Efficacy and safety of late-start Corifollitropin-alfa administration for controlled ovarian hyperstimulation in IVF: a cohort,case–control study

ObjectiveTo investigate efficacy and safety of a controlled ovarian stimulation (COS) protocol in which a single dose of Corifollitropin-alfa (CFα) was administered on day 4 of a GnRH-antagonist cycle.DesignCohort case–control study.SettingUniversity Hospital.PatientsOne hundred twenty-two normally cycling women expected to be normal responders to COS.InterventionsIn 61 patients, CFα (100–150 μg) was injected subcutaneously on day 4 of a spontaneous menstrual cycle; a GnRH-antagonist was added from day 8 (fixed protocol; 0.25 mg/day). If needed to complete follicular maturation, recombinant FSH (rFSH) daily injections (150/200 IU/day) were given from day 11. A control group of 61 matched women was stimulated with daily subcutaneous injections of rFSH (100–150 U/day) from day 4 of the cycle, and received GnRH-antagonist (0.25 mg/day) from day 8. IVF or ICSI was performed according to the sperm characteristics, and 1–2 embryos were transferred in utero under US guidance on day 2.ResultsNo cycle was cancelled and the mean number of retrieved COCs was comparable in patients and controls. About 60 % of CF-alfa treated women had no need of daily rFSH addition, and the mean number of injections/cycle was significantly lower in the CF-alfa group than in controls (p < 0.05). The ongoing PR/transfer was 36.8 % in CF-alfa group and 37.5 % in controls. No patient developed severe OHSS, and the incidence of moderate OHSS was similar in cases and controls.ConclusionsCFα may be started on day 4 of the cycle obtaining results comparable to those of a COS using day 4-start daily rFSH, with significantly less injections and a similar risk of OHSS.     

Adoptive T‐cell therapy for cancer: The era of engineered T cells

Tumors originate from a number of genetic events that deregulate homeostatic mechanisms controlling normal cell behavior. The immune system, devoted to patrol the organism against pathogenic events, can identify transformed cells, and in several cases cause their elimination. It is however clear that several mechanisms encompassing both central and peripheral tolerance limit antitumor immunity, often resulting into progressive diseases. Adoptive T‐cell therapy with either allogeneic or autologous T cells can transfer therapeutic immunity. To date, genetic engineering of T cells appears to be a powerful tool for shaping tumor immunity. In this review, we discuss the most recent achievements in the areas of suicide gene therapy, and TCR‐modified T cells and chimeric antigen receptor gene‐modified T cells. We provide an overview of current strategies aimed at improving the safety and efficacy of these approaches, with an outlook on prospective developments.     

Sleep- and wake-dependent changes in neuronal activity and reactivity demonstrated in fly neurons using in vivo calcium imaging

