Fracture resistance of human roots filled with mineral trioxide aggregate mixed with phosphate-buffered saline, with and without calcium hydroxide pre-medication.

AIM: To compare the fracture strength of extracted human roots with apical plugs of mineral trioxide aggregate (MTA) mixed with either Ca- and Mg-free phosphate-buffered saline (PBS) or water, with and without calcium hydroxide (CH) canal pre-medication. METHODOLOGY: A total of 180 single-rooted human teeth were prepared to resemble immature roots and divided into groups (n = 20). The negative control received canal irrigation only, and the positive control received intracanal treatment with CH for either two or twelve weeks. MTA mixed with water was used in Group 1: (i) without CH pre-medication - MTA(W); (ii) after 2 weeks CH pre-medication - 2/52CH + MTA(W); and (iii) after 12-week CH pre-medication - 12/52 CH + MTA(W). MTA mixed with PBS was used in Group 2: (i) without CH pre-medication - MTA(PBS); (ii) after 2-week CH pre-medication - 2/52CH + MTA(PBS); and (iii) after 12-week CH pre-medication - 12/52 CH + MTA(PBS). A compressive force was applied to each root until the point of fracture. The results were analysed by the Kruskal-Wallis and Dunn's multiple comparisons tests (P < 0.05). RESULTS: There was no significant difference between groups MTA(W), MTA(PBS) and 2/52CH + MTA(PBS), and all three groups were significantly (P < 0.01, P < 0.05 and P < 0.05, respectively) more resistant to fracture than the negative control. Within Group 1, the samples that received two- (P < 0.01) and twelve-week (P < 0.001) CH pre-treatment were more prone to fracture than those which did not. No difference was found amongst the control groups. The roots of the MTA(PBS) group had a higher dependability (P < 0.05) than the MTA(W) group when compared by the Weibull modulus. The difference was also present when a 2-week CH pre-medication was used. CONCLUSIONS: Mineral trioxide aggregate mixed with Ca- and Mg-free phosphate-buffered saline had a significant strengthening effect on the fracture resistance of structurally weak roots, even when short-term calcium hydroxide pre-medication had been used. MTA mixed with water lost its strengthening effect on human roots when 2- or 12-week CH pre-treatment had been used. Use of CH dressing for up to 12 weeks had no negative effect on fracture resistance of human roots.

Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome.

Persulfides (R-SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N-acetyl cysteine persulfide (NAC-SSH) in response to the prokaryote-specific enzyme nitroreductase. The donor, termed NDP-NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC-SSH. NDP-NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2 S. NDP-NAC induced these effects by the upregulation of beneficial small- and medium-chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome-related diseases by the targeted delivery of reactive sulfur species.

A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential.

Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2 S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2 O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H2 O2 revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H2 S donors sodium sulfide (Na2 S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide-releasing control compound in concert with common H2 S donors and thiols.

Therapeutic Delivery of H2S via COS: Small Molecule and Polymeric Donors with Benign Byproducts.

Carbonyl sulfide (COS) is a gas that may play important roles in mammalian and bacterial biology, but its study is limited by a lack of suitable donor molecules. We report here the use of N-thiocarboxyanhydrides (NTAs) as COS donors that release the gas in a sustained manner under biologically relevant conditions with innocuous peptide byproducts. Carbonic anhydrase converts COS into H2S, allowing NTAs to serve as either COS or H2S donors, depending on the availability of the enzyme. Analysis of the pseudo-first-order H2S release rate under biologically relevant conditions revealed a release half-life of 75 min for the small molecule NTA under investigation. A polynorbornene bearing pendant NTAs made by ring-opening metathesis polymerization was also synthesized to generate a polymeric COS/H2S donor. A half-life of 280 min was measured for the polymeric donor. Endothelial cell proliferation studies revealed an enhanced rate of proliferation for cells treated with the NTA over untreated controls.

Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.

AIM: To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. METHODS: A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity. RESULTS: During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. CONCLUSIONS: Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways.

