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Glioblastoma (GBM) brain tumors contain a subpopulation of self-renewing multipotent Glioblastoma stem-like cells (GSCs) that are believed to drive the near inevitable recurrence of GBM. We previously engineered temperature responsive scaffolds based on the polymer poly(N-isopropylacrylamide-co-Jeffamine M-1000 acrylamide) (PNJ) for the purpose of enriching GSCs in vitro from patient-derived samples. Here, we used PNJ scaffolds to study microenvironmental regulation of self-renewal and radiation response in patient-derived GSCs representing classical and proneural subtypes. GSC self-renewal was regulated by the composition of PNJ scaffolds and varied with cell type. PNJ scaffolds protected against radiation-induced cell death, particularly in conditions that also promoted GSC self-renewal. Additionally, cells cultured in PNJ scaffolds exhibited increased expression of the transcription factor HIF2α, which was not observed in neurosphere culture, providing a potential mechanistic basis for differences in radio-resistance. Differences in PNJ regulation of HIF2α in irradiated and untreated conditions also offered evidence of stem plasticity. These data show PNJ scaffolds provide a unique biomaterial for evaluating dynamic microenvironmental regulation of GSC self-renewal, radioresistance, and stem plasticity.

INTRODUCTION The purpose of the present study was to evaluate the long-term variations in maxillary second molar position in untreated subjects with normal occlusion. SETTING AND SAMPLE POPULATION A sample of 39 subjects (18 females and 21 males) selected from the University of Michigan Growth Study (UMGS) was followed longitudinally with digital dental casts at 3 observation times: T1, when the maxillary permanent second molars were fully erupted, T2, last observation available in the longitudinal series (38 subjects), and T3, at least 20 years after T2 (12 subjects). MATERIALS AND METHODS Digital measurements were recorded with an open-source software. Outcome variables were sagittal and transverse inclinations of the upper second molars. Two mixed-effect models were performed. RESULTS The maxillary second molars had a distolingual inclination at T1, T2 and T3. Sagittal and transverse inclination showed progressive significant uprighting from T1 through T3 (P

This is a summary report of clinical and regulatory issues discussed at the 2018 NINDS workshop, entitled “Accelerating Therapies for Antiepileptogenesis and Disease Modification.” The intent of the workshop was to optimize and accelerate development of therapies for antiepileptogenesis (AEG) and disease modification in the epilepsies. The working group discussed nomenclature for antiepileptogenic therapies, subdividing them into “antiepileptogenic therapies” and “disease modifying therapies,” both of which are urgently needed. We use the example of traumatic brain injury to explain issues and complexities in designing a trial for disease‐preventing antiepileptogenic therapies, including identifying timing of intervention, selecting the appropriate dose, and the need for biomarkers. We discuss the recent trials of vigabatrin to prevent onset and modify epilepsy outcome in children with tuberous sclerosis (Epistop and PreVeNT). We describe a potential approach to a disease modification trial in adults, using patients with temporal lobe epilepsy. Finally, we discuss regulatory hurdles for antiepileptogenesis and disease‐modifying trials.

BACKGROUND: Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species (ROS) production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in ROS production have been relatively unexplored. Current evidence suggests that elevated ROS production in ischemic tissues occurs due to accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Interestingly, mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. METHODS: Here, we investigated the role of succinate and succinate dehydrogenase (SDH) inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. RESULTS: Our results demonstrate that injection of succinate in neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart following myocardial infarction injury results in a robust regenerative response within 4 weeks following injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis following SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. CONCLUSIONS: Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.

Objectives To determine dentoalveolar and skeletal effects produced in mature patients by the Carriere Motion Class III (CM3) appliance followed by fixed appliances. Materials and Methods This retrospective study evaluated 32 patients at three time points: T1 (initial), T2 (removal of CM3), and T3 (posttreatment). Serial cephalograms were traced and digitized, and best-fit regional superimpositions were constructed. Eleven linear and 7 angular variables were measured. The starting forms of the CM3 patients were compared with a sample of untreated subjects with normal occlusions and well-balanced faces. Results The CM3 phase lasted 6.3 months, followed by a phase of fixed appliances lasting 12.9 months; the total duration of treatment was 19.2 months. Minimal skeletal changes were measured sagittally, with only a slight increase in lower anterior facial height observed during treatment. Most treatment changes were dentoalveolar in nature. Wits appraisal increased 4.0 mm during treatment. The molar relationship improved by 6.0 mm during phase I, a value that rebounded slightly during phase II, resulting in an improvement toward Class I of 4.8 mm. Best-fit regional superimpositions revealed anterior movement of upper molars relative to the maxilla and posterior movement of lower molars relative to the mandible. Conclusions The Carriere Motion Class III appliance is an effective and efficient method of resolving occlusal problems in minimally growing Class III patients. Primary treatment effects are dentoalveolar in nature with minimal skeletal alterations.

