Safety and Immunogenicity of a Replication-Defective Adenovirus Type 5 HIV Vaccine in Ad5-Seronegative Persons: A Randomized Clinical Trial (HVTN 054)

BACKGROUND: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients. CONCLUSIONS/SIGNIFICANCE: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119873

Treatment of symptomatic macromastia in a breast unit

BACKGROUND: Patients suffering from symptomatic macromastia are usually underserved, as they have to put up with very long waiting lists and are usually selected under restrictive criteria. The Oncoplastic Breast Surgery subspeciality requires a cross-specialty training, which is difficult, in particular, for trainees who have a background in general surgery, and not easily available. The introduction of reduction mammaplasty into a Breast Cancer Unit as treatment for symptomatic macromastia could have a synergic effect, making the scarce therapeutic offer at present available to these patients, who are usually treated in Plastic Departments, somewhat larger, and accelerating the uptake of oncoplastic training as a whole and, specifically, the oncoplastic breast conserving procedures based on the reduction mammaplasty techniques such as displacement conservative techniques and onco-therapeutic mammaplasty. This is a retrospective study analyzing the outcome of reduction mammaplasty for symptomatic macromastia in our Breast Cancer Unit. METHODS: A cohort study of 56 patients who underwent bilateral reduction mammaplasty at our Breast Unit between 2005 and 2009 were evaluated; morbidity and patient satisfaction were considered as end points. Data were collected by reviewing medical records and interviewing patients. RESULTS: Eight patients (14.28%) presented complications in the early postoperative period, two of them being reoperated on. The physical symptoms disappeared or significantly improved in 88% of patients and the degree of satisfaction with the care process and with the overall outcome were really high. CONCLUSION: Our experience of the introduction of reduction mammaplasty in our Breast Cancer Unit has given good results, enabling us to learn the use of different reduction mammaplasty techniques using several pedicles which made it possible to perform oncoplastic breast conserving surgery. In our opinion, this management policy could bring clear advantages both to patients (large-breasted and those with a breast cancer) and surgeons

Reconceptualizing CSR in the media industry as relational accountability

In this paper, we reconceptualize CSR in the media industries by combining empirical data with theoretical perspectives emerging from the communication studies and business ethics literature. We develop a new conception of what corporate responsibility in media organizations may mean in real terms by bringing Bardoel and d’Haenens’ (European Journal of Communication 19 165–194 2004) discussion of the different dimensions of media accountability into conversation with the empirical results from three international focus group studies, conducted in France, the USA and South Africa. To enable a critical perspective on our findings, we perform a philosophical analysis of its implications for professional, public, market, and political accountability in the media, drawing on the insights of Paul Virilio. We come to the conclusion that though some serious challenges to media accountability exist, the battle for responsible media industries is not lost. In fact, the speed characterizing the contemporary media environment may hold some promise for fostering the kind of relational accountability that could underpin a new understanding of CSR in the media

Impairment of Adenosinergic System in Rett syndrome: Novel Therapeutic Target to Boost BDNF Signalling

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.info:eu-repo/semantics/publishedVersio

Hemodynamic impact of isobaric levobupivacaine versus hyperbaric bupivacaine for subarachnoid anesthesia in patients aged 65 and older undergoing hip surgery

BackgroundThe altered hemodynamics, and therefore the arterial hypotension is the most prevalent adverse effect after subarachnoid anesthesia. The objective of the study was to determine the exact role of local anesthetic selection underlying spinal anesthesia-induced hypotension in the elderly patient. We conducted a descriptive, observational pilot study to assess the hemodynamic impact of subarachnoid anesthesia with isobaric levobupivacaine versus hyperbaric bupivacaine for hip fracture surgery.DescriptionHundred twenty ASA status I-IV patients aged 65 and older undergoing hip fracture surgery were enrolled. The primary objective of our study was to compare hemodynamic effects based on systolic blood pressure (SBP) and dyastolic blood pressure (DBP) values, heart rate (HR) and hemoglobin (Hb) and respiratory effects based on partial oxygen saturation (SpO2%) values. The secondary objective was to assess potential adverse events with the use of levobupivacaine versus bupivacaine. Assessments were performed preoperatively, at 30 minutes into surgery, at the end of anesthesia and at 48 hours and 6 months after surgery.Among intraoperative events, the incidence of hypotension was statistically significantly higher (p <0.05) in group BUPI (38.3%) compared to group LEVO (13.3%). There was a decrease (p <0.05) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 30 minutes intraoperatively (19% in group BUPI versus 17% in group LEVO). SpO2% increased at 30 minutes after anesthesia onset (1% in group BUPI versus 1.5% in group LEVO). Heart rate (HR) decreased at 30 minutes after anesthesia onset (5% in group BUPI versus 9% in group L). Hemoglobin (Hb) decreased from time of operating room (OR) admission to the end of anesthesia (9.3% in group BUPI versus 12.5% in group LEVO). The incidence of red blood cell (RBC) transfusion was 13.3% in group BUPI versus 31.7% in group LEVO, this difference was statistically significant. Among postoperative events, the incidence of congestive heart failure (CHF) was significantly higher in group BUPI (8,3%). At 6 months after anesthesia, no differences were found.ConclusionsGiven the hemodynamic stability and lower incidence of intraoperative hypotension observed, levobupivacaine could be the agent of choice for subarachnoid anesthesia in elderly patients

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

The Evolution of Social Orienting: Evidence from Chicks (Gallus gallus) and Human Newborns

Converging evidence from different species indicates that some newborn vertebrates, including humans, have visual predispositions to attend to the head region of animate creatures. It has been claimed that newborn preferences for faces are domain-relevant and similar in different species. One of the most common criticisms of the work supporting domain-relevant face biases in human newborns is that in most studies they already have several hours of visual experience when tested. This issue can be addressed by testing newly hatched face-na\uefve chicks (Gallus gallus) whose preferences can be assessed prior to any other visual experience with faces