Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old.

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.

Biomarkers for the diagnosis and monitoring of nitrous oxide intoxication: objectives and methodology of the SFBC Working Group.

The recreational use of nitrous oxide (N2O) is an emerging public health issue. Chronic N2O abuse may result in various clinical symptoms, encompassing neurological, psychiatric and cardiovascular outcomes. Despite the difficulties for the laboratory investigation of N2O intoxication, there is currently no guidelines in France to help both clinicians and biologists use appropriate biomarkers for the diagnosis and monitoring of patients with clinical symptoms potentially related to N2O intoxication. A multi-disciplinary Working Group, carried out under the auspices of the French Society of Clinical Biology (SFBC) and in collaboration with the French Societies of Emergency Medicine (SFMU), Analytical Toxicology (SFTA), Hemostasis and Thrombosis (SFTH), Vitamins and Biofactors (SFVB), and the French Federation of Neurology (FFN), was recently implemented to elaborate practical guidelines. The methodology of the Working Group is based on the critical analysis of the literature, and raising concerns and objectives are grouped into five working packages. The present manuscript primarily aims to expound upon the methodology and objectives of the ongoing SFBC Working Group on N2O.

Targeted Metabolomics Analysis Suggests That Tacrolimus Alters Protection against Oxidative Stress.

Tacrolimus (FK506) is an immunosuppressant that is experiencing a continuous rise in usage worldwide. The related side effects are known to be globally dose-dependent. Despite numerous studies on FK506, the mechanisms underlying FK506 toxicity are still not well understood. It is therefore essential to explore the toxicity mediated by FK506. To accomplish this, we conducted a targeted metabolomic analysis using LC-MS on the plasma samples of patients undergoing FK506 treatment. The aim was to identify any associated altered metabolic pathway. Another anti-calcineurin immunosuppressive therapy, ciclosporin (CSA), was also studied. Increased plasma concentrations of pipecolic acid (PA) and sarcosine, along with a decrease in the glycine/sarcosine ratio and a tendency of increased plasma lysine was observed in patients under FK506 compared to control samples. Patients under CSA do not show an increase in plasma PA compared to the control samples, which does not support a metabolic link between the calcineurin and PA. The metabolomics changes observed in patients under FK506 highlight a possible link between FK506 and the action of an enzyme involved in both PA and sarcosine catabolism and oxidative pathway, the Peroxisomal sarcosine oxidase (PIPOX). Moreover, PA could be investigated as a potential biomarker of early nephrotoxicity in the follow-up of patients under FK506.

Therapeutic interventions impact brain function and promote post-traumatic growth in adults living with post-traumatic stress disorder: A systematic review and meta-analysis of functional magnetic resonance imaging studies.

Introduction: The present systematic review and meta-analysis explores the impacts of cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), and prolonged exposure (PE) therapy on neural activity underlying the phenomenon of post-traumatic growth for adult trauma survivors. Methods: We utilized the following databases to conduct our systematic search: Boston College Libraries, PubMed, MEDLINE, and PsycINFO. Our initial search yielded 834 studies for initial screening. We implemented seven eligibility criteria to vet articles for full-text review. Twenty-nine studies remained for full-text review after our systematic review process was completed. Studies were subjected to several levels of analysis. First, pre-and post- test post-traumatic growth inventory (PTGI) scores were collected from all studies and analyzed through a forest plot using Hedges' g. Next, Montreal Neurological Institute (MNI) coordinates and t-scores were collected and analyzed using an Activation Likelihood Estimation (ALE) to measure brain function. T-scores and Hedges' g values were then analyzed using Pearson correlations to determine if there were any relationships between brain function and post-traumatic growth for each modality. Lastly, all studies were subjected to a bubble plot and Egger's test to assess risk of publication bias across the review sample. Results: Forest plot results indicated that all three interventions had a robust effect on PTGI scores. ALE meta-analysis results indicated that EMDR exhibited the largest effect on brain function, with the R thalamus (t = 4.23, p < 0.001) showing robust activation, followed closely by the R precuneus (t = 4.19, p < 0.001). Pearson correlation results showed that EMDR demonstrated the strongest correlation between increased brain function and PTGI scores (r = 0.910, p < 0.001). Qualitative review of the bubble plot indicated no obvious traces of publication bias, which was corroborated by the results of the Egger's test (p = 0.127). Discussion: Our systematic review and meta-analysis showed that CPT, EMDR, and PE each exhibited a robust effect on PTG impacts across the course of treatment. However, when looking closer at comparative analyses of neural activity (ALE) and PTGI scores (Pearson correlation), EMDR exhibited a more robust effect on PTG impacts and brain function than CPT and PE.

Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study.

BACKGROUND: Recreational use of nitrous oxide (N2O) leads to neurological disorders including combined subacute degeneration of spinal cord, psychological disorders, and thrombosis. Serum or urine N2O assays could not be routinely performed. Hence, it is necessary to investigate other biological markers such as metabolic markers. We aimed here to challenge the three main biological markers used for the diagnosis of nitrous oxide abuse as total vitamin B12, homocysteine, and methylmalonic acid. METHODS: We retrospectively collected clinical and biological data from 52 patients with known, documented chronic N2O abuse and associated clinical signs (peripheral neuropathy disability score or thrombosis event). Sera and plasma total vitamin B12, methylmalonic acid (MMA), and homocysteine were performed to identify the most specific marker of chronic N2O intoxication and related clinical outcomes. RESULTS: Plasma homocysteine was almost consistently increased in case of N2O chronic consumption, whereas MMA increase and total vitamin B12 decrease are not systematically found. Our results showed that none of the markers are correlated with levels of N2O consumptions. However, homocysteine and MMA are correlated with clinical severity, but MMA seems to be a better marker of clinical severity. CONCLUSION: There is no specific marker of nitrous oxide abuse according to levels of consumption, total vitamin B12 decrease could not be used either as consumption or as severity marker. However, we showed that homocysteine is consistently increased and could be used as marker of recent N2O consumption. On the other hand, we showed that MMA could be used as a marker of clinical gravity.

A case of pink urine associated with abdominal pain crisis / Un cas d'urines roses associées à des crises de douleurs abdominales

An adolescent girl consults a physician for abdominal pain attacks occurring regularly for 2 years. After eliminating gastroenterologic or gynecologic causes, an acute hepatic porphyria is suspected. The pink color of her urine seems consistent with the suspicion of porphyria; however, the urinary profile of porphyrins and its precursors is normal.

Une adolescente consulte son médecin pour des crises de douleurs abdominales survenant de manière régulière depuis environ 2 ans. Après avoir éliminé une étiologie gastro-intestinale ou gynécologique, une porphyrie aiguë hépatique est suspectée. Un bilan urinaire est alors réalisé. La coloration rose des urines est en faveur de cette hypothèse, cependant le profil urinaire des porphyrines et de ses précurseurs est normal, excluant une crise aiguë de porphyrie.

Undetectable triglycerides related to the combined intake of ascorbic acid and tacrolimus.

Management of triglyceride (TG) levels is essential in intensive care units (ICU), especially to manage the risk of pancreatitis induced by propofol. However, some therapeutics in ICU such as intravenous ascorbic acid protocol, especially used in the context of Covid-19 could lead to false decrease of triglycerides by analytical disruption of Trinder reaction. We report here the case of a sample with unmeasurable triglyceride levels partly due to high plasma ascorbic acid levels. However, repeated measure on the same sample four days later revealed that interference mechanism on TG was still present whereas the level of ascorbic acid was very reduced by oxidation degradation. Hence, additional interference mechanism was suspected. After clinical investigation, we found that the patient had also received high doses of tacrolimus due to a transplant. As previous studies reported that tacrolimus treatment lead to a decrease of the measured plasma activity of lipoprotein lipase (LPL), we hypothesized that tacrolimus or related metabolites could also interfere by direct inhibition of LPL involved in TG analytical method used.

Multidisciplinary quality improvement initiative to optimize acute neurovascular imaging for transient ischemic attack or minor stroke.

BACKGROUND: Neurovascular imaging for patients with high-risk transient ischemic attack (TIA) or minor stroke in the emergency department (ED) with computed tomography angiography (CTA) of the head and neck is the guideline-recommended standard of care, but it is underutilized in routine practice. We conducted a quality initiative to improve adherence to guidelines. METHODS: Between January 2017 and March 2019, we implemented a decision support tool integrated into the electronic ordering system to guide ED physicians to order a CTA on patients with high-risk TIA or minor stroke defined as ongoing neurological deficits in the ED or resolved motor or speech deficits in the preceding 48 h. Data were collected retrospectively pre-intervention and prospectively post-intervention. We used an interrupted time-series analysis for the before-after comparison of the use of CTA among patients who met criteria (main process measure) and those who did not meet criteria (balancing measure). RESULTS: Among 861 patients with TIA or minor stroke, the proportion of patients with high-risk events imaged with a CTA in the ED increased from 12.0% pre-intervention to 77.0% post-intervention and this shift was sustained over 11 months. CTA use in those without high-risk events increased to a lesser extent (15.3% versus 42.9%). The interrupted time-series analysis showed a step change immediately post-intervention where the increase in CTA use in patients with high-risk events was 51.7% higher than its use in those without high-risk events (p < 0.001). Compared to pre-intervention, the median ED length of stay increased by 2 h and neurology consultation in the ED was more frequent (5.8% versus 19.5%) post-intervention. CONCLUSION: We provide a detailed framework that improved adherence to acute imaging guidelines for patients with TIA or minor stroke and anticipate that our approach could improve acute imaging for such patients in most EDs.

