Chronology of the push pull effect on nonhuman primates—shift of the arterial pressure threshold

Fighter pilots are frequently exposed to high Gz acceleration which may induce in-flight loss of consciousness (G-LOC). One factor reducing tolerance to accelerations is a previous exposure to negative accelerations. This phenomenon, which happens during the first few seconds after the onset of the positive plateau, is called the push pull effect. Our goal was to validate a non human primate model in order to study push pull physiological mechanisms and possible changes in arterial pressure, which may occur after the first ten seconds of the positive acceleration plateau. Eight rhesus monkeys were centrifuged in profile runs, including positive Gz accelerations (+1.4, +2 and +3 Gz) with or without previous negative Gz acceleration (–2 and –3 Gz vs. +1.4 Gz). Heart rate, blood pressure and esophageal pressure were recorded during the entire centrifugation run. Results showed that the push pull effect was observed in the non human primate model. Moreover, the reduced tolerance to acceleration lingered longer than that during the first ten seconds after exposure to +Gz acceleration. It was found that, after the fourteenth second, mean blood arterial pressure stabilizes at a lower value, when the positive acceleration is preceded by a negative acceleration (15.8 kPa for –1 Gz and 15.5 for –2 Gz vs. 16.9 for 1.4 Gz). The chronology of the push pull effect seems to involve two periods. One has a short time span. The other one has a longer time span and could be induced by shift of pressure threshold, coming from exposure to previous negative acceleration.     

Multimodal investigation of dopamine D2/D3 receptors,default mode network suppression,and cognitive control in cocaine-use disorder

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [¹¹C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.Subject terms: Addiction, Cognitive control     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Obésité et diabète. Les variations des acides gras libres circulants sous charge orale en glucose

Résumé L'étude des variations des acides gras libres (AGL) du plasma est entreprise chez 58 sujets obèses et 18 sujets normaux témoins, mis dans des conditions d'exploration identiques. On constate chez les sujets obèses un comportement global des AGL qui est différent de celui des sujets normaux témoins dans la mesure où la dépression initiale de leur taux est plus lente et le maximum de chute est différé aux temps tardifs de l'épreuve. Il en résulte une tendance globale à une absence de réascension secondaire du taux des AGL circulants, à l'inverse de ce qui succède chez le sujet normal, où la valeur moyenne des AGL à la 4^ème h de l'épreuve est plus élevée que le taux moyen de base. Tant chez le sujet normal que chez le sujet obèse, on constate d'importantes variations individuelles. Les anomalies rencontrées chez les obèses sont d'autant plus évidentes que la tolérance glucidique se rapproche des conditions du diabète; cela laisse à penser qu'il existe, chez ces sujets, des relations étroites entre la dégradation de la tolérance glucidique et les anomalies du comportement des AGL circulants. Ce dernier problème est discuté en fonction des relations entre l'obésité et la maladie diabétique.

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Summary The variations of plasma non-esterified fatty acids (NEFA) in 58 obese subjects and 18 normal controls have been studied in identical conditions of investigation. The overall behavior of NEFA in the obese differed from that in the controls in that the initial fall was slower and the maximum depression occurred late in the test. Hence the overall tendency was for the secondary rise in the NEFA level to be missing, which was the reverse of what happened in the normals, in whom the mean NEFA value at the 4th h was above the starting value. Both in normals and in obese subjects there was a considerable individual variation. The anomalies in the obese became more marked as carbohydrate tolerance approached diabetic level; this suggests that there is in these subjects a close connexion between the decline of carbohydrate tolerance and the anomalies of plasma NEFA behavior. The latter is discussed in terms of the relationships between obesity and diabetes.

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Zusammenfassung Bei 58 Fettsüchtigen und 18 Normalpersonen wurden unter identischen Versuchsbedingungen die Variationen der freien Fettsäuren des Plasma (FFA) verfolgt. Bei Fettsüchtigen wurde ein von den Normalpersonen verschiedenes Gesamtverhalten der FFA festgestellt; der Unterschied ist umso grösser je langsamer die anfängliche Senkung des FFA-Spiegels bei den Fettsüchtigen erfolgt und je mehr das Maximum der Abnahme verzögert ist. Daraus ergibt sich eine Gesamttendenz zum Fehlen des sekundären Anstiegs des zirkulierenden FFA-Spiegels, im Gegensatz zu den Verhältnissen bei Normalpersonen, wo der Mittelwert der FFA in der 4. Stunde der Probe höher ist als der mittlere Ausgangswert. Sowohl bei Normalpersonen als auch bei Fettsüchtigen werden erhebliche individuelle Unterschiede beobachtet. Die bei Fettsüchtigen beobachteten Anomalien sind umso ausgesprochener je mehr sich ihre Kohlehydrattoleranz einer diabetischen Stoffwechsellage nähert; das lässt den Verdacht aufkommen, dass bei diesen Individuen eine enge Beziehung zwischen der verminderten Glukosetoleranz und dem abnormen Verhalten der zirkulierenden FFA besteht. Dieses Problem wird im Hinblick auf die Beziehungen zwischen Fettsucht und Diabetes mellitus besprochen.