Sleep in Drosophila shares many features with mammalian sleep, but it remains unknown whether spontaneous and evoked activity of individual neurons change with the sleep/wake cycle in flies as they do in mammals. Here we used calcium imaging to assess how the Kenyon cells in the fly mushroom bodies change their activity and reactivity to stimuli during sleep, wake, and after short or long sleep deprivation. As before, sleep was defined as a period of immobility of >5 min associated with a reduced behavioral response to a stimulus. We found that calcium levels in Kenyon cells decline when flies fall asleep and increase when they wake up. Moreover, calcium transients in response to two different stimuli are larger in awake flies than in sleeping flies. The activity of Kenyon cells is also affected by sleep/wake history: in awake flies, more cells are spontaneously active and responding to stimuli if the last several hours (5–8 h) before imaging were spent awake rather than asleep. By contrast, long wake (≥29 h) reduces both baseline and evoked neural activity and decreases the ability of neurons to respond consistently to the same repeated stimulus. The latter finding may underlie some of the negative effects of sleep deprivation on cognitive performance and is consistent with the occurrence of local sleep during wake as described in behaving rats. Thus, calcium imaging uncovers new similarities between fly and mammalian sleep: fly neurons are more active and reactive in wake than in sleep, and their activity tracks sleep/wake history.The fundamental features that characterize mammalian sleep also define Drosophila melanogaster sleep (1–3). Most crucially, in both flies and mammals, sleep is distinguished from simple rest (quiet wake) by an increased arousal threshold, i.e., a reduced ability to respond to external stimuli. Moreover, in flies and mammals sleep is controlled homeostatically by the duration as well by the intensity of prior wake, suggesting basic similarities in the mechanisms of sleep regulation across species. Thus, in flies both sleep deprivation and a rich learning experience lead to a sleep rebound characterized by overall increased sleep time, increased arousal threshold, and longer sleep episodes (4–6). As in mammals, overall neuronal activity in flies is also high during wake and low during sleep (6–8). Specifically, a seminal study using local field potential (LFP) recordings from the Drosophila medial protocerebrum found high spike-like potentials that disappeared after the block of synaptic transmission in the mushroom bodies (MBs) (7). This high spike activity was present when flies were moving or had been quiescent for only a few seconds, but disappeared with sleep (i.e., after periods of immobility >5 min), when the overall LFP power in all frequencies also decreased by ∼60% (7). The study concluded that neural activity in the sleeping fly brain, or at least in a central region spanning the MBs, resembles that seen in mammals in several brainstem cell groups including noradrenergic neurons, whose firing strongly declines or stops completely during sleep (9). A more recent study in tethered flies able to walk on an air-suspended ball also found that periods of immobility >5 min are associated with increased arousal thresholds and with “flat” LFPs (6). LFPs, however, reflect the activity of thousands of cells (10), and the use of modified stereotrodes to resolve single-unit activity in flies is still in its infancy (11). Glass or tungsten microelectrodes, on the other hand, have recorded one neuron at a time in flies (e.g., refs. 12–14) and, to our knowledge, have not measured changes across sleep and wake.Our goal was to study many fly neurons simultaneously while preserving single-cell resolution, to determine how sleep and wake affect spontaneous activity and the ability of neurons to react to stimuli. It was recently shown in rats that during sleep deprivation single cortical neurons may go unpredictably “offline,” as they normally do during sleep, with negative effects on performance (15). Thus, we also asked whether this phenomenon occurs in flies. We focused on the MBs, large areas of the Drosophila brain involved in olfactory learning (16, 17) and sleep regulation (18, 19), and used in vivo calcium imaging (20, 21) to measure spontaneous and evoked neuronal activity in the MB principal neurons, the Kenyon cells, during sleep, wake, and in response to different periods of sleep deprivation.     

Thalamo-cortical network activity between migraine attacks: Insights from MRI-based microstructural and functional resting-state network correlation analysis

Background

Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks.

Methods

Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores.

Results

In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally.

Conclusions

The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology.

     

Sigh in supine and prone position during acute respiratory distress syndrome

Interventions aimed at recruiting the lung of patients with acute respiratory distress syndrome (ARDS) are not uniformly effective. Because the prone position increases homogeneity of inflation of the lung, we reasoned that it might enhance its potential for recruitment. We ventilated 10 patients with early ARDS (PaO2/FIO2, 121 +/- 46 mm Hg; positive end-expiratory pressure, 14 +/- 3 cm H2O) in supine and prone, with and without the addition of three consecutive "sighs" per minute to recruit the lung. Inspired oxygen fraction, positive end-expiratory pressure, and minute ventilation were kept constant. Sighs increased PaO2 in both supine and prone (p < 0.01). The highest values of PaO2 (192 +/- 41 mm Hg) and end-expiratory lung volume (1840 +/- 790 ml) occurred with the addition of sighs in prone and remained significantly elevated 1 hour after discontinuation of the sighs. The increase in PaO2 associated with the sighs, both in supine and prone, correlated linearly with the respective increase of end-expiratory lung volume (r = 0.82, p < 0.001). We conclude that adding a recruitment maneuver such as cyclical sighs during ventilation in the prone position may provide optimal lung recruitment in the early stage of ARDS.     

Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis

Results of unrelated cord blood transplantation (UCBT) in childhood acute myeloid leukemia (AML) have not been previously reported. We analyzed 95 children receiving UCB transplants for AML (20 in first complete remission [CR1], 47 in CR2, and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 5.2 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 78% +/- 4%, acute graft-versus-host disease (GVHD) was 35% +/- 5%, and 100-day transplantation-related mortality (TRM) was 20% +/- 4%. In multivariable analysis, a collected NC dose higher than 5.2 x 107/kg was associated with a lower 100-day TRM. The 2-year CI of relapse was 29% +/- 5% and was associated with disease status. The 2-year leukemia-free survival (LFS) was 42% +/- 5% (59% +/- 11% in CR1, 50% +/- 8% in CR2, and 21% +/- 9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS compared with other patients (44% +/- 11% vs 40% +/- 8%). In CR2, LFS was not influenced by the length of CR1 (53% +/- 11% in CR1 < 9.5 months compared with 50% +/- 12% in later relapses). We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.     

Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation

Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP).A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls.INFγ rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25–1, P = 0.04). Although not significant, interleukin (IL)-1β rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1α rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09–4.41, P = 0.02, and OR 0.42, 95% CI 0.21–0.84, P = 0.01).This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM.