rejecting experimental runs in which leakage is detected. The measured characteristics of our device agree well with a numerical model. Our demonstration of repeated, fast and high-performance quantum error-correction cycles, together with recent advances in ion traps10, support our understanding that fault-tolerant quantum computation will be practically realizable.

Visualizing structure-mediated interactions in supercoiled DNA molecules.

We directly visualize the topology-mediated interactions between an unwinding site on a supercoiled DNA plasmid and a specific probe molecule designed to bind to this site, as a function of DNA supercoiling and temperature. The visualization relies on containing the DNA molecules within an enclosed array of glass nanopits using the Convex Lens-induced Confinement (CLiC) imaging method. This method traps molecules within the focal plane while excluding signal from out-of-focus probes. Simultaneously, the molecules can freely diffuse within the nanopits, allowing for accurate measurements of exchange rates, unlike other methods which could introduce an artifactual bias in measurements of binding kinetics. We demonstrate that the plasmid's structure influences the binding of the fluorescent probes to the unwinding site through the presence, or lack, of other secondary structures. With this method, we observe an increase in the binding rate of the fluorescent probe to the unwinding site with increasing temperature and negative supercoiling. This increase in binding is consistent with the results of our numerical simulations of the probability of site-unwinding. The temperature dependence of the binding rate has allowed us to distinguish the effects of competing higher order DNA structures, such as Z-DNA, in modulating local site-unwinding, and therefore binding.

Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke.

Neonatal acute ischemic stroke is a cause of neonatal brain injury that occurs more frequently in males, resulting in associated neurobehavioral disorders. The bases for these sex differences are poorly understood but might include the number, morphology and activation of microglia in the developing brain when subjected to stroke. Interestingly, poly (ADP-ribose) polymerase (PARP) inhibition preferentially protects males against neonatal ischemia. This study aims to examine the effects of PJ34, a PARP inhibitor, on microglial phenotypes at 3 and 8 days and on neurobehavioral disorders in adulthood for both male and female P9 mice subjected to permanent middle cerebral artery occlusion (pMCAo). PJ34 significantly reduced the lesion size by 78% and reduced the density of CX3CR1gfp-labeled microglial cells by 46% when examined 3 days after pMCAo in male but not in female mice. Eight days after pMCAo, the number of Iba1+/Cox-2+ cells did not differ between male and female mice in the cortical peri-infarct region. In the amygdala, Iba1+/Cox-2+ (M1-like) cell numbers were significantly decreased in PJ34-treated males but not in females. Conversely, Iba1+/Arg-1+ (M2-like) and Arg-1+/Cox-2+ (Mtransitional) cell numbers were significantly increased in PJ34-treated females. Regarding neurobehavioral disorders during adulthood, pMCAo induced a motor coordination deficit and a spatial learning deficit in female mice only. PJ34 prevented MBP fibers, motor coordination and learning disorders during adulthood in female mice. Our data show significant sex differences in the effects of PARP inhibition on microglia phenotypes following neonatal ischemia, associated with improved behavior and myelination during adulthood in females only. Our findings suggest that modulating microglial phenotypes may play key roles in behavior disorders and white matter injury following neonatal stroke.

CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice.

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

Lifestyle and cardiometabolic risk in adults with type 1 diabetes: a review.

Over the past decades, there has been a major upward shift in the prevalence of cardiometabolic risk (CMR) factors (central obesity, insulin resistance, hypertension and dyslipidemia) in patients with type 1 diabetes, which could have either an additive or a synergistic effect on risk for cardiovascular disease. These metabolic changes are occurring in parallel to the worldwide obesity epidemic and the widespread use of intensive insulin therapy. Poor lifestyle habits (poor diet quality, sedentary behaviours and smoking) are known to be driving factors for increased CMR factors in the general population. The objective of this review is to explore the lifestyle habits of adults with type 1 diabetes and its potential association with CMR factors. Evidence suggests that adherence to dietary guidelines is low in subjects with type 1 diabetes with a high prevalence of patients consuming an atherogenic diet. Sedentary habits are also more prevalent than in the general population, possibly because of the additional contribution of exercise-induced hypoglycemic fear. Moreover, the prevalence of smokers is still significant in the population with type 1 diabetes. All of these behaviours could trigger a cascade of metabolic anomalies that may contribute to increased CMR factors in patients with type 1 diabetes. The intensification of insulin treatment leading to new daily challenges (e.g. carbohydrates counting, increase of hypoglycemia) could contribute to the adoption of poor lifestyle habits. Preventive measures, such as identification of patients at high risk and promotion of lifestyle changes, should be encouraged. The most appropriate therapeutic measures remain to be established.

