Estimating the Timing of Mother-to-Child Transmission of the Human Immunodeficiency Virus Type 1 Using a Viral Molecular Evolution Model

Background: Mother-to-child transmission (MTCT) is responsible for most pediatric HIV-1 infections worldwide. It can occur during pregnancy, labor, or breastfeeding. Numerous studies have used coalescent and molecular clock methods to understand the epidemic history of HIV-1, but the timing of vertical transmission has not been studied using these methods. Taking advantage of the constant accumulation of HIV genetic variation over time and using longitudinally sampled viral sequences, we used a coalescent approach to investigate the timing of MTCT. Materials and Methods Six-hundred and twenty-two clonal env sequences from the RNA and DNA viral population were longitudinally sampled from nine HIV-1 infected mother-and-child pairs [range: 277–1034 days]. For each transmission pair, timing of MTCT was determined using a coalescent-based model within a Bayesian statistical framework. Results were compared with available estimates of MTCT timing obtained with the classic biomedical approach based on serial HIV DNA detection by PCR assays. Results: Four children were infected during pregnancy, whereas the remaining five children were infected at time of delivery. For eight out of nine pairs, results were consistent with the transmission periods assessed by standard PCR-based assay. The discordance in the remaining case was likely confused by co-infection, with simultaneous introduction of multiple maternal viral variants at the time of delivery. Conclusions: The study provided the opportunity to validate the Bayesian coalescent approach that determines the timing of MTCT of HIV-1. It illustrates the power of population genetics approaches to reliably estimate the timing of transmission events and deepens our knowledge about the dynamics of viral evolution in HIV-infected children, accounting for the complexity of multiple transmission events

Calibration of Nebular Emission-line Diagnostics: II. Abundances

(Abridged) We examine standard methods of measuring nebular chemical abundances, including estimates based on direct T_e measurements, and also bright-line diagnostics. We use observations of 4 LMC HII regions whose ionizing stars have classifications ranging from O7 to WN3. We assume a 2-zone T_e structure to compute ionic abundances. We compare with photoionization models tailored to the properties of the individual objects, and emphasize the importance of correctly relating T_e in the two zones, which can otherwise cause errors of ~0.2 dex in abundance estimates. There are no spatial variations to within 0.1 - 0.15 dex in any of the objects, even one hosting 3 WR stars. Our data agree with the modeled R23 and S23 diagnostics of O and S. We present the first theoretical tracks for S23, which are in excellent agreement with a larger dataset. However, contrary to earlier suggestions, S23 is much more sensitive to the ionization parameter than is R23, because S23 does not sample S IV. We therefore introduce S234 = ([SII]+[SIII]+[SIV])/H-beta. Predicted and observed spatial variations in S234 are dramatically reduced in contrast to S23. The intensity of [SIV]10.5 microns is easily estimated from a simple relation between [SIV]/[SIII] and [OIII]/[OII]. This method of estimating S234 yields excellent agreement with our models, hence we give a theoretical calibration for S234. The double-valued structure of S23 and S234 remains an important problem as for R23, and presently we consider the S diagnostics reliable only at Z < 0.5 Z_sol. However, the slightly larger dynamic range and excellent compatibility with theoretical predictions suggest the S diagnostics to be more effective abundance indicators than R23.Comment: Accepted to ApJ. 24 pages, 11 figures, uses emulateapj.st

Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: effect of local infusions in the somatosensory cortex and thalamus

OBJECTIVE Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. METHODS Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. RESULTS Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. SIGNIFICANCE These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA

Les tarots Sola-Busca à la Brera

Acquis par l’État italien en 2009 auprès des héritiers Sola et confié à la Pinacoteca di Brera de Milan, où il rejoint le tarot Brambilla (quarante-huit cartes enluminées, attribuées à Bonifacio Bembo et peintes, vers 1445, pour le duc de Milan Filippo Maria Visconti), le tarot Sola-Busca, gravé (au burin) et peint vers 1490, représente le seul ensemble complet antérieur à 1600. De structure classique – soixante-dix-huit cartes, avec cinquante-six cartes en quatre couleurs latines, vingt et u..

COMPRESSIONI SEVERE DEL NERVO MEDIANO AL CARPO: UTILIZZO DEI FATTORI DI CRESCITA (PRP) IN ASSOCIAZIONE AL TRATTAMENTO CHIRURGICO