Objective The aim of this study was to develop a prediction model that combines the information derived from chronological age (analysed as a curvilinear variable), gender and the CVM method to predict mandibular growth. Settings and sample population 50 participants (29 females, 21 males) were selected from the AAOF Craniofacial Growth Legacy Collection, the Michigan Growth Study and the Denver Child Growth study. Materials and methods In this investigation, 456 lateral cephalograms were analysed by applying a mixed effect model. The outcome variable was the annualized increment in total mandibular length (Co-Gn) during the year following the lateral cephalogram on which the cervical stage and chronological age were evaluated. The predictive variables were chronological age up to the fifth order, gender, stage of cervical vertebral maturation, as well as interactions between age and gender, age and cervical stage, and gender and cervical stage. Results Cervical stage, chronological age up to the fourth order, gender, and the interaction between age and gender were significant predictors of annualized increments in mandibular length. The annualized increment in Co-Gn was significantly greater for CS 3 when compared to all other cervical stages. Further, annualized increments in Co-Gn for CS 1 and CS 2 were significantly greater when compared to CS 5. Conclusions Cervical stage, chronological age and gender can be used jointly to predict the annualized increment in mandibular growth. Cervical stage 3 exhibited the greatest annualized increase in mandibular length.

Introduction During the decision-making process, physicians rely on heuristics that consist of simple, useful procedures for solving problems, intuitive shortcuts that produce reliable decisions based on limited information. In clinical situations characterized by a high degree of uncertainty such as those encountered in orthodontics, cognitive biases and judgment errors related to heuristics are not uncommon. This study aimed at promoting trust in the effective interface between the intuitive reasoning of the orthodontic practitioner and the computational heuristics emerging from simple statistical models. Methods We propose an integrative model based on the interaction between clinical reasoning and 2 computational tools, cluster analysis and fast-and-frugal trees, to extract a structured craniofacial representation of untreated subjects with Class III malocclusion and to forecast the worsening of the malocclusion over time. Results Cluster analysis of cephalometric values from 144 growing subjects with Class III malocclusion followed longitudinally (T1: mean age, 10.2 ± 1.9 years; T2: mean age, 13.8 ± 2.7 years) produced 3 morphologic subgroups with predominant sagittal, vertical, and slight maxillomandibular imbalances. Fast-and-frugal trees applied to different subgroups extracted heuristics that improved the prediction of key features associated with adverse craniofacial growth. Conclusions Provided that cephalometric values are placed in the appropriate framework, the matching between simple and fast computational approaches and clinical reasoning could help the intuitive logic, perception, and cognitive inferences of orthodontic practitioners on the outcome of patients affected by Class III disharmony, decreasing errors associated with flawed judgments and improving the accuracy of decision making.

Aim The aim of this study was to analyze dental and soft tissue profile development in children with normal occlusions to establish age- and gender-specific reference intervals for German children during their active growth period. Subjects and methods The study group consisted of a sample of 31 untreated Caucasian subjects with normal occlusions. Dental casts were analyzed at four different stages of dentitional development. Extraoral profile photographs were available for 19 subjects at stages T2–T4. In these subjects 11 angular measurements and 14 indices were analyzed. Statistical comparisons of gender-specific differences were performed by Mann–Whitney U tests (p ≤ 0.05). Results Upper and lower posterior and total arch perimeters were recorded to be significantly larger in male subjects until the late mixed dentition. Subsequently, there was a tendency toward larger dimensions in males for those parameters. Upper and lower intercanine, interpremolar and intermolar widths were significantly larger in males throughout the entire observation period. There were no statistically significant gender differences with regard to most angular measurements in the dental arches, including molar rotation, palatal volume, overbite, overjet and molar relationship at later dental stages. Conclusion In untreated subjects with normal occlusion, dental arch and soft tissue parameters can be considered age-dependent. For some dental parameters, gender-specific differences were found that should be taken into consideration during diagnosis and treatment planning of growing children. The obtained longitudinal data of untreated children provide useful information for orthodontic diagnosis, treatment planning and future research projects.

