The broad receptive field of the olfactory receptors constitutes the basis of a combinatorial code that allows animals to detect and discriminate many more odorants than the actual number of receptor ...types that they express. One drawback is that high odor concentrations recruit lower affinity receptors which can lead to the perception of qualitatively different odors. Here we addressed the contribution that signal-processing in the antennal lobe makes to reduce concentration dependence in odor representation. By means of calcium imaging and pharmacological approach we describe the contribution that GABA receptors play in terms of the amplitude and temporal profiles of the signals that convey odor information from the antennal lobes to higher brain centers. We found that GABA reduces the amplitude of odor elicited signals and the number of glomeruli that are recruited in an odor-concentration-dependent manner. Blocking GABA receptors decreases the correlation among glomerular activity patterns elicited by different concentrations of the same odor. In addition, we built a realistic mathematical model of the antennal lobe that was used to test the viability of the proposed mechanisms and to evaluate the processing properties of the AL network under conditions that cannot be achieved in physiology experiments. Interestingly, even though based on a rather simple topology and cell interactions solely mediated by GABAergic lateral inhibitions, the AL model reproduced key features of the AL response upon different odor concentrations and provides plausible solutions for concentration invariant recognition of odors by artificial sensors.
The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease ...(SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.
CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in ...clinical practice is still a nascent technology.
CRISPR/Cas9 technology is not yet used as a single therapy to treat tumors but it can be combined with traditional treatment strategies to provide personalized gene therapy for patients. The combination with chemotherapy, radiation and immunotherapy has been proven to be a powerful means of screening, identifying, validating and correcting tumor targets. Recently, CRISPR/Cas9 technology and CAR T-cell therapies have been integrated to open novel opportunities for the production of more efficient CAR T-cells for all patients. GMP-compatible equipment and reagents are already available for several clinical-grade systems at present, creating the basis and framework for the accelerated development of novel treatment methods.
Here we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy highlighting how this technology is opening new opportunities for treating tumors.
The use of alternative hematopoietic stem cell (HSC) donors has been witnessing important progress, mainly due to: (i) better HLA matching at the allelic level between donor and recipient in ...unrelated HSC transplantation (HSCT) translating into better patient outcome; (ii) better donor choice and patient selection in unrelated, often HLA-mismatched, cord blood transplantation and (iii) new strategies of adoptive cell therapy aimed at improving the results of T-cell-depleted haploidentical HSCT from a relative. Currently, it is possible to find an HSC donor for virtually almost all children with an indication to receive allogeneic HSCT and lacking an HLA-identical sibling. Each of the three options of HSCT from alternative donors has advantages and limitations. Therefore, any physician has to carefully evaluate, for each single pediatric patient in need of an allograft, all the possible alternatives to choose the best HSC donor, taking into account type of disease to be treated, urgency of transplantation, donor characteristics and center's experience. This review will analyze in detail the advantages and limitations of each of the three options of alternative donor HSCT and the main criteria to be used for choosing the most suitable donor for pediatric patients lacking an HLA-identical sibling.
Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to ...advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.
A liquid chromatography–electrospray tandem mass spectrometry (LC–MS/MS) method for the determination of antibiotics in water was developed and applied to Brazilian surface waters. Amoxicillin, ...ampicillin, cefalexin (CEF), ciprofloxacin (CIP), norfloxacin (NOR), sulfamethoxazole, tetracycline (TET), and trimethoprim were selected as target compounds due to their high consumption pattern in Brazil. LC and MS conditions were optimized to produce the maximum analytic response for each compound. Anion exchange and polymeric solid-phase extraction cartridges, in series, were employed during the extraction procedures. Recovery, linear range, limit of detection (LOD), and limit of quantification were calculated. LOD varied from 0.13 ng L
−1
for CIP and NOR to 0.76 ng L
−1
for TET. Surface water samples from the Atibaia watershed (São Paulo State, Brazil) were analyzed. Results showed that seasonal and anthropogenic aspects dictated the levels of antibiotics in the samples. An overall frequency of detection of 55% was observed during the rainy period, whereas a higher percentage (88%) was noticed for samples collected during the dry season. In the Atibaia River, sample concentrations ranged from 29 ng L
−1
for CEF to 0.5 ng L
−1
for NOR. In a sewage-affected stream, however, concentrations up to 2422 ng L
−1
CEF were found.
Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional ...modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.
Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV‐iron is considered a safe procedure, but severe ...hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV‐iron therapy safer; however, the current protocols are still non‐specific, non‐evidence‐based empirical measures which neglect the fact that the majority of IV‐iron reactions are not IgE‐mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV‐iron reactions represent complement activation‐related pseudo‐allergy (CARPA), at least in part. The review compares the features of IV‐iron reactions to those of immune and non‐immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV‐iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV‐iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high‐risk IV‐iron patients.
Because of their immunomodulatory and engraftment-promoting properties, mesenchymal stromal cells (MSCs) have been tested in the clinical setting both to facilitate haematopoietic recovery and to ...treat steroid-resistant acute GVHD. More recently, experimental findings and clinical trials have focused on the ability of MSCs to home to damaged tissue and to produce paracrine factors with anti-inflammatory properties, resulting in functional recovery of the damaged tissue. The mechanisms through which MSCs exert their therapeutic potential rely on some key properties of the cells: the ability to secrete soluble factors capable of stimulating survival and recovery of injured cells; the capacity to home to sites of damage and the ability to blunt exaggerated immune responses. These fundamental properties are being tested within a novel therapeutic field defined as Regenerative Medicine. This review deals with recent research on the anti-inflammatory/reparative properties of MSCs and considers the possible mechanisms of function responsible for these effects. Moreover, current and potential clinical applications of MSC-based treatment strategies in the context of Regenerative Medicine are being discussed. Key issues such as optimal timing of MSC administration, cell dose and schedule of administration, advantages and disadvantages of using autologous or allogeneic cells are still open. Nonetheless, MSCs promise to represent a revolution for many severe or presently untreatable disorders.
The prevalence of asthma increased worldwide until the 1990s, but since then there has been no clear temporal pattern. The present study aimed to assess time trends in the prevalence of current ...asthma, asthma-like symptoms and allergic rhinitis in Italian adults from 1990 to 2010. The same screening questionnaire was administered by mail or phone to random samples of the general population (age 20-44 yrs) in Italy, in the frame of three multicentre studies: the European Community Respiratory Health Survey (ECRHS) (1991-1993; n = 6,031); the Italian Study on Asthma in Young Adults (ISAYA) (1998-2000; n = 18,873); and the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (2007-2010; n = 10,494). Time trends in prevalence were estimated using Poisson regression models in the centres that repeated the survey at different points in time. From 1991 to 2010, the median prevalence of current asthma, wheezing and allergic rhinitis increased from 4.1% to 6.6%, from 10.1% to 13.9% and from 16.8% to 25.8%, respectively. The prevalence of current asthma was stable during the 1990s and increased (relative risk 1.38, 95% CI 1.19-1.59) from 1998-2000 to 2007-2010, mainly in subjects who did not report allergic rhinitis. The prevalence of allergic rhinitis has increased continuously since 1991. The asthma epidemic is not over in Italy. During the past 20 yrs, asthma prevalence has increased by 38%, in parallel with a similar increase in asthma-like symptoms and allergic rhinitis.
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