RéSUMé: CONTEXTE: L'imagerie neurovasculaire pour les patients présentant un risque élevé d'accident ischémique transitoire (AIT) ou d'accident vasculaire cérébral mineur aux services d'urgence, avec une angiographie par tomodensitométrie (CTA) de la tête et du cou, est la norme de soins recommandée par les directives, mais elle est sous-utilisée dans la pratique courante. Nous avons mené une initiative de qualité pour améliorer le respect des lignes directrices. MéTHODES: Entre janvier 2017 et mars 2019, nous avons mis en place un outil d'aide à la décision intégré au système de commande électronique pour guider les médecins du service d'urgence à prescrire un CTA sur des patients atteints d'un AIT à haut risque ou d'un AVC mineur défini comme des déficits neurologiques en cours au service des urgences ou une résolution de la motricité ou des troubles de la parole dans les 48 heures précédentes. Les données ont été recueillies rétrospectivement avant l'intervention et prospectivement après l'intervention. Nous avons utilisé une analyse de séries chronologiques interrompues pour la comparaison avant-après de l'utilisation du CTA chez les patients qui répondaient aux critères (mesure principale du processus) et ceux qui ne répondaient pas aux critères (mesure d'équilibrage). RéSULTATS: Parmi les 861 patients atteints d'un AIT ou d'un AVC mineur, la proportion de patients présentant des événements à haut risque imagés avec un CTA au service d'urgence est passé de 12,0 % avant l'intervention à 77,0 % après l'intervention et ce changement s'est maintenu pendant 11 mois. L'utilisation de CTA chez les personnes sans événements à haut risque a augmenté dans une moindre mesure (15,3 % contre 42,9 %). L'analyse des séries chronologiques interrompues a montré un changement d'étape immédiatement après l'intervention où l'augmentation de l'utilisation du CTA chez les patients présentant des événements à haut risque était 51,7 % plus élevée que son utilisation chez ceux sans événements à haut risque (p < 0,001). Par rapport à la pré-intervention, la durée médiane du séjour au SU a augmenté de deux heures et les consultations de neurologie au SU étaient plus fréquentes (5,8 % contre 19,5 %) après l'intervention. CONCLUSION: Nous fournissons un cadre détaillé qui a amélioré le respect des lignes directrices en matière d'imagerie aiguë pour les patients souffrant d'AIT ou d'AVC mineur et nous prévoyons que notre approche pourrait améliorer l'imagerie aiguë pour ces patients dans la plupart des urgences.

Electronic Structure of a Diiron Complex: A Multitechnique Experimental Study of [(dppf)Fe(CO) 3]+/0.

Here we explore the electronic structure of the diiron complex [(dppf)Fe(CO)3]0/+ [10/+; dppf = 1,1'-bis(diphenylphosphino)ferrocene] in two oxidation states by an advanced multitechnique experimental approach. A combination of magnetic circular dichroism, X-ray absorption and emission, high-frequency electron paramagnetic resonance (EPR), and Mössbauer spectroscopies is used to establish that oxidation of 10 occurs on the carbonyl iron ion, resulting in a low-spin iron(I) ion. It is shown that an unequivocal result is obtained by combining several methods. Compound 1+ displays slow spin dynamics, which is used here to study its geometric structure by means of pulsed EPR methods. Surprisingly, these data show an association of the tetrakis[3,5-bis(trifluoromethylphenyl)]borate counterion with 1+.

Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. METHODS: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18-40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. RESULTS: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min-1 kg-1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 µmol/l; interaction 'exercise' × 'group', p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma L-arginine (p < 0.05)-in particular when HbA1c was high (mean estimation: -4.0, p < 0.05)-and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. Graphical abstract CONCLUSIONS/INTERPRETATION: Participants with uncomplicated type 1 diabetes displayed reduced availability of L-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. TRIAL REGISTRATION: clinicaltrials.gov NCT02051504.