OBJECTIVES: To determine the skeletal and dental changes with Microimplant Assisted Rapid Palatal Expansion (MARPE) appliances in growing and non-growing patients using cone beam computed tomography (CBCT) and 3D imaging analysis. METHODS: The sample was comprised of 25 patients with transverse maxillary discrepancy treated with Maxillary Skeletal Expander (MSE, a type of MARPE appliance). CBCT scans were taken before and after maxillary expansion; the interval was 6 ± 4.3 months. The sample was divided into growing and non-growing groups using cervical vertebrae and midpalatal suture maturation. Linear and angular three dimensional dentoskeletal changes were assessed after cranial base superimposition. The treatment groups were compared with Independent Sample t-test (P < .05). RESULTS: Both groups displayed marked transverse changes with a similar ratio of skeletal to dental transverse changes and parallel sutural opening from the PNSANS; a similar amount of expansion occurred in the anterior and the posterior regions of the maxilla. The maxilla expanded skeletally without rotational displacements in both groups. The small downward-forward displacements were similar in both groups, except that the growing group had a significantly greater vertical displacement of the canines (1.7 ±1.0 mm in growing patients, 0.6 ±0.8 mm in non-growing patients; P = 0.02) and ANS (1.1 ±0.6 mm in the growing group, 0.5 ±0.5 mm in the non-growing group; P = 0.004). CONCLUSIONS: Treatment of patients with MARPE appliance is effective in growing and non-growing patients. While greater skeletal and dental changes were observed in growing patients, a similar ratio of skeletal to dental transverse changes was observed in both groups.

Heart failure represents the end result of different pathophysiologic processes, which culminate in functional impairment. Regardless of its aetiology, the presentation of heart failure usually involves symptoms of pump failure and congestion, which forms the basis for clinical diagnosis. Pathophysiologic descriptions of heart failure with reduced ejection fraction (HFrEF) are being established. Most commonly, HFrEF is centred on a reactive model where a significant initial insult leads to reduced cardiac output, further triggering a cascade of maladaptive processes. Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias. The pathophysiologic processes behind remodelling in heart failure are complex and reflect systemic neurohormonal activation, peripheral vascular effects and localised changes affecting the cardiac substrate. These abnormalities have been the subject of intense research. Much of the translational successes in HFrEF have come from targeting neurohormonal responses to reduced cardiac output, with blockade of the renin-angiotensin-aldosterone system (RAAS) and beta-adrenergic blockade being particularly fruitful. However, mortality and morbidity associated with heart failure remains high. Although systemic neurohormonal blockade slows disease progression, localised ventricular remodelling still adversely affects contractile function. Novel therapy targeted at improving cardiac contractile mechanics in HFrEF hold the promise of alleviating heart failure at its source, yet so far none has found success. Nevertheless, there are increasing calls for a proximal, 'cardiocentric' approach to therapy. In this review, we examine HFrEF therapy aimed at improving cardiac function with a focus on recent trials and emerging targets.

The non-contractile cytoskeleton in cardiomyocytes is comprised of cytoplasmic actin, microtubules, and intermediate filaments. In addition to providing mechanical support to these cells, these structures are important effectors of tension-sensing and signal transduction and also provide networks for the transport of proteins and organelles. The majority of our knowledge on the function and structure of these cytoskeletal networks comes from research on proliferative cell types. However, in recent years, researchers have begun to show that there are important cardiomyocyte-specific functions of the cytoskeleton. Here we will discuss the current state of cytoskeletal biology in cardiomyocytes, as well as research from other cell types, that together suggest there is a wealth of knowledge on cardiac health and disease waiting to be uncovered through exploration of the complex signaling networks of cardiomyocyte non-sarcomeric cytoskeletal proteins.

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Casup2+/suphandling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder primarily caused by mutations in the β-myosin heavy-chain gene. The proximal subfragment 2 region (S2), 126 amino acids of myosin, binds with the C0-C2 region of cardiac myosin-binding protein-C to regulate cardiac muscle contractility in a manner dependent on PKA-mediated phosphorylation. However, it is unknown if HCM-associated mutations within S2 dysregulate actomyosin dynamics by disrupting its interaction with C0-C2, ultimately leading to HCM. Herein, we study three S2 mutations known to cause HCM: R870H, E924K, and E930Δ. First, experiments using recombinant proteins, solid-phase binding, and isothermal titrating calorimetry assays independently revealed that mutant S2 proteins displayed significantly reduced binding with C0-C2. In addition, CD revealed greater instability of the coiled-coil structure in mutant S2 proteins compared with S2Wt proteins. Second, mutant S2 exhibited 5-fold greater affinity for PKA-treated C0-C2 proteins. Third, skinned papillary muscle fibers treated with mutant S2 proteins showed no change in the rate of force redevelopment as a measure of actin–myosin cross-bridge kinetics, whereas S2Wt showed increased the rate of force redevelopment. In summary, S2 and C0-C2 interaction mediated by phosphorylation is altered by mutations in S2, which augment the speed and force of contraction observed in HCM. Modulating this interaction could be a potential strategy to treat HCM in the future.

