Purpose
To evaluate the marginal gaps of CAD/CAM (CEREC 3) produced crowns made from leucite‐reinforced glass‐ceramic (IPS Empress CAD) blocks (LG), and lithium‐disilicate (IPS e.max CAD) blocks ...before (LD‐B), and after (LD‐A) crystallization firing.
Materials and Methods
A human molar tooth (#19) was mounted with adjacent teeth on a typodont and prepared for a full‐coverage ceramic crown. The typodont was assembled in the mannequin head to simulate clinical conditions. After tooth preparation 15 individual optical impressions were taken by the same operator using titanium dioxide powder and a CEREC 3 camera per manufacturer's instructions. One operator designed and machined the crowns in leucite‐reinforced glass‐ceramic blocks (n = 5) and lithium‐disilicate blocks (n = 10) using the CEREC 3 system. The crowns were rigidly seated on the prepared tooth, and marginal gaps (μm) were measured with an optical microscope (500×) at 12 points, 3 on each of the M, B, D, and L surfaces of the leucite‐reinforced glass‐ceramic crowns and the lithium‐disilicate crowns before and after crystallization firing. Results were analyzed by two‐way ANOVA followed by a Tukey's post hoc multiple comparison test (α = 0.05).
Results
The overall mean marginal gaps (μm) for the crowns evaluated were: LG = 49.2 ± 5.5, LD‐B = 42.9 ± 12.2, and LD‐A = 57.2 ± 16.0. The marginal gaps for LG and LD‐B were not significantly different, but both were significantly less than for LD‐A.
Conclusions
The type of ceramic material did not affect the marginal gap of CAD/CAM crowns. The crystallization firing process required for lithium‐disilicate crowns resulted in a significant increase in marginal gap size, likely due to shrinkage of the ceramic during the crystallization process. Clinical Relevance: The marginal gap of CAD/CAM‐fabricated lithium disilicate crowns increases following crystallization firing. The marginal gap still remains within clinically acceptable parameters.
There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively ...profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies.
•Deep proteomic profiling reveals mechanistic differences among medulloblastomas•Proteomic-defined SHH subtypes do not differ in RNA expression•MYC phosphorylation events define a higher risk subset of group 3 patients•Inhibiting PRKDC may sensitize MYC-activated medulloblastoma tumors to radiation
Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.
Dark adaptation measures photoreceptor recovery following intense light stimulation. Time to recovery reflects retinal function. We describe a novel method of relative foveal dark adaptation using an ...iPhone. Data from a small number of healthy subjects were studied to assess reproducibility, effects of age, and consider potential clinical utility.BACKGROUND/OBJECTIVEDark adaptation measures photoreceptor recovery following intense light stimulation. Time to recovery reflects retinal function. We describe a novel method of relative foveal dark adaptation using an iPhone. Data from a small number of healthy subjects were studied to assess reproducibility, effects of age, and consider potential clinical utility.Relative foveal dark adaption was studied in 6 normal subjects across ages from 20 to 81 years and across differing testing conditions. Foveal bleaching is produced by fixating a bright white circle on an iPhone for variable times. After foveal bleaching an annular surround appears to complete a bullseye stimulus with surround initially brighter than centre. As the fovea recovers the centre regains brightness. Relative foveal dark adaptation, the time for the visual anchor to shift from surround to centre, was studied across a range of bleaching times, ages, and testing conditions.METHODSRelative foveal dark adaption was studied in 6 normal subjects across ages from 20 to 81 years and across differing testing conditions. Foveal bleaching is produced by fixating a bright white circle on an iPhone for variable times. After foveal bleaching an annular surround appears to complete a bullseye stimulus with surround initially brighter than centre. As the fovea recovers the centre regains brightness. Relative foveal dark adaptation, the time for the visual anchor to shift from surround to centre, was studied across a range of bleaching times, ages, and testing conditions.Dispersion of dark adaptation times grows with increasing age. Foveal bleaching for 30 s was as effective as longer times. Testing times with a 30 s bleach were less than 1 min. Foveal dark adaptation was reproducible within each subject and was unaffected by ambient room lighting, pupil size, and light attenuation. Repeat, immediately sequential testing was similarly reproducible except after long bleaching.RESULTSDispersion of dark adaptation times grows with increasing age. Foveal bleaching for 30 s was as effective as longer times. Testing times with a 30 s bleach were less than 1 min. Foveal dark adaptation was reproducible within each subject and was unaffected by ambient room lighting, pupil size, and light attenuation. Repeat, immediately sequential testing was similarly reproducible except after long bleaching.This method of dark adaptation is intuitive, repeatable, and relatively unaffected by testing condition. Testing times are brief, requiring only an iPhone screen positioned at reading distance. Relative foveal dark adaptation may be a useful tool to assess macular health.CONCLUSIONSThis method of dark adaptation is intuitive, repeatable, and relatively unaffected by testing condition. Testing times are brief, requiring only an iPhone screen positioned at reading distance. Relative foveal dark adaptation may be a useful tool to assess macular health.
Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. ...Here, we describe a “cell village” experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic variation, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus. We also detected expression QTLs corresponding to GWAS loci for brain traits and discovered novel disease-relevant regulators of progenitor proliferation and differentiation such as CACHD1. This approach provides scalable ways to elucidate the effects of genes and genetic variation on cellular phenotypes.