Adaptation of an Adult Web Application for Type 1 Diabetes Self-management to Youth Using the Behavior Change Wheel to Tailor the Needs of Health Care Transition: Qualitative Interview Study.

BACKGROUND: Youth (aged 14-24 years) living with type 1 diabetes (T1D) encounter increased challenges in their diabetes self-management (DSM), especially during the transition to adult care. Although DSM education and support are imperative, there is insufficient information on how web-based digital tools tailored to their demands can be developed. OBJECTIVE: On the basis of the Behavior Change Wheel, this study aims to identify, among youth living with T1D, the needs and factors influencing their DSM in the context of health care transition and to inform the adaptation (content and features) of an adult self-guided web application (Support). METHODS: Internet-based semistructured individual interviews based on a phenomenological study design were conducted with 21 youths, and transcripts were analyzed using an inductive approach with concept mapping. RESULTS: Factors influencing T1D self-management were categorized into barriers and facilitators and then as external or internal. Features influencing the accessibility to information, increasing the sense of support, and use of the tool were positively accepted. Features unrelated to their expectations of digital tool use or difficulty navigating were viewed negatively. Participants expressed an interest in reliable, practical, and novel educational content. Although youth considered the information provided by medical professionals to be important, peer exchange was deemed necessary to obtain a practical perspective and real-life examples. CONCLUSIONS: Compared with the adult population, in addition to tailored content and a simplified information search process, when building a DSM education and support digital tool for youth, features should be selected to encourage supervised peer exchange.

Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model.

BACKGROUND: As a potent anticoagulant agent, rivaroxaban exposes a risk of bleeding. An effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of an overdose of rivaroxaban in a rabbit model of bleeding and thrombosis. METHODS: First, a dose-ranging study assessed the minimal rivaroxaban dose that increased bleeding. Then, 48 anesthetized and ventilated rabbits were randomized into four groups: control (saline), rivaroxaban (rivaroxaban and saline), rFVIIa (rivaroxaban and rFVIIa), and PCC (rivaroxaban and PCC). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis, detected as cyclic flow reductions, which were recorded over 20 min. Then the following were measured: ear immersion bleeding time, clotting times, anti-Xa activity, thrombelastometric parameters, and thrombin generation test. Ultimately, a hepatosplenic section was performed and the total amount of blood loss after 15 min was evaluated as primary endpoint. RESULTS: Rivaroxaban increased blood loss (17 g [8-32] vs. 7 g [5-18] for control (median [range]), P = 0.0004), ear bleeding time, clotting times, thrombelastographic clotting time, and decreased thrombin generation. In contrast, rFVIIa decreased ear bleeding time (92 s [65-115] vs. 140 s [75-190], P < 0.02), but without efficacy on blood loss. PCC and rFVIIa decreased activated partial thromboplastin time as well as thrombelastographic clotting time. Regarding safety, neither rFVIIa nor PCC increased cyclic flow reductions. CONCLUSION: rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.

Simvastatin in traumatic brain injury: effect on brain edema mechanisms.