The study was aimed at evaluating the sagittal and transversal inclinations of upper second molars in untreated adolescents with normal occlusion.A sample of 41 subjects (16 females, 25 males) was selected from the University of Michigan Growth Study (UMGS). Digital dental casts with fully erupted second molars in occlusion were chosen (mean age 14.9 ± 1.3 years). Digital measurements were recorded with the open source software 3D Slicer ( www.slicer.org ). The digital measurements of the UMGS sample were compared with the manual measurements collected by Andrews from his sample of untreated class I subjects with normal overbite and overjet. Two mixed effect models (sagittal and transversal inclinations) were performed. The "random effect" was represented by the subjects, while the "fixed effects" were the two compared groups, the side of the arch (right and left), and the group × side interaction. Outcome variables were sagittal and transversal inclinations of the upper second molars.The UMGS group showed a significantly greater distal crown angulation (-18.9°) with respect to the Andrews sample (0.4°, P 0.0001). As for the transversal inclination, the UMGS group exhibited significantly greater lingual crown inclination (-10.6° versus -8.0°, P = 0.0118).Fully erupted maxillary second molars in a sample of adolescent subjects with normal occlusion showed significantly greater distal and lingual inclinations when compared with Andrews' values. The finding of a distal crown inclination in contrast with Andrews' observation of a mesial crown inclination suggests that revision in tip prescription for preadjusted brackets may be considered.ZIEL: Ziel der Studie war es, die sagittale und transversale Neigung der oberen zweiten Molaren bei unbehandelten Jugendlichen mit normaler Okklusion zu evaluieren.Eine Stichprobe von 41 Probanden (16 weiblich, 25 männlich) wurde aus der University of Michigan Growth Study (UMGS) ausgewählt. Es wurden digitale Zahnabdrücke mit vollständig durchgebrochenen zweiten Molaren in Okklusion ausgesucht (Durchschnittsalter 14,9 ± 1,3 Jahre). Die digitalen Messungen erfolgten mit der Open-Source-Software 3D Slicer ( www.slicer.org ). Die digitalen Messungen der UMGS-Stichprobe wurden mit den manuellen Messungen verglichen, die Andrews an seiner Stichprobe von unbehandelten Klasse-I-Probanden mit normalem Overbite und Overjet erhoben hatte. Zwei Mixed-effect-Modelle (sagittale und transversale Neigungen) wurden durchgeführt. Der „Zufallseffekt“ wurde durch die Probanden repräsentiert, die „festen Effekte“ durch die beiden verglichenen Gruppen, die Seite des Zahnbogens (rechts und links) und die Interaktion Gruppe × Seite. Ergebnisvariablen waren sagittale und transversale Inklinationen der oberen zweiten Molaren.Die UMGS-Gruppe zeigte im Vergleich zur Andrews-Gruppe eine signifikant größere distale Kronenangulation (−18,9° vs. 0,4°, p 0,0001). Hinsichtlich der transversalen Neigung wies die UMGS-Gruppe eine signifikant größere linguale Kronenneigung auf (−10,6° vs. −8,0°, p = 0,0118).Vollständig durchgebrochene obere zweite Molaren in einer Stichprobe von jugendlichen Probanden mit normaler Okklusion zeigten im Vergleich zu den Andrews-Werten signifikant größere distale und linguale Neigungen. Der Befund einer distalen Kronenneigung im Gegensatz zu Andrews’ Beobachtung einer mesialen Kronenneigung deutet darauf hin, dass eine Überarbeitung der Tip-Vorgabe bei voreingestellten Brackets in Betracht gezogen werden kann.