La Sindrome del Tunnel Carpale (STC) è la malattia da compressione nervosa più frequente, causata dalla compressione del nervo mediano a livello del canale carpale. Colpisce prevalentemente il sesso femminile, nel quale si manifesta generalmente dopo i 50 anni (al pari dei soggetti di sesso maschile) ed è legata soprattutto a fattori di rischio di tipo lavorativo. Clinicamente nelle fasi iniziali si manifesta con parestesie e scosse, le parestesie in particolare possono essere evocate anche attraverso la percussione a livello del tunnel carpale, segno questo detto di Tinel. Altri segni e sintomi importanti sono il segno di Phalen, ovvero la comparsa di parestesie in seguito al mantenimento del polso in flessione forzata per 60 secondi, la mancata abduzione palmare del pollice e l’ipotrofia dell’eminenza tenar. L’esame strumentale più efficace per far diagnosi di certezza è l’Elettromiografia, ovvero la stimolazione elettrica del nervo mediano atta a valutare la risposta di parametri quali la Velocità di conduzione nervosa sensitiva, che spesso risulta inevocabile e le Ampiezze dei Potenziali d’azione, sia sensitivi che motori. Il trattamento può essere di due tipi: conservativo e chirurgico. Il primo è indicato nelle forme lievi, mentre il secondo nelle forme gravi-moderate. Nel nostro studio sono stati reclutati 17 pazienti affetti da STC suddivisi in due gruppi di 7 e 10 soggetti ciascuno e sottoposti ad intervento chirurgico, eseguito ambulatorialmente, in anestesia locale e con ischemia di tutto l’arto. Una mini incisione ha permesso l’accesso al legamento trasverso del carpo che è stato accuratamente sezionato sia prossimalmente che distalmente. Al primo gruppo di pazienti è stato quindi applicato, direttamente a contatto col nervo, un dischetto costituito da fattori di crescita (il PRP ovvero Platelet-Rich Plasma) ricavato da centrifugazione di sangue autologo, che a 30 giorni dall’operazione ha fornito una differenza di risposte in positivo, sia cliniche che elettromiografiche, statisticamente significative rispetto al secondo gruppo di pazienti trattato, invece, tramite la sola decompressione chirurgica. In conclusione tale studio si propone di sostenere l’utilità dei fattori di crescita nel recupero post-chirurgico della STC e nella rigenerazione nervosa che raramente avviene completamente in pazienti con compressione severa che si sottopongono all’intervento chirurgico convenzionale

Experimental treatment options in absence epilepsy

Contains fulltext : 182124.pdf (preprint version ) (Open Access)Background: The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy perse but also for other genetic - previously called idiopathic - forms of epilepsy. The recent discovery of a highly excitable cortical zone in these models is considered as a new therapeutic target area. Methods: Here, we provide an overview regarding the search for new therapeutical options as has been investigated in the genetic rodent models (mainly WAG/Rij and GAERS) including drugs and whether antiepileptogenesis can be achieved, various types of electrical and optogenetical invasive stimulations, different types of non-invasive stimulation and finally whether absence seizures can be predicted and prevented. Results: Many factors determine either the cortical and or thalamic excitability or the interaction between cortex and thalamus and offer new possibilities for new anti-absence drugs, among others metabotropic glutamatergic positive and negative allosteric modulators. The inhibition of epileptogenesis by various drugs with its widespread consequences seems feasible, although its mechanisms remain obscure and seems different from the anti-absence action. Surgical intervention on the cortical zone initiating seizures, either with radiosurgery using synchrotron-generated microbeams, or ablation techniques might reduce spike-and-wave discharges in the rodent models. High frequency electrical subcortical or cortical stimulation might be a good way to abort ongoing spike-and-wave discharges. In addition, possibilities for prevention with real-time EEG analyses in combination with electrical stimulation could also be a way to fully control these seizures. Conclusion: Although it is obvious that some of these treatment possibilities will not be used for absence epilepsy and/or need to be further developed, all can be considered as proof of principle and provide clear directives for further developments

Soft Sweeps III: The Signature of Positive Selection from Recurrent Mutation

Polymorphism data can be used to identify loci at which a beneficial allele has recently gone to fixation, given that an accurate description of the signature of selection is available. In the classical model that is used, a favored allele derives from a single mutational origin. This ignores the fact that beneficial alleles can enter a population recurrently by mutation during the selective phase. In this study, we present a combination of analytical and simulation results to demonstrate the effect of adaptation from recurrent mutation on summary statistics for polymorphism data from a linked neutral locus. We also analyze the power of standard neutrality tests based on the frequency spectrum or on linkage disequilibrium (LD) under this scenario. For recurrent beneficial mutation at biologically realistic rates, we find substantial deviations from the classical pattern of a selective sweep from a single new mutation. Deviations from neutrality in the level of polymorphism and in the frequency spectrum are much less pronounced than in the classical sweep pattern. In contrast, for levels of LD, the signature is even stronger if recurrent beneficial mutation plays a role. We suggest a variant of existing LD tests that increases their power to detect this signature

Découverte d’une rareté de la carte à jouer du XVIIe siècle français

Charles Henry François Desmartins, par ailleurs commissaire des guerres, invente et commercialise de nombreux jeux dans les années 1670. L’un d’eux, « de l’infanterie de l’Europe » était connu par ses règles mais les cartes censées l’accompagner semblaient perdues. Ces cartes gravées représentent des soldats de divers pays d’Europe. Un jeu a été découvert au minutier central, lié à deux actes qui permettent d’éclairer les affaires de Desmartins et les conditions de publication de ce jeu.Charles Henry François Desmartins, a French war commissioner, designed and commercialised many card games in the 1670s. One of them, ’On European Infantry’, is known through its rules but the cards to play it, engraved with soldiers from different European countries, were seemingly lost. However, a set has been discovered in the Parisian central repository of notarial documents, tied to two acts shedding light on Desmartins’ business and the context of the game publication