OBJECTIVES: Traumatic brain injury causes deleterious brain edema, leading to high mortality and morbidity. Brain edema exacerbates neurologic deficits and may be attributable to the breakdown of endothelial cell junction protein, leukocyte infiltration, and matrix metalloproteinase activation. These all contribute to loss of blood-brain barrier integrity. The pleiotropic effects of statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, may inhibit posttraumatic brain edema. We therefore investigated the effect of acute simvastatin on neurologic deficits, cerebral edema, and its origins. DESIGN: Randomized laboratory animal study. SETTINGS: University-affiliated research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were subjected to lateral fluid percussion traumatic brain injury. Our preliminary dose-effect study indicated that 37.5 mg/kg simvastatin, administered orally 1 hr and 6 hrs after traumatic brain injury, has the greatest anti-edematous effect. This dose was used to study its effects on brain edema and on its mechanisms. MEASUREMENTS AND MAIN RESULTS: We first assessed the effects of simvastatin 24 hrs after traumatic brain injury on brain edema, brain claudin-5 expression, and the vascular endothelial-cadherin (pTyr731)/total vascular endothelial-cadherin ratio, matrix metalloproteinase-9 activity, intercellular adhesion molecule-1 expression, and polymorphonuclear neutrophil infiltration. We also evaluated blood-brain barrier permeability by measuring Evans blue and fluorescein sodium salt extravasation into the cerebral parenchyma. We then investigated whether simvastatin reduces neurologic deficits, edema, and blood-brain barrier permeability earlier than 24 hrs; these effects were evaluated 6 hrs after traumatic brain injury. The anti-edematous effect of simvastatin 24 hrs after traumatic brain injury was associated with increased claudin-5 and decreased intercellular adhesion molecule-1, polymorphonuclear neutrophil infiltration, and blood-brain barrier permeability, with no effect on matrix metalloproteinase-9 activity or vascular endothelial-cadherin phosphorylation. Earlier, 6-hrs after traumatic brain injury, simvastatin reduced neurologic deficits, cerebral edema, and blood-brain barrier permeability. CONCLUSIONS: Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity.

Neuropharmacology in traumatic brain injury: from preclinical to clinical neuroprotection?

Traumatic brain injury (TBI) constitutes a major health problem worldwide and is a leading cause of death and disability in individuals, contributing to devastating socioeconomic consequences. Despite numerous promising pharmacological strategies reported as neuroprotective in preclinical studies, the translation to clinical trials always failed, albeit the great diversity of therapeutic targets evaluated. In this review, first, we described epidemiologic features, causes, and primary and secondary injuries of TBI. Second, we outlined the current literature on animal models of TBI, and we described their goals, their advantages and disadvantages according to the species used, the type of injury induced, and their clinical relevance. Third, we defined the concept of neuroprotection and discussed its evolution. We also identified the reasons that might explain the failure of clinical translation. Then, we reviewed post-TBI neuroprotective treatments with a focus on the following pleiotropic drugs, considered "low hanging fruit" with high probability of success: glitazones, glibenclamide, statins, erythropoietin, and progesterone, that were largely tested and demonstrated efficient in preclinical models of TBI. Finally, our review stresses the need to establish a close cooperation between basic researchers and clinicians to ensure the best clinical translation for neuroprotective strategies for TBI.

Insulin-like Growth Factors may be Markers of both Traumatic Brain Injury and Fear-Related Stress.

Insulin-like growth factors (IGF) are potent neurotrophic and neurorepair factors that were recently proposed as biomarkers of traumatic brain injury (TBI) and associated psychiatric comorbidities, in particular post-traumatic stress disorder (PSTD). We tested the hypothesis that the IGF system is differentially deregulated in the acute and early chronic stages of TBI, and under acute stress. Plasma and brain IGF1 and IGF2 levels were evaluated in mice 3 weeks and 3 days after a controlled cortical impact (CCI)-induced mild-to-moderate TBI. The effects of conditioned fear on IGF levels and its interaction with TBI (TBI followed, 3 weeks later, by fear-inducing procedures) were also evaluated. In the plasma, IGF1 decreased 3 weeks post-TBI only (-9%), whereas IGF2 remained unaffected. In the brain, IGF1 increased only in the cortex and hippocampus at 3 weeks post-TBI (up to +650%). At 3 days, surpringly, this increase was more diffuse and more important in sham (craniotomized) animals. Additionally, IGF2 immunostaining in brain ventricles was reorganized in TBI animals at both post-TBI stages. Conditioned fear exposure did not influence the effects of early chronic TBI on plasma IGF1 levels, but reduced plasma IGF2 (-6%) levels. It also dampened the effects of TBI on brain IGF systems, but brain IGF1 level and IGF2 tissue distribution remained statistically different from controls under these conditions. In co-exposed animals, DNA methylation increased at the hippocampal Igf1 gene promoter. These results show that blood IGF1 and IGF2 are most reduced in the early chronic phase of TBI and after exposure to a stressful event, and that the brain IGF system is up-regulated after TBI, and more so in the acute phase.

From positron emission tomography to cell analysis of the 18-kDa Translocator Protein in mild traumatic brain injury.

