miR135a administration ameliorates brain ischemic damage by preventing TRPM7 activation during brain ischemia.

BACKGROUND: miRNA-based strategies have recently emerged as a promising therapeutic approach in several neurodegenerative diseases. Unregulated cation influx is implicated in several cellular mechanisms underlying neural cell death during ischemia. The brain constitutively active isoform of transient receptor potential melastatin 7 (TRPM7) represents a glutamate excitotoxicity-independent pathway that significantly contributes to the pathological Ca2+ overload during ischemia. AIMS: In the light of these premises, inhibition of TRPM7 may be a reasonable strategy to reduce ischemic injury. Since TRPM7 is a putative target of miRNA135a, the aim of the present paper was to evaluate the role played by miRNA135a in cerebral ischemia. Therefore, the specific objectives of the present paper were: (1) to evaluate miR135a expression in temporoparietal cortex of ischemic rats; (2) to investigate the effect of the intracerebroventricular (icv) infusion of miR135a on ischemic damage and neurological functions; and (3) to verify whether miR135a effects may be mediated by an alteration of TRPM7 expression. METHODS: miR135a expression was evaluated by RT- PCR and FISH assay in temporoparietal cortex of ischemic rats. Ischemic volume and neurological functions were determined in rats subjected to transient middle cerebral artery occlusion (tMCAo) after miR135a intracerebroventricular perfusion. Target analysis was performed by Western blot. RESULTS: Our results demonstrated that, in brain cortex, 72 h after ischemia, miR135a expression increased, while TRPM7 expression was parallelly downregulated. Interestingly, miR135a icv perfusion strongly ameliorated the ischemic damage and improved neurological functions, and downregulated TRPM7 protein levels. CONCLUSIONS: The early prevention of TRPM7 activation is protective during brain ischemia.

Cetuximab as third-line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild-type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials.

The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Symmetry breaking and effects of nutrient walkway in time-dependent bone remodeling incorporating poroelasticity.

Bone is an extraordinary biological material that continuously adapts its hierarchical microstructure to respond to static and dynamic loads for offering optimal mechanical features, in terms of stiffness and toughness, across different scales, from the sub-microscopic constituents within osteons-where the cyclic activity of osteoblasts, osteoclasts, and osteocytes redesigns shape and percentage of mineral crystals and collagen fibers-up to the macroscopic level, with growth and remodeling processes that modify the architecture of both compact and porous bone districts. Despite the intrinsic complexity of the bone mechanobiology, involving coupling phenomena of micro-damage, nutrients supply driven by fluid flowing throughout hierarchical networks, and cells turnover, successful models and numerical algorithms have been presented in the literature to predict, at the macroscale, how bone remodels under mechanical stimuli, a fundamental issue in many medical applications such as optimization of femur prostheses and diagnosis of the risk fracture. Within this framework, one of the most classical strategies employed in the studies is the so-called Stanford's law, which allows uploading the effect of the time-dependent load-induced stress stimulus into a biomechanical model to guess the bone structure evolution. In the present work, we generalize this approach by introducing the bone poroelasticity, thus incorporating in the model the role of the fluid content that, by driving nutrients and contributing to the removal of wastes of bone tissue cells, synergistically interacts with the classical stress fields to change homeostasis states, local saturation conditions, and reorients the bone density rate, in this way affecting growth and remodeling. Through two paradigmatic example applications, i.e. a cylindrical slice with internal prescribed displacements idealizing a tract of femoral diaphysis pushed out by the pressure exerted by a femur prosthesis and a bone element in a form of a bent beam, it is highlighted that the present model is capable to catch more realistically both the transition between spongy and cortical regions and the expected non-symmetrical evolution of bone tissue density in the medium-long term, unpredictable with the standard approach. A real study case of a femur is also considered at the end in order to show the effectiveness of the proposed remodeling algorithm.

Antioxidant supplementation to medium for in vitro embryo production in Felis catus.

The development of in vitro embryo production (IVEP) techniques in Felis catus is a fitting model with potential application to the conservation of endangered felid species. To improve the quality of IVEP techniques an appropriate balance of pro- and antioxidants should be provided. Under in vitro conditions, high levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) mRNA provide a defence mechanism against oxidative stress for embryos. In order to improve the development of cat oocytes, the effects of SOD and CAT supplemented to in vitro maturation (IVM) medium and of GPx supplemented to in vitro fertilization (IVF) medium on development and embryo production in vitro were evaluated. Data showed an increase of 70 and 77 % of cleaved embryo and blastocyst formation, respectively, in the experiment with SOD and CAT addition to IVM medium; in the experiment with GPx addition to IVF medium the number of cleaved embryos doubled and the number of embryos increased by 96 %. Therefore, our results were positive and encourage us to continue studies on cat oocytes evaluating the effects of various dosages and combination of antioxidants.

Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.

BACKGROUND: An organ-preserving strategy may be a valid alternative in the treatment of selected patients with rectal cancer after neoadjuvant radiotherapy. Preoperative assessment of the risk for tumor recurrence is a key component of surgical planning. The aim of the present study was to increase the current knowledge on the risk factors for tumor recurrence. METHODS: The present study included individual participant data of published studies on rectal cancer surgery. The literature was reviewed according to according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data checklist (PRISMA-IPD) guidelines. Series of patients, whose data were collected prospectively, having neoadjuvant radiotherapy followed by transanal local excision for rectal cancer were reviewed. Three independent series of univariate/multivariate binary logistic regression models were estimated for the risk of local, systemic and overall recurrence, respectively. RESULTS: We identified 15 studies, and 7 centers provided individual data on 517 patients. The multivariate analysis showed higher local and overall recurrences for ypT3 stage (OR 4.79; 95% CI 2.25-10.16 and OR 6.43 95% CI 3.33-12.42), tumor size after radiotherapy > 10 mm (OR 5.86 95% CI 2.33-14.74 and OR 3.14 95% CI 1.68-5.87), and lack of combined chemotherapy (OR 3.68 95% CI 1.78-7.62 and OR 2.09 95% CI 1.10-3.97), while ypT3 was the only factor correlated with systemic recurrence (OR 5.93). The analysis of survival curves shows that the overall survival is associated with ypT and not with cT. CONCLUSIONS: Local excision should be offered with caution after neoadjuvant chemoradiotherapy to selected patients with rectal cancers, who achieved a good response to neoadjuvant chemoradiotherapy.

Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT).

While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.

Towards a patient-specific estimation of intra-operative femoral fracture risk.

Total Hip Arthroplasty requires pre-surgical evaluation between un-cemented and cemented prostheses. A Patient with intra-operative periprosthetic fracture and another with a successful outcome were recruited, and their finite element models were constructed by processing CT data, assuming elastic-plastic behavior of the bone as function of the local density. To resemble the insertion of the prosthesis into the femur, a fictitious thermal dilatation is applied to the broach volume. Strain-based fracture risk factor is estimated, depicting results in terms of the total mechanical strain expressed using a simple "traffic lights" color code to provide immediate, concise, and intelligible pre-operative information to surgeons.

Biocide triclosan impairs byssus formation in marine mussels Mytilus galloprovincialis.

The effects of the biocide Triclosan, used in personal care products and known as a common environmental contaminant, on byssal apparatus were studied in the marine mussel Mytilus galloprovincialis. Experimental evidences indicated that an exposure for 7 days at a concentration of 10 µg/L induced marked alterations in the byssus gland resulting in a significant delay in byssus regrowth and in a decrease in threads resistance to traction. Such alterations in animals exposed to tidal and waves action would cause a significant loss in ecological fitness and severely impact on mussel survival. Triclosan release in coastal environments therefore should be more carefully monitored to prevent drastic consequences.

Ocular ultrasonographic and biometric features of European brown hares (Lepus europaeus).

The aim of this work is to assess the normal ultrasonographic features and dimensions of eyes in European hares. Corneal thickness, anterior chamber depth, lens thickness, vitreous chamber depth and eye axial length were measured by ultrasound in 40 healthy hares (Lepus europaeus), 20 males and 20 females, mean age of 5.5 months (range 2-15 months). The effects of sex, side, age and body weight on each feature were recorded. Results show that ocular dimensions were not affected by considered variables except for the lenses thickness and axial length that were correlated with age and body weight. Our study concludes that although ocular structures had similar feature compared to other species, the description of the characteristics of the eye of the European hare is important to widen the knowledge of a species not completely known from the normal anatomical point of view. The lens dimensions could have a predictive value in determining the age of young hares.

Titanium TSME appliance for patients allergic to nickel.

AIM: The aim of this article is to describe the use of a titanium TSME appliance for patients with allergy to resin and nickel. We aim to highlight the optimal way to avoid problems such as stomatitis and peri-labial dermatitis, which generally appear in patients who use traditional orthodontic appliances made in acrylic resin and steel. MATERIALS AND METHODS: The construction of a titanium appliance is described and a case treated with it is reported. RESULTS: The titanium TSME presented in this paper has excellent biocompatibility due to its ability to form superficial oxides, which prevent oxidation and thus corrosion. CONCLUSION: The non-allergic properties of titanium allow to propose it as an alternative in patients with a long-term history of allergic reactions to nichel.

Allelic and Epitopic Characterization of Intra-Kidney Allograft Anti-HLA Antibodies at Allograft Nephrectomy.

The reasons for the increased incidence of de novo anti-human leukocyte antibody (HLA) donor-specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti-HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid-phase assays, anti-HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti-HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti-HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti-HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti-HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.

Motivating systems-oriented research on environmental and policy changes for obesity prevention.

BACKGROUND: Research on the types of interventions needed for population-level prevention of childhood obesity in complex societal systems can benefit from greater use of systems-science concepts and tools. OBJECTIVES: We report outcomes of a funding programme promoting incorporation of systems-science approaches into studies of imminent policy or environmental changes potentially impacting childhood obesity. METHODS: Seven funding cycles over 3 years yielded 172 initial submissions from 29 US states and 25 other countries were analyzed. RESULTS: Submissions focused primarily on aspects of school or child-care settings, parks and recreational settings, or access to healthy food; about half reflected attention to systems perspectives. CONCLUSIONS: Analysis of initial submissions as well as the 15 funded projects showed some success in motivating use of systems concepts and tools but suggested the need for a more focused effort to educate and prepare the childhood obesity prevention research community for this potentially crucial type of research.

Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor-Specific Anti-HLA Antibodies.

Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non-HLA-sensitized patients who had received an ABO-compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation.

There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new-generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir-based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty-five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti-HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New-generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.

Singularity-free finite element model of bone through automated voxel-based reconstruction.

Computed tomography (CT) provides both anatomical and density information about tissues. Bone is segmented by raw images and Finite Element Method (FEM) voxel-based meshing technique is achieved by matching each CT voxel to a single finite element (FE). As a consequence of the automated model reconstruction, unstable elements - i.e. elements insufficiently anchored to the whole model and thus potentially involved in partial rigid body motion - can be generated, a crucial problem in obtaining consistent FE models, hindering mechanical analyses. Through the classification of instabilities on topological connections between elements, a numerical procedure is proposed in order to avoid unconstrained models.