Comparison of geomechanical deformation induced by megatonne-scale CO2 storage at Sleipner, Weyburn, and In Salah.

Geological storage of CO2 that has been captured at large, point source emitters represents a key potential method for reduction of anthropogenic greenhouse gas emissions. However, this technology will only be viable if it can be guaranteed that injected CO2 will remain trapped in the subsurface for thousands of years or more. A significant issue for storage security is the geomechanical response of the reservoir. Concerns have been raised that geomechanical deformation induced by CO2 injection will create or reactivate fracture networks in the sealing caprocks, providing a pathway for CO2 leakage. In this paper, we examine three large-scale sites where CO2 is injected at rates of ~1 megatonne/y or more: Sleipner, Weyburn, and In Salah. We compare and contrast the observed geomechanical behavior of each site, with particular focus on the risks to storage security posed by geomechanical deformation. At Sleipner, the large, high-permeability storage aquifer has experienced little pore pressure increase over 15 y of injection, implying little possibility of geomechanical deformation. At Weyburn, 45 y of oil production has depleted pore pressures before increases associated with CO2 injection. The long history of the field has led to complicated, sometimes nonintuitive geomechanical deformation. At In Salah, injection into the water leg of a gas reservoir has increased pore pressures, leading to uplift and substantial microseismic activity. The differences in the geomechanical responses of these sites emphasize the need for systematic geomechanical appraisal before injection in any potential storage site.

Effect of saliva and blood contamination on the bi-axial flexural strength and setting time of two calcium-silicate based cements: Portland cement and biodentine.

This study evaluated the effect of contamination with saliva and blood on the bi-axial flexural strength and setting time of pure gray Portland cement and Biodentine (Septodont, Allington, UK). A one-way ANOVA showed that contamination caused no significant difference between the cements in bi-axial flexural strength (P> 0.05). However there was a significant difference in setting time (P

Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.

Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned; the human homologue, CUBN, was mapped to the same region. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.

Kinematic evaluation of one- and two-level Maverick lumbar total disc replacement caudal to a long thoracolumbar spinal fusion.

PURPOSE: Adjacent level degeneration that occurs above and/or below long fusion constructs is a documented clinical problem that is widely believed to be associated with the considerable change in stiffness caused by the fusion. Some researchers have suggested that early degeneration at spinal joints adjacent to a fusion could be treated by implanting total disc replacements at these levels. It is thought that further degeneration could be prevented through the disc replacement's design aims to reproduce normal disc heights, kinematics and tissue loading. For this reason, there is a clinical need to evaluate if a total disc replacement can maintain both the quantity of motion (i.e. range) and the quality of motion (i.e. center of rotation and coupling) at segments adjacent to a long spinal fusion. The purpose of this study was to experimentally evaluate range of motion (ROM-the intervertebral motion measured) and helical axis of motion (HAM) changes due to one- and two-level Maverick total disc replacement (TDR) adjacent to a long spinal fusion. METHODS: Seven spine specimens (T8-S1) were used in this study (66 ± 19 years old, 3F/4 M). A continuous pure moment of ±5.0 Nm was applied to the specimen in flexion-extension (FE), lateral bending (LB) and axial rotation (AR), with a compressive follower preload of 400 N. The 5.0 Nm data were analyzed to evaluate the operated segment biomechanics at the level of the disc replacements. The data were also analyzed at lower moments using a modified version of Panjabi's proposed "hybrid" method to evaluate adjacent segment kinematics (intervertebral motion at the segments adjacent to the fusion) under identical overall (T8-S1) specimen rotations. The motion of each vertebra was monitored with an optoelectronic camera system. The biomechanical test was completed for (1) the intact condition and repeated after each surgical technique was applied to the specimen, (2) capsulotomy at L4-L5 and L5-S1, (3) T8-L4 fusion and capsulotomy at L4-L5 and L5-S1, (4) Maverick at L4-L5, and (5) Maverick at L5-S1. The capsulotomy was performed to allow measurement of facet joint loads in a companion study. Paired t tests were used to determine if differences in the kinematic parameters measured were significant. Holm-Sidak corrections for multiple comparisons were applied where appropriate. RESULTS: Under the 5.0 Nm loads, L4-L5 ROMs tended to decrease in all directions following L4-L5 Maverick replacement (mean = 22 %, compared to the fused condition). Two-level Maverick implantation also tended to reduce L4-S1 ROM (mean 18, 7 and 31 % in FE, LB and AR, respectively, compared to the fused condition without TDR). Following TDR replacement, the HAM location tended to shift posteriorly in FE (at L5-S1), anteriorly in AR, and inferiorly in LB. However, although the above-mentioned trends were observed, neither one- nor two-level TDR replacement showed statistically significant ROM or HAM change in any of the three directions. At the identical T8-S1 posture identified by the modified hybrid analysis, the L4-L5 and L5-S1 levels underwent significant larger motions, relative to the overall specimen rotation, after fusion. In the hybrid analysis, there were no significant differences between the ROM after fusion with intact natural discs at L4-L5 and L5-S1 and the motions at those levels with one or two TDRs implanted. CONCLUSIONS: The present results demonstrated that one or two Maverick discs implanted subjacent to a long thoracolumbar fusion preserved considerable and intact-like ranges of motion and maintained motion patterns similar to the intact specimen, in this ex vivo study with applied pure moments and compressive follower preload. The hybrid analysis demonstrated that, after fusion, the TDR-implanted levels are required to undergo large rotations, relative to those necessary before fusion, in order to achieve the same motion between T8 and S1. Additional clinical and biomechanical research is necessary to determine if such a kinematic demand would be made on these levels clinically and the biomechanical performance of these implants if it were.