Hypervitaminosis A is associated with immunological non-response in HIV-1-infected adults: a case-control study.

For people living with HIV, determinants of immunological non-response (INR) to combined antiretroviral therapy (cART) have not been fully elucidated. In a case-control study, we evaluated the influence of the nutritional and antioxidant status in HIV-1 adults whose cART was initiated between January 2001 and December 2013. Cases had persistent CD4 counts < 350/µL vs. > 350/µL for controls, after at least 2 years of cART with persistent viral loads (VL) < 50 copies/mL. Twelve cases and twenty-eight control subjects with the same CD4 count at cART initiation were compared for their nutritional and antioxidant status after age adjustment at dosage assessment. Patients were predominantly male (70%), Caucasian (82%) and at AIDS stage (62%). The median age was 53, and the median CD4 count was 245/mm3 for cases and 630/mm3 for controls after a median time of 7 years on cART. Despite higher energy intakes in cases, anthropometric data was comparable between groups who had similar vitamins B9/B12/C/D/E, zinc, citrulline and glutamine levels. Nine cases (75%) and 8 controls (29%) had hypervitaminosis A (> 2.70 µmol/L) (p = 0.030). Cases had lower erythrocyte resistance when exposed to a controlled free radical attack (p = 0.014). Most cases had hypervitaminosis A and altered antioxidant capacities that could affect immunological response. Wide-scale studies are required, but in the meantime, screening of their vitamin A status must be encouraged in these patients.

Beyond the muscular effects - onabotulinumtoxinA injections for pain control in chronic knee osteoarthritis: a case report.

We present a long-standing case of an 88-year-old woman with multiple comorbidities receiving intra-articular Botox® (onabotulinumtoxinA) injections for bilateral chronic knee osteoarthritis. She reported improved pain control and function supported by validated outcome measures.

Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts.

Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D3-creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended. Together, these measures decreased, by a first order of magnitude, creatine concentrations in the incubation medium at the start of creatine-uptake studies and allowed to functionally discriminate between 4 hemizygous male and 4 heterozygous female patients with X-linked SLC6A8 deficiency, and between this cohort of eight patients and controls. The functional assay corroborated genetic diagnosis of SLC6A8 deficiency. Gene anomalies in our small cohort included splicing site (c.912G > A [p.Ile260_Gln304del], c.778-2A > G and c.1495 + 2 T > G), substitution (c.407C > T) [p.Ala136Val] and deletion (c.635_636delAG [p.Glu212Valfs*84] and c.1324delC [p.Gln442Lysfs*21]) variants with reduced creatine transporter function validating their pathogenicity, including that of a previously unreported c.1324delC variant. The present assay adaptations provide an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations. It might apply to drug testing or other evaluations in the genetic and metabolic horizons covered by the emerging functions of creatine and its transporter, in a way, however, requiring and completed by additional studies on female patients and blood-brain barrier permeability properties of selected compounds. As a whole, the proposed assay of creatine transporter positively adds to currently existing measurements of this transporter activity, and determining on a large scale the extent of its exact suitability to detect female patients should condition in the future its transfer in clinical practice.

Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency.

Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation. In these patients, CPT2 gene studies was prompted by prior fluxomic explorations of mitochondrial ß-oxidation on intact whole blood cells incubated with pentadeuterated ([16-2H3, 15-2H2])-palmitate. Clinical indication for fluxomic explorations was at least one acute rhabdomyolysis episode complicated, in 5 of 11 patients, by acute renal failure. Major trigger of rhabdomyolysis was febrile infection. In all patients, fluxomic data indicated deficient CPT2 function showing normal deuterated palmitoylcarnitine (C16-Cn) formation rates associated with increased ratios between generated C16-Cn and downstream deuterated metabolites (Σ deuterated C2-Cn to C14-Cn). Subsequent gene studies showed in all patients pathogenic gene variants in either homozygous or compound heterozygous forms. Consistent with literature data, allelic frequency of the c.338C > T[p.Ser113Leu] mutation amounted to 68.2% in our cohort. Other missense mutations included c.149C > A[p.Pro50His] (9%), c.200C > G[p.Ala200Gly] (4.5%) and previously unreported c.1171A > G[p.ser391Gly] (4.5%) and c.1420G > C[p.Ala474Pro] (4.5%) mutations. Frameshift c.1666-1667delTT[p.Leu556val*16] mutation (9%) was observed in two patients unknown to be related.