Traumatic brain injury (TBI) leads to a deleterious neuroinflammation, originating from microglial activation. Monitoring microglial activation is an indispensable step to develop therapeutic strategies for TBI. In this study, we evaluated the use of the 18-kDa translocator protein (TSPO) in positron emission tomography (PET) and cellular analysis to monitor microglial activation in a mild TBI mouse model. TBI was induced on male Swiss mice. PET imaging analysis with [18F]FEPPA, a TSPO radiotracer, was performed at 1, 3 and 7 days post-TBI and flow cytometry analysis on brain at 1 and 3 days post-TBI. PET analysis showed no difference in TSPO expression between non-operated, sham-operated and TBI mice. Flow cytometry analysis demonstrated an increase in TSPO expression in ipsilateral brain 3 days post-TBI, especially in microglia, macrophages, lymphocytes and neutrophils. Moreover, microglia represent only 58.3% of TSPO+ cells in the brain. Our results raise the question of the use of TSPO radiotracer to monitor microglial activation after TBI. More broadly, flow cytometry results point the lack of specificity of TSPO for microglia and imply that microglia contribute to the overall increase in TSPO in the brain after TBI, but is not its only contributor.

Histological and Behavioral Evaluation after Traumatic Brain Injury in Mice: A Ten Months Follow-Up Study.

Traumatic brain injury (TBI) is a chronic pathology, inducing long-term deficits that remain understudied in pre-clinical studies. In this context, exploration, anxiety-like behavior, cognitive flexibility, and motor coordination were assessed until 5 and 10 months after an experimental TBI in the adult mouse, using two cohorts. In order to differentiate age, surgery, and remote gray and white matter lesions, three groups (unoperated, sham-operated, and TBI) were studied. TBI induced delayed motor coordination deficits at the pole test, 4.5 months after injury, that could be explained by gray and white matter damages in ipsilateral nigrostriatal structures (striatum, internal capsule) that were spreading to new structures between cohorts, at 5 versus 10 months after the injury. Further, TBI induced an enhanced exploratory behavior during stressful situations (active phase during actimetry test, object exploration in an open field), risk-taking behaviors in the elevated plus maze 5 months after injury, and a cognitive inflexibility in the Barnes maze that persisted until 9 months after the injury. These behavioral modifications could be related to the white and gray matter lesions observed in ipsi- and contralateral limbic structures (amygdala, hilus/cornu ammonis 4, hypothalamus, external capsule, corpus callosum, and cingular cortex) that were spreading to new structures between cohorts, at 5 months versus 10 months after the injury. The present study corroborates clinical findings on TBI and provides a relevant rodent chronic model which could help in validating pharmacological strategies against the chronic consequences of TBI.

Behavioral tests that reveal long-term deficits after permanent focal cerebral ischemia in mouse.

Efforts are still needed regarding the research of therapeutics for ischemic stroke. While in experimental studies the protective effect of pharmacological agents is often highlighted by a reduction of the lesion size evaluated in the short term (days), in clinical studies a functional recovery of patients suffering from stroke is expected on the long-term (months and years). Long-term functional preclinical studies are highly recommended to evaluate potential neuroprotective agents for stroke, rather than an assessment of the infarction size at a short time point. The present study thus aimed to select among various behavioral tests those able to highlight long-term deficits (3 months) after cerebral ischemia in mice. Permanent focal cerebral ischemia was carried out in male Swiss mice by intraluminal occlusion of the left middle cerebral artery (MCA). Fourteen behavioral tests were assessed from 7 days to 90 days after ischemia (locomotor activity, neurological score, exit circle test, grip and string tests, chimney test, adhesive removal test, pole test, beam-walking tests, elevated plus maze, marble burying test, forced swimming test, novel object recognition test). The present study clearly identified a battery of behavioral tests able to highlight deficits up to 3 months in our mouse model of permanent MCA occlusion (locomotor activity, neurological score, adhesive removal test, pole test, beam-walking tests, elevated plus maze, marble burying test, forced swimming test and novel object recognition test). This battery of behavioral tests highlighting long-term deficits is useful to study future neuroprotective strategies for stroke treatment.

Housekeeping while brain's storming Validation of normalizing factors for gene expression studies in a murine model of traumatic brain injury.