A new grading for easy and concise description of functional status after spinal cord lesions.

BACKGROUND: Disability scales do not enable the transmission of concise, meaningful and daily function description for clinical purposes. STUDY DESIGN: Cross-sectional statistical analysis of 328 patients' Spinal Cord Independence Measure (SCIM) III item scores (SIS). OBJECTIVE: To develop a concise and clinically interpretable data-based characterization of daily task accomplishment for patients with spinal cord lesions (SCLs). SETTING: Multi-center study at 13 spinal units in 6 countries. METHODS: Patients were grouped into clusters characterized by smaller differences between the patients' SIS within the clusters than between their centers, using the k-medoides algorithm. The number of clusters (k) was chosen according to the percent of SIS variation they explained and the clinical distinction between them. RESULTS: Analysis showed that k=8 SIS clusters offer a good description of the patient population. The eight functional clusters were designated as A-H, each cluster (grade) representing a combination of task accomplishments. Higher grades were usually (but not always) associated with patients implementing more difficult tasks. Throughout rehabilitation, the patients' functional grade improved and the distribution of patients with similar functional grades within the total SCIM III score deciles remained stable. CONCLUSIONS: A new classification based on SIS clusters enables a concise description of overall functioning and task accomplishment distribution in patients with SCL. A software tool is used to identify the patients' functional grade. Findings support the stability and utility of the grades for characterizing the patients' functional status.

What lies behind the quality assurance of your materials?

In dentistry, all reputable manufacturers comply with international standards. This is important for quality assurance of dental materials. How such standards came into being and have evolved, however, is perhaps less well-known. This paper covers the necessity and formulation of standards and illustrates their application with reference to materials that may be considered as potential alternatives to dental amalgam. In addition, the uncertainties around such a framework following Brexit are summarised. Robust standards are essential for consumer protection and international trade.

Dental amalgam: the history and legacy you perhaps never knew?

Much has been written about dental amalgam. Over many years, it has served the profession well, yet on environmental grounds its use is being phased down. This article seeks to explore key milestones in the history and development of this versatile material, as well as highlighting how international standards have assisted in reducing environmental mercury contamination.

Dental education at Dundee Dental Hospital and School - a notable past and inspiring future.