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Resumen Se emprendió el estudio de las variaciones de los ácidos grasos libres (AGL) del plasma en 58 individuos obesos y 18 testigos normales, puestos en idénticas condiciones de exploración Se constata que en los sujetos obesos un comportamiento global de los AGL es diferente al de los individuos testigos normales en la medida o la depresión de su porcentaje es más lento y el máximo de caída se difiere a los tiempos tardíos de la prueba. Resulta una tendencia global a una ausencia de reascensión secundaria del porcentaje de los AGL circulantes, al contrario de lo que sucede en el individuo normal, en el que el valor medio de los AGL a las cuatro horas de la prueba es más elevado que el porcentaje medio de base. Tanto en el sujeto normal como en el sujeto obeso, se comprueban importantes variaciones individuales. Las anomalías encontradas en los obesos son mucho más evidentes cuando la tolerancia se acerca a las condiciones de la diabetes; esto lleva a pensar que existe, en estos individuos, estrechas relaciones entre la degradación y la tolerancia glucídica y las anomalias del comportamiento de los AGL circulantes. Este último problema se discute en función de las relaciones entre la obesidad y la enfermedad diabética.

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Riassunto Le variazioni dei NEFA plasmatici sono state studiate in 58 pazienti obesi e in 18 individui normali di controllo, posti in condizioni sperimentali identiche. Nei soggetti obesi è stato osservato un comportamento globale dei NEFA diverso da quello degli individui normali di controllo, nel senso che la depressione iniziale è più lenta e la massima caduta si verifica nelle fasi tardive della prova. Ne risulta una tendenza globale all'assenza di risalita secondaria dei NEFA circolanti, contrariamente a quanto avviene nel soggetto normale, in cui il valore medio dei NEFA alla 4^a ora del test è più elevato rispetto al livello medio di base. Sia nel soggetto normale che nell'obeso, si riscontrano importanti variazioni individuali. Le anomalie rilevate negli obesi sono tanto più evidenti quanto più la tolleranza al glucosio si avvicina alle condizioni esistenti nel diabete: ciò induce a ritenere che in questi soggetti esistano stretti rapporti tra la diminuzione della tolleranza al glucosio e le anomalie del comportamento dei NEFA circolanti. Quest'ultimo problema viene discusso alla luce delle relazioni tra obesità e malattia diabetica.

     

Are the results of electrophysiological study different in patients with a pre-excitation syndrome, with and without syncope?

AIMS: Syncope in Wolff-Parkinson-White (WPW) syndrome may reveal an arrhythmic event or is not WPW syndrome related. The aim of the study is to evaluate the results of electrophysiological study in WPW syndrome according to the presence or not of syncope and the possible causes of syncope. METHODS AND RESULTS: Among 518 consecutive patients with diagnosis of WPW syndrome, 71 patients, mean age 34.5 +/- 17, presented syncope. Transoesophageal electrophysiological study in control state and after isoproterenol infusion was performed in the out-patient clinic. Atrioventricular re-entrant tachycardia (AVRT) was more frequently induced than in asymptomatic patients (n = 38, 53.5%, P < 0.01), less frequently than in those with tachycardia; atrial fibrillation (AF) and/or antidromic tachycardia (ATD) was induced in 28 patients (39%) more frequently (P < 0.05) than in asymptomatic patients or those with tachycardia. The incidence of high-risk form [rapid conduction over accessory pathway (AP) and AF or ATD induction] was higher in syncope group (n = 18, 25%, P < 0.001) than in asymptomatic subjects (8%) or those with tachycardias (7.5%). Maximal rate conducted over AP was similar in patients with and without syncope, and higher in patients with spontaneous AF, but without syncope. Results were not age-related. CONCLUSION: Tachycardia inducibility was higher in patients with syncope than in the asymptomatic group. The incidence of malignant WPW syndrome was higher in patients with syncope than in asymptomatic or symptomatic population, but the maximal rate conducted over AP was not higher and another mechanism could be also implicated in the mechanism of syncope.     

Tracer kinetic modeling of [11C]AFM,a new PET imaging agent for the serotonin transporter

[¹¹C]AFM, or [¹¹C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [¹¹C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [¹¹C]AFM binding potential (BP_ND) matched well with the known regional SERT densities. For routine use of [¹¹C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [¹¹C]AFM is a suitable PET radioligand to image and quantify SERT in humans.     

Impact of Rotavirus Vaccine on Premature Infants

Infants born preterm are at a higher risk of complications and hospitalization in cases of rotavirus diarrhea than children born at term. We evaluated the impact of a rotavirus vaccination campaign (May 2007 to May 2010) on hospitalizations for rotavirus gastroenteritis in a population of children under 3 years old born prematurely (before 37 weeks of gestation) in the Brest University Hospital birth zone. Active surveillance from 2002 to 2006 and a prospective collection of hospitalizations for rotavirus diarrhea were initiated in the pediatric units of Brest University Hospital until May 2010. Numbers of hospitalizations for rotavirus diarrhea among the population of children born prematurely, before and after the start of the vaccination program, were compared using a Poisson regression model controlling for epidemic-to-epidemic variation. A total of 217 premature infants were vaccinated from 2007 to 2010. Vaccine coverage for a complete course of three doses was 41.9%. The vaccine safety in premature infants was similar to that in term infants. The vaccination program led to a division by a factor of 2.6 (95% confidence interval [CI], 1.3 to 5.2) in the number of hospitalizations for rotavirus diarrhea during the first two epidemic seasons following vaccine introduction and by a factor of 11 (95% CI, 3.5 to 34.8) during the third season. We observed significant effectiveness of the pentavalent rotavirus vaccine on the number of hospitalizations in a population of prematurely born infants younger than 3 years of age. A multicenter national study would provide better assessment of this impact. (This study [Impact of Systematic Infants Vaccination Against Rotavirus on Gastroenteritis Hospitalization: a Prospective Study in Brest District, France (IVANHOE)] has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00740935","term_id":"NCT00740935"}}NCT00740935.)     

Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: A french multicenter study

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9 years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5 years (range: 1.6-35). Two patients developed Waldenström's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36 months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6 mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.