BACKGROUND: Traumatic brain injury models are widely studied, especially through gene expression, either to further understand implied biological mechanisms or to assess the efficiency of potential therapies. A large number of biological pathways are affected in brain trauma models, whose elucidation might greatly benefit from transcriptomic studies. However the suitability of reference genes needed for quantitative RT-PCR experiments is missing for these models. RESULTS: We have compared five potential reference genes as well as total cDNA level monitored using Oligreen reagent in order to determine the best normalizing factors for quantitative RT-PCR expression studies in the early phase (0-48 h post-trauma (PT)) of a murine model of diffuse brain injury. The levels of 18S rRNA, and of transcripts of beta-actin, glyceraldehyde-3P-dehydrogenase (GAPDH), beta-microtubulin and S100beta were determined in the injured brain region of traumatized mice sacrificed at 30 min, 3 h, 6 h, 12 h, 24 h and 48 h post-trauma. The stability of the reference genes candidates and of total cDNA was evaluated by three different methods, leading to the following rankings as normalization factors, from the most suitable to the less: by using geNorm VBA applet, we obtained the following sequence: cDNA(Oligreen); GAPDH > 18S rRNA > S100beta > beta-microtubulin > beta-actin; by using NormFinder Excel Spreadsheet, we obtained the following sequence: GAPDH > cDNA(Oligreen) > S100beta > 18S rRNA > beta-actin > beta-microtubulin; by using a Confidence-Interval calculation, we obtained the following sequence: cDNA(Oligreen) > 18S rRNA; GAPDH > S100beta > beta-microtubulin > beta-actin. CONCLUSION: This work suggests that Oligreen cDNA measurements, 18S rRNA and GAPDH or a combination of them may be used to efficiently normalize qRT-PCR gene expression in mouse brain trauma injury, and that beta-actin and beta-microtubulin should be avoided. The potential of total cDNA as measured by Oligreen as a first-intention normalizing factor with a broad field of applications is highlighted. Pros and cons of the three methods of normalization factors selection are discussed. A generic time- and cost-effective procedure for normalization factor validation is proposed.

Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury.

We and others have demonstrated that fibrates [peroxisome proliferator-activated receptor (PPAR)alpha agonists] and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) exerted neuroprotective and pleiotropic effects in experimental models of traumatic brain injury (TBI). Because the combination of statins and fibrates synergistically enhanced PPARalpha activation, we hypothesized that the combination of both drugs may exert more important and/or prolonged beneficial effects in TBI than each alone. In this study, we examined the combination of fenofibrate with simvastatin, administered 1 and 6 h after injury, on the consequences of TBI. First, our dose-effect study demonstrated that the most efficient dose of simvastatin (37.5 mg/kg) reduced post-traumatic neurological deficits and brain edema. Then, the effects of the combination of fenofibrate (50 mg/kg) and simvastatin (37.5 mg/kg), given p.o. at 1 and 6 h after TBI, were evaluated on the TBI consequences in the early and late phase after injury. The combination exerted more sustained neurological recovery-promoting and antiedematous effects than monotherapies, and it synergistically decreased the post-traumatic brain lesion. Furthermore, a delayed treatment given p.o. at 3 and 8 h after TBI with the combination was still efficient on neurological deficits induced by TBI, but it failed to reduce the brain edema at 48 h. The present data represent the first demonstration that the combination of fenofibrate and simvastatin exerts prolonged and synergistic neuroprotective effects than each drug alone. Thus, these results may have important therapeutic significance for the treatment of TBI.

Evidence for impairment of hepatic energy homeostasis in head-injured rat.

Traumatic brain injury (TBI) is known to induce a metabolic adaptation characterized by a nitrogen transfer from the periphery to the liver. However, the consequences of TBI on liver energy status are poorly documented. We evaluated the consequences of TBI on liver energy homeostasis in rats. In a first set of experiments, rats were randomized into two groups: a TBI group traumatized by fluid percussion, and an ad libitum fed group (AL) of healthy rats. The rats were sacrificed at 2, 3, or 4 days (D2, D3, and D4, respectively to determine the kinetic of hepatic energy changes). Since TBI leads to a profound anorexia, in a second set of experiments TBI rats received enteral nutrition (TBI-EN group) for 4 days to specifically assess the role of anorexia in the hepatic disturbances. TBI led to a decrease in hepatic glycogen (D2: TBI 3.9 +/- 1.9 vs. AL 18.9 +/- 2.6 mg/g, p < 0.05) and ATP (D2: TBI 540 +/- 57 vs. AL 850 +/- 44 nmol/g, p < 0.05) contents. These effects were not linked to anorexia, since they were observed when rats were fed using continuous enteral nutrition. Interestingly, there was no adaptation of the mitochondrial oxidative capacity to compensate for the increase in energy requirements (cytochrome C oxidase activity: AL, 82 +/- 5; TBI, 82 +/- 4; and TBI-EN, 87 +/- 3 micromol/min/g, NS). These findings demonstrate that TBI is responsible for an impairment of liver energy homeostasis. Moreover, these alterations are related neither to anorexia nor to decreased mitochondrial oxidative capacity.