Dundee Dental Hospital and School has been present on Park Place, Dundee for over 100 years. During this time, it has been at the forefront of dental care and education, first as part of the University of St Andrews and subsequently the University of Dundee. This innovation continues with novel undergraduate curricula for dental and dental therapy students, providing early clinical experience and integrating clinical teaching with the appropriate sciences. We also offer several taught postgraduate programmes, popular particularly with international students. Dundee was at the forefront of the response to the COVID-19 pandemic, with the Scottish Dental Clinical Effectiveness Programme leading the world on guidance for safe clinical practice. Innovative solutions for the ongoing delivery of teaching and assessment also were developed. Research underpins teaching and the delivery of dental care and Dundee has an international reputation for its research portfolio. All of the above can only be achieved by close working relationships between the University and NHS, which will be strengthened further by the creation of the Dundee Dental Research Hospital and School. Our international reputation will continue to attract students and staff from across the world.

The three-dimensional structure of the FMO protein from Pelodictyon phaeum and the implications for energy transfer.

The Fenna-Matthews-Olson (FMO) antenna protein from the green bacterium Pelodictyon phaeum mediates the transfer of energy from the peripheral chlorosome antenna complex to the membrane-bound reaction center. The three-dimensional structure of this protein has been solved using protein crystallography to a resolution limit of 2.0 Å, with R(work) and R(free) values of 16.6 and 19.9%, respectively. The structure is a trimer of three identical subunits related by a threefold symmetry axis. Each subunit has two beta sheets that surround 8 bacteriochlorophylls. The bacteriochlorophylls are all five-coordinated, with the axial ligand being a histidine, serine, backbone carbonyl, or bound water molecule. The arrangement of the bacteriochlorophylls is generally well conserved in comparison to other FMO structures, but differences are apparent in the interactions with the surrounding protein. In this structure the position and orientation of the eighth bacteriochlorophyll is well defined and shows differences in its location and the coordination of the central Mg compared to previous models. The implications of this structure on the ability of the FMO protein to perform energy transfer are discussed in terms of the experimental optical measurements.

Weaning from prolonged invasive ventilation in motor neuron disease: analysis of outcomes and survival.

INTRODUCTION: Non-invasive ventilation (NIV) improves prognosis in patients with motor neuron disease (MND) in the absence of major bulbar involvement. However, some experience a rapid and unexpected decline in respiratory function and may undergo emergency tracheal intubation. Weaning from invasive ventilation can be difficult, and reported independence from invasive ventilation is uncommon with poor prognosis. The outcomes of patients with MND referred to a specialist weaning service following emergency tracheal intubation were examined and compared with MND patients electively initiating NIV. METHODS: A case note review was performed on all patients with MND invasively ventilated and referred to a specialist weaning service between 1992 and 2007. Outcomes were compared with those electively commenced on NIV during the same period. RESULTS: Thirty patients were referred for weaning from invasive ventilation which was started in 17 before MND was diagnosed. Fourteen patients (47%) were weaned from invasive ventilation but still required NIV, 13 failed to wean, and three died. Seventeen were discharged home from hospital. The median survival from tracheal intubation was 13.7 months (95% CI 0 to 30.8) for those previously diagnosed and 7.2 months (95% CI 5.1 to 9.4) for those not previously known to have MND. Comparison with patients initiated electively on NIV demonstrated similar survival estimates to that from emergency intubation (median 9.4 (95% CI 6.9 to 12.0) vs 7.8 (95% CI 2.6 to 12.9) months respectively). CONCLUSION: The prognosis in MND following acute respiratory failure and intubation is not always complete ventilator dependence if patients are offered a comprehensive weaning programme.

SCIM III is reliable and valid in a separate analysis for traumatic spinal cord lesions.