Introduction This study aimed to evaluate the 3-dimensional (3D) mandibular dental changes over 42 years using the registration of digital models. Methods The sample comprised digital dental models of 8 untreated subjects (4 males and 4 females) with normal occlusion measured longitudinally at ages 17 years (T1) and 60 years (T2). Using 13 landmarks placed on the mucogingival junction, we registered the T2 model on the T1 model. Three-dimensional changes in the position of the landmarks on the buccal cusp tip of the posterior teeth and incisal edge of the central incisors were measured by 2 examiners. Registration and measurements were performed using SlicerCMF (version 3.1; http://www.slicer.org ) software. Intra- and interrater agreements were evaluated using intraclass correlation coefficients and the Bland-Altman method. One-sample t tests were used for evaluating interphase 3D dental changes (P Results Adequate intra- and interrater reproducibility was found. From T1 to T2, the mandibular teeth showed significant 3D positional changes. A significant dental eruption relative to the mucogingival junction was observed for the anterior and posterior teeth. Anteroposterior movements of mandibular teeth were not significant except for the right molar that drifted mesially. Transverse movements included slight lingual tipping at canines and premolars regions. Conclusions Dental changes in untreated normal occlusion were very slight from early to mature adulthood. The eruption of the mandibular teeth was the most consistent finding. A tendency for mesial movement of molars and lingual movement of first premolars and canines was observed in the mandible during the aging process.

OBJECTIVE This investigation evaluates the evidence of case-based reasoning (CBR) in providing additional information on the prediction of future Class III craniofacial growth. SETTINGS AND SAMPLE POPULATION The craniofacial characteristics of 104 untreated Class III subjects (7-17 years of age), monitored with two lateral cephalograms obtained during the growth process, were evaluated. MATERIALS AND METHODS Data were compared with the skeletal characteristics of subjects who showed a high degree of skeletal imbalance ('prototypes') obtained from a large data set of 1263 Class III cross-sectional subjects (7-17 years of age). RESULTS The degree of similarity of longitudinal subjects with the most unbalanced prototypes allowed the identification of subjects who would develop a subsequent unfavourable skeletal growth (accuracy: 81%). The angle between the palatal plane and the sella-nasion line (PP-SN angle) and the Wits appraisal were two additional craniofacial features involved in the early prediction of the adverse progression of the Class III skeletal imbalance. CONCLUSIONS Case-based reasoning methodology, which uses a personalized inference method, may bring additional information to approximate the skeletal progression of Class III malocclusion.

Staphylococcus aureus bacteraemia (SAB) is associated with high mortality and morbidity rates. Yet, there is currently no adequate diagnostic test for early and rapid diagnosis of SAB. Therefore, this study was aimed at exploring the potential for clinical implementation of a nuclease-activatable fluorescent probe for early diagnosis of SAB. To this end, clinical blood culture samples from patients with bloodstream infections were incubated for 1 h with the “smart” activatable P2&3TT probe, the total assay time being less than 2 h. Cleavage of this probe by the secreted S. aureus enzyme micrococcal nuclease results in emission of a readily detectable fluorescence signal. Incubation of S. aureus-positive blood culture samples with the P2&3TT probe resulted in 50-fold higher fluorescence intensity levels than incubation with culture-negative samples. Moreover, incubation of the probe with non-S. aureus-positive blood cultures yielded essentially background fluorescence intensity levels for cultures with Gram-negative bacteria, and only ~ 3.5-fold increased fluorescence intensity levels over background for cultures with non-S. aureus Gram-positive bacteria. Importantly, the measured fluorescence intensities were dose-dependent, and a positive signal was clearly detectable for S. aureus-positive blood cultures with bacterial loads as low as ~ 7,000 colony-forming units/mL. Thus, the nuclease-activatable P2&3TT probe distinguishes clinical S. aureus-positive blood cultures from non-S. aureus-positive blood cultures and culture-negative blood, accurately, rapidly and with high sensitivity. We conclude that this probe may enhance the diagnosis of SAB.

Objectives To develop a prediction model that combined information derived from chronological age, sex, and the cervical vertebral maturation (CVM) method to predict the pubertal spurt in mandibular growth. Materials and Methods A total of 50 subjects (29 females, 21 males) were selected from the American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection, the University of Michigan Growth Study, and the Denver Child Growth study. A total of 456 lateral cephalograms were analyzed, and a multilevel logistic model was applied. The outcome variable was the presence or absence of the mandibular pubertal growth peak. The predictive variables were chronological age up to the third order, sex, presence or absence of CS 3 interactions between age and sex, age and CS 3, sex and CS 3. Results The mean age ± standard deviation (SD) at the first cephalogram was 8.2 ± 0.5 years, whereas the mean age at the last cephalogram was 16.5 ± 1.1 years. The mean interval ± SD between two consecutive cephalograms was 1.0 ± 0.1 years. The mean age ± SD at the lateral cephalogram obtained immediately before the mandibular pubertal growth peak was 12.1 ± 1.1 years for females and 13.2 ± 0.8 years for males. The greatest increase in mandibular length occurred after CS 3 in 78% of the subjects. The presence of CS 3, age, second-order age, sex, and the interaction between age and sex were all statistically significant predictors of the mandibular pubertal growth spurt. Conclusions CS 3, chronological age, and sex can be used jointly to predict the pubertal peak in mandibular growth.

