The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping

Morphodynamical modelling of field-scale swash events

In the present work, data for three single swash events are selected from those available for an accretive tide that occurred at Le Truc Vert beach (France) during a measurement field campaign at that location. These events are primarily chosen because of the different final bed change they produced, namely variable accretion, seaward erosion/landward deposition and variable erosion along the swash zone. These data are compared to results obtained from a ‘state-of-the-art’ numerical fully-coupled 1D morphodynamical shallow water solver, driven by measurements made of those events in the lower swash/inner surf zone. It is found that the hydrodynamics is reasonably well represented, although the computed results exhibit reduced maximum inundations in comparison with the observed ones. The model reproduces the correct order of magnitude of the morphodynamic change after each event, and sometimes the pattern of erosion and deposition, but this change is generally underestimated. Sensitivity analyses are conducted with respect to more uncertain physical parameters and assumed initial conditions. They suggest that initial spatial distributions for velocity and pre-suspended sediment concentration play a key role in the quantitative and qualitative prediction of the bed change

Impact of a dexmedetomidine intravenous infusion in septic dogs: preliminary study

Sepsis represents an increasing health emergency both in human and veterinary medicine Dexmedetomidine is an alpha-2 agonist drug with sedative and analgesic properties recently used critically ill patient in human ICU. The purpose of this work was to evaluate hemodynamics effects of a continuous infusion of dexmedetomidine in septic dogs

Errors in neuroradiology

Approximately 4 % of radiologic interpretation in daily practice contains errors and discrepancies that should occur in 2-20 % of reports. Fortunately, most of them are minor degree errors, or if serious, are found and corrected with sufficient promptness; obviously, diagnostic errors become critical when misinterpretation or misidentification should significantly delay medical or surgical treatments. Errors can be summarized into four main categories: observer errors, errors in interpretation, failure to suggest the next appropriate procedure, failure to communicate in a timely and a clinically appropriate manner. Misdiagnosis/misinterpretation percentage should rise up in emergency setting and in the first moments of the learning curve, as in residency. Para-physiological and pathological pitfalls in neuroradiology include calcification and brain stones, pseudofractures, and enlargement of subarachnoid or epidural spaces, ventricular system abnormalities, vascular system abnormalities, intracranial lesions or pseudolesions, and finally neuroradiological emergencies. In order to minimize the possibility of error, it is important to be aware of various presentations of pathology, obtain clinical information, know current practice guidelines, review after interpreting a diagnostic study, suggest follow-up studies when appropriate, communicate significant abnormal findings appropriately and in a timely fashion directly with the treatment team

Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model.

Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk-stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P \u3c .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score \u3e 0.6 were independent predictors of CR (all P \u3c .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy

Apoptosis as a Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer

Apoptotic cells stimulate compensatory proliferation through the caspase-3-cPLA-2-COX-2-PGE-2-STAT3 Phoenix Rising pathway as a healing process in normal tissues. Phoenix Rising is however usurped in cancer, potentially nullifying pro-apoptotic therapies. Cytotoxic therapies also promote cancer cell plasticity through epigenetic reprogramming, leading to epithelial-to-mesenchymal-transition (EMT), chemo-resistance and tumor progression. We explored the rela-tionship between such scenarios, setting-up an innovative, straightforward one-pot in vitro model of therapy-induced prostate cancer repopulation. Cancer (castration-resistant PC3 and androgen-sensitive LNCaP), or normal (RWPE-1) prostate cells, are treated with etoposide and left recovering for 18 days. After a robust apoptotic phase, PC3 setup a coordinate tissue-like response, repopulating and acquiring EMT and chemo-resistance; repopulation occurs via Phoenix Rising, being dependent on high PGE-2 levels achieved through caspase-3-promoted signaling; epigenetic inhibitors interrupt Phoenix Rising after PGE-2, preventing repopulation. Instead, RWPE-1 repopulate via Phoenix Rising without reprogramming, EMT or chemo-resistance, indicating that only cancer cells require reprogramming to complete Phoenix Rising. Intriguingly, LNCaP stop Phoenix-Rising after PGE-2, failing repopulating, suggesting that the propensity to engage/complete Phoenix Rising may influence the outcome of pro-apoptotic therapies. Concluding, we established a reliable system where to study prostate cancer repopulation, showing that epigenetic reprogramming assists Phoenix Rising to promote post-therapy cancer repopulation and acquired cell-resistance (CRAC)

Relationship between soluble receptor for advanced glycation end products (sRAGE), body composition and fat distribution in healthy women