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•Brief overexpression of NGN2 converts human stem cells to functional NPCs•Molecular and cellular phenotypes are measured in hPSC-derived NPC “villages”•An IFITM3 SNP explains most inter-donor variation in NPC viral susceptibility•CACHD1 is a novel regulator of neurogenesis
Wells et al. describe an experimental platform that pools rapidly generated neural progenitor cells from multiple human donors into the same culture flask to detect the genetic factors associated with molecular phenotypes and to identify an IFITM3 single nucleotide polymorphism that explains a sizable proportion of inter-donor variation in Zika virus vulnerability.
For patients undergoing cardiac resynchronization therapy (CRT) with implantable cardioverter-defibrillator (ICD; CRT-D), the effect of an improvement in left ventricular ejection fraction (LVEF) on ...appropriate ICD therapy may have significant implications regarding management at the time of ICD generator replacement.
We conducted a meta-analysis to determine the effect of LVEF recovery following CRT on the incidence of appropriate ICD therapy. A search of multiple electronic databases identified 709 reports, of which 6 retrospective cohort studies were included (n = 1740). In patients with post-CRT LVEF ≥35% (study n = 4), the pooled estimated rate of ICD therapy (5.5/100 person-years) was significantly lower than patients with post-CRT LVEF <35% incidence rate difference (IRD): -6.5/100 person-years, 95% confidence interval (95% CI): -8.8 to -4.2, P < 0.001. Similarly, patients with post-CRT LVEF ≥45% (study n = 4) demonstrated lower estimated rates of ICD therapy (2.3/100 person-years) compared with patients without such recovery (IRD: -5.8/100 person-years, 95% CI: -7.6 to -4.0, P < 0.001). Restricting analysis to studies discounting ICD therapies during LVEF recovery (study n = 3), patients with LVEF recovery (≥35 or ≥45%) had significantly lower rates of ICD therapy compared with patients without such recovery (P for both <0.001). Patients with primary prevention indication for ICD, regardless of LVEF recovery definition, had very low rates of ICD therapy (0.4 to 0.8/100-person years).
Recovery of LVEF post-CRT is associated with significantly reduced appropriate ICD therapy. Patients with improvement of LVEF ≥45% and those with primary prevention indication for ICD appear to be at lowest risk.
Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes ...compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls.
Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale.
Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes.
Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.
Canavan disease (CD) is a fatal leukodystrophy caused by mutation of the aspartoacylase (ASPA) gene, which leads to deficiency in ASPA activity, accumulation of the substrate N‐acetyl‐L‐aspartate ...(NAA), demyelination, and spongy degeneration of the brain. There is neither a cure nor a standard treatment for this disease. In this study, human induced pluripotent stem cell (iPSC)‐based cell therapy is developed for CD. A functional ASPA gene is introduced into patient iPSC‐derived neural progenitor cells (iNPCs) or oligodendrocyte progenitor cells (iOPCs) via lentiviral transduction or TALEN‐mediated genetic engineering to generate ASPA iNPC or ASPA iOPC. After stereotactic transplantation into a CD (Nur7) mouse model, the engrafted cells are able to rescue major pathological features of CD, including deficient ASPA activity, elevated NAA levels, extensive vacuolation, defective myelination, and motor function deficits, in a robust and sustainable manner. Moreover, the transplanted mice exhibit much prolonged survival. These genetically engineered patient iPSC‐derived cellular products are promising cell therapies for CD. This study has the potential to bring effective cell therapies, for the first time, to Canavan disease children who have no treatment options. The approach established in this study can also benefit many other children who have deadly genetic diseases that have no cure.
Canavan disease (CD) is a leukodystrophy caused by mutation of the aspartoacylase(ASPA) gene. A functional ASPA gene is introduced into patient induced pluripotent stem cell (iPSC)‐derived neural progenitor or oligodendrocyte progenitor cells. After transplantation into CD (Nur7) mice, the engrafted cells could rescue major pathological features of CD, including vacuolation, defective myelination, and motor function deficits, and prolonge survival.
Chloride regulation in the pain pathway Price, Theodore J; Cervero, Fernando; Gold, Michael S ...
Brain Research Reviews,
04/2009, Letnik:
60, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Abstract Melzack and Wall's Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the ...notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential ( Eanion ), which subsequently impacts fast synaptic inhibition mediated by GABAA , and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cation-chloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of Eanion which in turn appears to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury. This review summarizes the current state of knowledge in this area with particular attention to how such findings relate to endogenous mechanisms of hyperalgesia and allodynia and potential applications for therapeutics based on modulation of intracellular Cl− gradients or pharmacological interventions targeting GABAA receptors.
Canavan disease (CD) is a leukodystrophy caused by aspartoacylase (ASPA) gene mutation with no cure so far. In this study, a functional ASPA was introduced into patient iPSC‐derived neural progenitor ...cells (iNPCs) and the engineered ASPA iNPCs could rescue major pathological features of CD in a disease mouse model. These patient iPSC‐derived cellular products are promising cell therapies for CD patients. Image designed and prepared by Olivia Sun
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