Expanding the Grading of Recommendations Assessment, Development, and Evaluation (Ex-GRADE) for Evidence-Based Clinical Recommendations: Validation Study

Clinicians use general practice guidelines as a source of support for their intervention, but how much confidence should they place on these recommendations? How much confidence should patients place on these recommendations? Various instruments are available to assess the quality of evidence of research, such as the revised Wong scale (R-Wong) which examines the quality of research design, methodology and data analysis, and the revision of the assessment of multiple systematic reviews (R-AMSTAR), which examines the quality of systematic reviews

Streptozotocin, Type I Diabetes Severity and Bone

As many as 50% of adults with type I (T1) diabetes exhibit bone loss and are at increased risk for fractures. Therapeutic development to prevent bone loss and/or restore lost bone in T1 diabetic patients requires knowledge of the molecular mechanisms accounting for the bone pathology. Because cell culture models alone cannot fully address the systemic/metabolic complexity of T1 diabetes, animal models are critical. A variety of models exist including spontaneous and pharmacologically induced T1 diabetic rodents. In this paper, we discuss the streptozotocin (STZ)-induced T1 diabetic mouse model and examine dose-dependent effects on disease severity and bone. Five daily injections of either 40 or 60 mg/kg STZ induce bone pathologies similar to spontaneously diabetic mouse and rat models and to human T1 diabetic bone pathology. Specifically, bone volume, mineral apposition rate, and osteocalcin serum and tibia messenger RNA levels are decreased. In contrast, bone marrow adiposity and aP2 expression are increased with either dose. However, high-dose STZ caused a more rapid elevation of blood glucose levels and a greater magnitude of change in body mass, fat pad mass, and bone gene expression (osteocalcin, aP2). An increase in cathepsin K and in the ratio of RANKL/OPG was noted in high-dose STZ mice, suggesting the possibility that severe diabetes could increase osteoclast activity, something not seen with lower doses. This may contribute to some of the disparity between existing studies regarding the role of osteoclasts in diabetic bone pathology. Examination of kidney and liver toxicity indicate that the high STZ dose causes some liver inflammation. In summary, the multiple low-dose STZ mouse model exhibits a similar bone phenotype to spontaneous models, has low toxicity, and serves as a useful tool for examining mechanisms of T1 diabetic bone loss

Dynamic Energy Landscapes of Riboswitches Help Interpret Conformational Rearrangements and Function

Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate; barrier-free landscape in which a direct, dominant “downhill” pathway to the minimum free energy structure is apparent; and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the “new view” of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design

Bond strength comparison of color-change adhesives for orthodontic bonding using a self-etching primer

Sara Ekhlassi, Jeryl D English, Joe C Ontiveros, John M Powers, Harry I Bussa, Gary N Frey, Clark D Colville, Randy K EllisHouston Department of Orthodontics, The University of Texas Dental Branch, Houston, TX, USABackground: The purpose of this study was to compare the shear bond strengths of two color-change adhesives with a commonly used conventional light-cure adhesive while using a self-etching primer, and to compare any changes in shear bond strengths over time.Methods: One hundred and eighty extracted bovine incisors were randomly divided into nine groups of 20 teeth each. The teeth were prepared with a self-etching primer (Transbond™ Plus) Metal lower incisor brackets were bonded directly to each tooth with two different color-change adhesives (TransbondPlus and Grengloo™) and a control (Transbond XT). The teeth were debonded at three different time points (15 minutes, 24 hours, 1 week) using an Instron at 1.0 mm/min. The teeth that were to be debonded at 24 hours and 1 week were stored in distilled water at 37°C to simulate the oral environment. The data were analyzed by two-way analysis of variance and with Fisher's protected least-significant difference multiple comparisons test at the P < 0.05 level of significance. Adhesive remnant index (ARI) scores were calculated for each debonded tooth.Results: Transbond Plus at 1 week had the highest mean shear bond strength (14.7 mPa). Grengloo tested at 24 hours had the lowest mean shear bond strength (11.3 mPa). The mean shear bond strengths for the remaining seven groups had a range of 12–14.5 mPa. Grengloo had >80% samples presenting with an ARI score of 1 at all times. Interestingly, both Transbond groups had ARI scores of 3 in more than 50% of their samples.Conclusion: Time had no significant effect on the mean shear bond strength of Transbond XT, Grengloo, or Transbond Plus adhesive.Keywords: bond strength, color-change adhesives, self-etching primer, orthodontic bonding&nbsp