High plasma apolipoprotein B identifies obese subjects who best ameliorate white adipose tissue dysfunction and glucose-induced hyperinsulinemia after a hypocaloric diet.

Background: To optimize the prevention of type 2 diabetes (T2D), high-risk obese subjects with the best metabolic recovery after a hypocaloric diet should be targeted. Apolipoprotein B lipoproteins (apoB lipoproteins) induce white adipose tissue (WAT) dysfunction, which in turn promotes postprandial hypertriglyceridemia, insulin resistance (IR), and hyperinsulinemia. Objective: The aim of this study was to explore whether high plasma apoB, or number of plasma apoB lipoproteins, identifies subjects who best ameliorate WAT dysfunction and related risk factors after a hypocaloric diet. Design: Fifty-nine men and postmenopausal women [mean ± SD age: 58 ± 6 y; body mass index (kg/m2): 32.6 ± 4.6] completed a prospective study with a 6-mo hypocaloric diet (-500 kcal/d). Glucose-induced insulin secretion (GIIS) and insulin sensitivity (IS) were measured by 1-h intravenous glucose-tolerance test (IVGTT) followed by a 3-h hyperinsulinemic-euglycemic clamp, respectively. Ex vivo gynoid WAT function (i.e., hydrolysis and storage of 3H-triolein-labeled triglyceride-rich lipoproteins) and 6-h postprandial plasma clearance of a 13C-triolein-labeled high-fat meal were measured in a subsample (n = 25). Results: Postintervention first-phase GIISIVGTT and total C-peptide secretion decreased in both sexes, whereas second-phase and total GIISIVGTT and clamp IS were ameliorated in men (P < 0.05). Baseline plasma apoB was associated with a postintervention increase in WAT function (r = 0.61) and IS (glucose infusion rate divided by steady state insulin (M/Iclamp) r = 0.30) and a decrease in first-phase, second-phase, and total GIISIVGTT (r = -0.30 to -0.35) without sex differences. The association with postintervention amelioration in WAT function and GIISIVGTT was independent of plasma cholesterol (total, LDL, and HDL), sex, and changes in body composition. Subjects with high baseline plasma apoB (1.2 ± 0.2 g/L) showed a significant increase in WAT function (+105%; P = 0.012) and a decrease in total GIISIVGTT (-34%; P ≤ 0.001), whereas sex-matched subjects with low plasma apoB (0.7 ± 0.1 g/L) did not, despite equivalent changes in body composition and energy intake and expenditure. Conclusions: High plasma apoB identifies obese subjects who best ameliorate WAT dysfunction and glucose-induced hyperinsulinemia, independent of changes in adiposity after consumption of a hypocaloric diet. We propose that subjects with high plasma apoB represent an optimal target group for the primary prevention of T2D by hypocaloric diets. This trial was registered at BioMed Central as ISRCTN14476404.

Improved Reperfusion and Vasculoprotection by the Poly(ADP-Ribose)Polymerase Inhibitor PJ34 After Stroke and Thrombolysis in Mice.