Purpose: Soluble receptor for advanced glycation end products (sRAGE) is a decoy receptor which sequesters RAGE ligands and acts as a cytoprotective agent. To date, it is unclear whether the lower sRAGE levels observed in obesity are a marker of increased overall adiposity or reflect increases in particular fat depots. Therefore, we evaluated in healthy women the relationship among sRAGE and indicators of adiposity, including abdominal visceral (VAT) and epicardial visceral (EAT) adipose tissues, to explore the potential role of sRAGE as an earlier biomarker of cardiometabolic risk. Methods: Plasma sRAGE levels were quantified by an enzyme-linked immunosorbent assay in 47 healthy women. Total fat mass (FM) and fat-free mass were estimated with bioimpedance analysis. Anthropometric measures and biochemical data were recorded. Subcutaneous adipose tissue, VAT and EAT volumes were measured by magnetic resonance imaging. Results: Obese women had lower sRAGE levels compared to normal-weight women. sRAGE levels were also lower in women with a waist circumference (WC) larger than 80 cm. Correlation analyses indicated an inverse association of sRAGE with body mass index and FM. Concerning adipose tissue distribution, sRAGE inversely correlated with WC, EAT and VAT depots. In a multiple stepwise regression analysis, performed to emphasize the role of fat distribution, EAT volume was the only predictor of sRAGE. Conclusions: Lower sRAGE levels reflect accumulation of visceral fat mainly at the epicardial level and are present in advance of metabolic complications in adult women. sRAGE quantification might be an early marker of cardiometabolic risk

Wave breaking using a roller approach in a hybrid finite volume finite difference boussinesq type model

A new scheme implementing a roller approach into a hybrid finite-volume finite-difference Boussinesq-type model is presented. The relevant mathematics are outlined and a numerical solver is described. Predictions obtained from the model are validated against physical observations, demonstrating the capabilities of the scheme to replicate the complex hydrodynamic processes that occur during wave breaking. The benefits of both the hybrid scheme and the roller approach are discussed. The results illustrate the feasibility of modelling the breaking process with a rotational roller method in a finite-volume finite-difference scheme and show the obtainable accuracies. Finally, further tests and improvements to the model are proposed

Magnetic Anisotropy Trends along a Full 4f-Series: The fn+7Effect

[Image: see text] The combined experimental and computational study of the 13 magnetic complexes belonging to the Na[LnDOTA(H(2)O)] (H(4)DOTA = tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid and Ln = Ce–Yb) family allowed us to identify a new trend: the orientation of the magnetic anisotropy tensors of derivatives differing by seven f electrons practically coincide. We name this trend the f(n+7) effect. Experiments and theory fully agree on the match between the magnetic reference frames (e.g., the easy, intermediate, and hard direction). The shape of the magnetic anisotropy of some couples of ions differing by seven f electrons might seem instead different at first look, but our analysis explains a hidden similarity. We thus pave the way toward a reliable predictivity of the magnetic anisotropy of lanthanide complexes with a consequent reduced need of computational and synthetical efforts. We also offer a way to gain information on ions with a relatively small total angular momentum (i.e., Sm(3+) and Eu(3+)) and on the radioactive Pm(3+), which are difficult to investigate experimentally

Effect of platelet lysate on human cells involved in different phases of wound healing

Background Platelets are rich in mediators able to positively affect cell activity in wound healing. Aim of this study was to characterize the effect of different concentrations of human pooled allogeneic platelet lysate on human cells involved in the different phases of wound healing (inflammatory phase, angiogenesis, extracellular matrix secretion and epithelialization). Methodology/Principal Findings Platelet lysate effect was studied on endothelial cells, monocytes, fibroblasts and keratinocytes, in terms of viability and proliferation, migration, angiogenesis, tissue repair pathway activation (ERK1/2) and inflammatory response evaluation (NFκB). Results were compared both with basal medium and with a positive control containing serum and growth factors. Platelet lysate induced viability and proliferation at the highest concentrations tested (10% and 20% v/v). Whereas both platelet lysate concentrations increased cell migration, only 20% platelet lysate was able to significantly promote angiogenic activity (p<0.05 vs. control), comparably to the positive control. Both platelet lysate concentrations activated important inflammatory pathways such as ERK1/2 and NFκB with the same early kinetics, whereas the effect was different for later time-points. Conclusion/Significance These data suggest the possibility of using allogeneic platelet lysate as both an alternative to growth factors commonly used for cell culture and as a tool for clinical regenerative application for wound healing