Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease

LASER in periodontal treatment: is it an effective treatment or science fiction?

There are several studies that evaluate the use of lasers in periodontal treatment in non-surgical or surgical therapy. However, while several studies showed clinically beneficial effects of some lasers in periodontal treatment, there are few clinical reports of additional advantages of lasers as adjunctive treatments in periodontology. The aim of this paper is to demonstrate and critically analyze the level of scientific evidence of effects of low-level lasers and high-power lasers in periodontology. A narrative review of the studies was carried out in each topic and type of laser or periodontal treatment. In nonsurgical periodontal therapy the results showed that there is an additional clinical benefit when using a diode laser (DL) associated with scaling and root planing (SRP) in patients with moderate to severe periodontitis. The Er:YAG laser seems to be the most suitable for nonsurgical periodontal therapy and promotes the same clinical effects as conventional therapy. In periodontal surgery vaporization of the gingival or mucosal tissue can be carried out with DL, CO2, Nd:YAG, Er:YAG and Er,Cr:YSGG lasers. Photobiomodulation (PBM), mediated by low-level lasers associated with non-surgical periodontal therapy, promotes additional benefits in the short term and accelerates the bone and gingival tissue repair process and also reduces postoperative symptoms of periodontal surgery. The effect of antimicrobial Photodynamic Therapy is relevant in the initial reevaluation periods. Studies have shown controversial results of the use of lasers in periodontics, and this fact may be due to the lack of standard parameters of irradiation in each clinical application

Influence of antimicrobial photodynamic therapy as an adjunctive to scaling and root planing on alveolar bone loss: A systematic review and meta-analysis of animal studies.

BACKGROUND: The study aimed to evaluate the effect of antimicrobial photodynamic therapy (aPDT) as adjunctive therapy to scaling and root planing in experimental periodontitis in rats, with or without systemic involvement, by means of histometric analysis of the furcation region. METHODS: Systematic search was done using PubMed/MEDLINE, SCOPUS, EMBASE and ProQuest databases. Quantitative analysis of alveolar bone loss, with subcategories for the experimental periods studied, was performed. The analysis was performed through the mean difference (MD), with 95% confidence intervals (CIs) and according to SYRCLE guidelines. RESULTS: Nine studies were considered eligible. A statistically favorable difference was observed for the use of aPDT in all periods studied in systemically healthy animals at 7 (P < 0.00001; MD: -0.71; 95% CI: [-0.85, -0.58]; I2: 90%), 15 (P < 0.00001; MD: -0.49; 95% CI: [-0.62, -0.37]; I2: 88%), and 30 (P < 0.00001; MD: -0.53; 95% CI: [-0.65, -0.41]; I2: 80%) days postoperatively. The difference was also observed for modified animals at 7 (P < 0.00001; MD: -1.03; 95% CI: [-1.43, -0.62]; I2: 97%), 15 (P < 0.00001; MD: -1.04; 95% CI: [-1.62, -0.46]; I2: 99%), and 30 (P < 0.00001; MD: -0.88; 95% CI: [-1.37, -0.39]; I2: 97%) days postoperatively. CONCLUSION: The adjunctive use of aPDT favored the reduction of alveolar bone loss in experimental periodontitis in rats, and this result was more evident in systemically compromised rats

economic costs and spatial distribution analysis in an Endemic Northeastern City, Brazil

publishersversionpublishe

Classical and semi-classical energy conditions

The standard energy conditions of classical general relativity are (mostly) linear in the stress-energy tensor, and have clear physical interpretations in terms of geodesic focussing, but suffer the significant drawback that they are often violated by semi-classical quantum effects. In contrast, it is possible to develop non-standard energy conditions that are intrinsically non-linear in the stress-energy tensor, and which exhibit much better well-controlled behaviour when semi-classical quantum effects are introduced, at the cost of a less direct applicability to geodesic focussing. In this article we will first review the standard energy conditions and their various limitations. (Including the connection to the Hawking--Ellis type I, II, III, and IV classification of stress-energy tensors). We shall then turn to the averaged, nonlinear, and semi-classical energy conditions, and see how much can be done once semi-classical quantum effects are included.Comment: V1: 25 pages. Draft chapter, on which the related chapter of the book "Wormholes, Warp Drives and Energy Conditions" (to be published by Springer), will be based. V2: typos fixed. V3: small typo fixe

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

GPs' decision-making when prescribing medicines for breastfeeding women: Content analysis of a survey

<p>Abstract</p> <p>Background</p> <p>Many breastfeeding women seek medical care from general practitioners (GPs) for various health problems and GPs may consider prescribing medicines in these consultations. Prescribing medicines to a breastfeeding mother may lead to untimely cessation of breastfeeding or a breastfeeding mother may be denied medicines due to the possible risk to her infant, both of which may lead to unwanted consequences. Information on factors governing GPs' decision-making and their views in such situations is limited.</p> <p>Methods</p> <p>GPs providing shared maternity care at the Royal Women's Hospital, Melbourne were surveyed using an anonymous postal survey to determine their knowledge, attitudes and practices on medicines and breastfeeding, in 2007/2008 (n = 640). Content analysis of their response to a question concerning decision-making about the use of medicine for a breastfeeding woman was conducted. A thematic network was constructed with basic, organising and global themes.</p> <p>Results</p> <p>335 (52%) GPs responded to the survey, and 253 (76%) provided information on the last time they had to decide about the use of medicine for a breastfeeding woman. Conditions reported were mastitis (24%), other infections (24%) and depressive disorders (21%). The global theme that emerged was "<it>complexity of managing risk in prescribing for breastfeeding women"</it>. The organising themes were: <it>certainty around decision-making; uncertainty around decision-making; need for drug information to be available, consistent and reliable; joint decision-making; the vulnerable "third party" </it>and <it>infant feeding decision</it>. Decision-making is a spectrum from a straight forward decision, such as treatment of mastitis, to a complicated one requiring multiple inputs and consideration. GPs use more information seeking and collaboration in decision-making when they perceive the problem to be more complex, for example, in postnatal depression.</p> <p>Conclusion</p> <p>GPs feel that prescribing medicines for breastfeeding women is a contentious issue. They manage the risk of prescribing by gathering information and assessing the possible effects on the breastfed infant. Without evidence-based information, they sometimes recommend cessation of breastfeeding unnecessarily.</p

3D superimposition of craniofacial imaging—The utility of multicentre collaborations

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149360/1/ocr12281.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149360/2/ocr12281_am.pd