Benefits from thrombolysis with recombinant tissue plasminogen activator (rt-PA) after ischemic stroke remain limited due to a narrow therapeutic window, low reperfusion rates, and increased risk of hemorrhagic transformations (HT). Experimental data showed that rt-PA enhances the post-ischemic activation of poly(ADP-ribose)polymerase (PARP) which in turn contributes to blood-brain barrier injury. The aim of the present study was to evaluate whether PJ34, a potent PARP inhibitor, improves poor reperfusion induced by delayed rt-PA administration, exerts vasculoprotective effects, and finally increases the therapeutic window of rt-PA. Stroke was induced by thrombin injection (0.75 UI in 1 µl) in the left middle cerebral artery (MCA) of male Swiss mice. Administration of rt-PA (0.9 mg kg-1) or saline was delayed for 4 h after ischemia onset. Saline or PJ34 (3 mg kg-1) was given intraperitoneally twice, just after thrombin injection and 3 h later, or once, 3 h after ischemia onset. Reperfusion was evaluated by laser Doppler, vascular inflammation by immunohistochemistry of vascular cell adhesion molecule-1 (VCAM-1) expression, and vasospasm by morphometric measurement of the MCA. Edema, cortical lesion, and sensorimotor deficit were evaluated. Treatment with PJ34 improved rt-PA-induced reperfusion and promoted vascular protection including reduction in vascular inflammation (decrease in VCAM-1 expression), HT, and MCA vasospasm. Additionally, the combined treatment significantly reduced brain edema, cortical lesion, and sensorimotor deficit. In conclusion, the combination of the PARP inhibitor PJ34 with rt-PA after cerebral ischemia may be of particular interest in order to improve thrombolysis with an extended therapeutic window.

Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury.

We previously demonstrated that fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, reduced the neurological deficit, the edema and the cerebral lesion induced by traumatic brain injury (TBI). In order to elucidate these beneficial effects, in the present study, we investigated, in the same TBI model, fenofibrate's effects on the inflammation and oxidative stress. Male Sprague Dawley rats were randomized in four groups: non-operated, sham-operated, TBI + vehicle, TBI + fenofibrate. TBI was induced by lateral fluid percussion of the temporoparietal cortex. Rats were given fenofibrate (50 mg/kg) or its vehicle (water containing 0.2% methylcellulose), p.o. 1 and 6 h after brain injury. A neurological assessment was done 24 h after TBI, then rats were killed and the brain COX2, MMP9 expression, GSx, GSSG levels were determined. The same schedule of treatment was used to evaluate the effect of fenofibrate on immunohistochemistry of 3NT, 4HNE and iNOS at 24 h post-injury. Our results showed that fenofibrate promotes neurological recovery by exerting anti-inflammatory effect evidenced by a decrease in iNOS, COX2 and MMP9 expression. In addition, fenofibrate showed anti-oxidant effect demonstrated by a reduction of markers of oxidative stress: loss of glutathione, glutathione oxidation ratio, 3NT and 4HNE staining. Our data suggest that PPARalpha activation could mediate pleiotropic effects and strengthen that it could be a promising therapeutic strategy for TBI.

Effect of an immune-enhancing diet on lymphocyte in head-injured rats: what is the role of arginine?

OBJECTIVE: The benefit of immune-enhancing diets (IEDs) in the intensive care unit remains controversial. Considering their complexity, the role of each component, in particular arginine (Arg), in their properties is largely unknown. The aim of this study was to determine the role of arginine in the immunomodulatory effects of an IED (Crucial) in head-injured rats. DESIGN: Thirty-four rats were randomized into five groups: AL (ad libitum), HI (head-injured), HI-STD (HI + standard enteral nutrition, EN), HI-STD-Arg (HI + standard EN + Arg in equimolar concentration to Arg in IED), and HI-IED (HI + IED). These isocaloric and isonitrogenous diets were administered over 4 days. After death, the thymus was removed and weighed. The density of CD25, CD4 and CD8 on lymphocytes from blood and from Peyer patches was evaluated. Mesenteric lymph nodes, liver and spleen were cultured for analysis of enterobacterial translocation and dissemination. MEASUREMENTS AND RESULTS: HI induced an atrophy of the thymus which was not corrected by the standard diet (HI 0.27 +/- 0.03, HI-STD 0.35 +/- 0.03 vs. AL 0.49 +/- 0.02 g; p < 0.05). However, the standard diet supplemented with arginine limited the thymic atrophy and the IED restored thymus weight. CD25 density and interleukin-2 production were increased only in the HI-STD-Arg and HI-IED groups (p < 0.05). Head injury induced enterobacterial translocation and dissemination which were blunted only in the HI-STD-Arg group (p < 0.05). CONCLUSIONS: In this rat HI model, arginine appears to be safe, contributes to a large extent to the immunomodulatory effects of the IED, and seems to limit enterobacterial translocation and dissemination more efficiently alone than in an IED.