STUDY DESIGN: A multi-center international cohort study. OBJECTIVE: To evaluate the reliability and validity of the third version of the Spinal Cord Independence Measure (SCIM III), separately for patients with traumatic spinal cord lesions (SCLs). SETTING: A total of 13 spinal cord units in six countries from North America, Europe and the Middle-East. METHODS: SCIM III and Functional Independence Measure (FIM) were assessed for 261 patients with traumatic SCLs, on admission to rehabilitation and before discharge, by two raters. Conventional statistical measures were used to evaluate the SCIM III reliability and validity. RESULTS: In almost all SCIM III tasks, the total agreement between the paired raters was >80%. The κ coefficients were all >0.6 and statistically significant. Pearson's coefficients of the correlations between the paired raters were >0.9, the mean differences between raters were nonsignificant and the intraclass correlation coefficients (ICCs) were ≥ 0.95. Cronbach's α values for the entire SCIM III scale were 0.833-0.835. FIM and SCIM III total scores were correlated (r=0.84, P<0.001). SCIM III was more responsive to changes than FIM. In all subscales, SCIM III identified more changes in function than FIM, and in 3 of the 4 subscales, differences in responsiveness were statistically significant (P<0.02). CONCLUSION: The results confirm the reliability and validity of SCIM III for patients with traumatic SCLs in a number of countries.

Expected spinal cord independence measure, third version, scores for various neurological levels after complete spinal cord lesions.

STUDY DESIGN: Multicenter international cohort study. OBJECTIVE: The objective of this study was to establish target values for Spinal Cord Independence Measure (SCIM) III scoring in rehabilitation for clinically complete spinal cord lesion (SCL) neurological levels. SETTING: In total, 13 spinal cord units in six countries from North America, Europe and the Middle East were taken. METHODS: Total SCIM III scores and gain at discharge from rehabilitation were calculated for SCL levels in 128 patients with American Spinal Injury Association Impairment Scale (AIS) grade A on admission to rehabilitation. RESULTS: Median, quartiles, mean and s.d., values of discharge SCIM III scores and SCIM III gain for the various SCL levels are presented. Total SCIM III scores and gain were significantly correlated with the SCL level (r=0.730, r=0.579, P<0.001). CONCLUSIONS: Calculated discharge SCIM III scores can be used as target values for functional achievements at various neurological levels in patients after AIS A SCL. They are generally, but not always, inversely correlated with SCL level.

Targeted Program in an Academic Rheumatology Practice to Improve Compliance With Opioid Prescribing Guidelines for the Treatment of Chronic Pain.

OBJECTIVE: The Centers for Disease Control and Prevention (CDC) and many state governments have issued guidelines for opioid prescribing for the treatment of chronic noncancer-associated pain. We sought to decrease practice variation and increase compliance with these guidelines in a tertiary academic rheumatology practice by developing an interdisciplinary opioid working group and using electronic health record (EHR)-integrated data feedback. METHODS: Division leadership and providers established shared goals at interdisciplinary meetings involving rheumatology, pain medicine, nursing, and pharmacy. Interventions included educational sessions on opioid prescribing guidelines and the sharing of individual de-identified prescribing patterns. An opioid dashboard page within the EHR allowed every provider to see individualized and division-wide data that tracked process measures based on CDC and state-specific guidelines. Baseline data from June to August 2017 were compared with monthly data through December 2018. RESULTS: At baseline, 40% of patients had an active opioid agreement (a Pennsylvania guideline and a New Jersey law), 25% had a urine drug screen result within 12 months of their most recent opioid prescription, and 24% had a concurrent benzodiazepine prescription. After 16 months, these percentages improved to 88%, 66%, and 16%, respectively. The average number of opioid tablets prescribed per month decreased from 59,733 to 48,966 (-18%; P = 0.02). CONCLUSION: Shared goals developed through interdisciplinary input and readily accessible data feedback can markedly increase provider compliance with national and state-specific guidelines for opioid prescribing for the treatment of chronic noncancer-associated pain in rheumatology.

Amino acid-based H2S donors: N-thiocarboxyanhydrides that release H2S with innocuous byproducts.

A library of N-thiocarboxyanhydrides (NTAs) derived from natural amino acids with benign byproducts and controlled H2S-release kinetics is reported. Minimal acute in vitro toxicity was observed in multiple cell lines, while longer-term toxicity in cancer cells was observed, with slow-releasing donors exhibiting the greatest cytotoxic effects.