Objectives: The purpose of this three-dimensional (3D) study was to assess retrospectively the middle cranial fossa and central skull base of patients treated with the Herbst appliance (HA). Materials and Methods: 3D surface virtual models of 40 Class II, division 1 malocclusion patients were generated from cone-beam computed tomography (CBCT) acquired before treatment (T0) and after 8 months of HA treatment (T1). T0 and T1 3D models were superimposed volumetrically at the anterior cranial fossa. Twenty subjects who had been treated with the Herbst appliance (HAG) were compared to 20 subjects who were not treated orthopedically. The latter group served as a comparison control group (CG). Quantitative assessments of the location and directional changes were made with linear and angular measurements between anatomical landmarks. Qualitative assessments of the spatial behavior of the middle cranial fossa and central skull base relative to the anterior cranial fossa were displayed graphically for visualization with color maps and semitransparent overlays. Non-parametric tests were performed to compare the between the HAG and CG. Results: Point-to-point linear measurements and skeletal rotation (pitch, roll, and yaw) changes were very small along the observational period and were not significantly different between HAG and CG. Visual analysis of color maps and overlays confirmed that no changes in the cranial base were associated with HA. Conclusions: HA therapy did not produce clinically significant changes in the middle cranial fossa and central skull base.

Made available in DSpace on 2018-12-11T17:13:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-01 The aim of this study was to evaluate midpalatal suture maturation in adults, as observed in cone beam computed tomography (CBCT) images. CBCT scans from 78 subjects (64 female and 14 male, age range from 18 to 66 years) were evaluated. Midpalatal suture maturation was verified on the central cross-sectional axial slice in the superior–inferior dimension of the palate, using methods validated previously. Intra-examiner agreement was analyzed by weighted kappa test. Multinomial logistic regression was used to test whether sex and chronological age (adults

Objective To evaluate the role of treatment timing on long-term dentoskeletal effects of Class II treatment with removable functional appliances followed by full-fixed appliance therapy. Materials and methods A group of 46 patients (23 females and 23 males) with Class II malocclusion treated consecutively with either Bionator or Activator, followed by fixed appliances was compared with a matched control group of 31 subjects (16 females and 15 males) with untreated Class II malocclusion. The treated sample was evaluated at T1, start of treatment (mean age: 9.9 ± 1.3 years); T2, end of functional treatment and prior to fixed appliances (mean age: 11.9 ± 1.3 years); and T3, long-term observation (mean age: 18.3 ± 2.1 years). The treated and the control samples were divided into pre-pubertal and pubertal groups according to skeletal maturity observed at the start of treatment. Statistical comparisons were performed with independent sample t-tests. Results When treatment was initiated before puberty, Class II correction was mostly confined to the dentoalveolar changes, with significant improvements of both overjet and molar relationships. On the other hand, treatment with the outset at puberty produced significant long-term improvement of sagittal skeletal relationships, which were mainly sustained by mandibular changes. Conclusions Treatment with removable functional appliances (Bionator or Activator) followed by full-fixed appliances produced significant skeletal long-term changes when it begins at puberty. Prepubertal Class II treatment results primarily in dentoalveolar changes.

Rapid and accurate bacterial detection methods are needed for clinical diagnostic, water, and food testing applications. The wide diversity of bacterial nucleases provides a rich source of enzymes that could be exploited as signal amplifying biomarkers to enable rapid, selective detection of bacterial species. With the exception of the use of micrococcal nuclease activity to detect Staphylococcus aureus, rapid methods that detect bacterial pathogens via their nuclease activities have not been developed. Here, we identify endonuclease I as a robust biomarker for E. coli and develop a rapid ultrasensitive assay that detects its activity. Comparison of nuclease activities of wild-type and nuclease-knockout E. coli clones revealed that endonuclease I is the predominant DNase in E. coli lysates. Endonuclease I is detectable by immunoblot and activity assays in uropathogenic E. coli strains. A rapid assay that detects endonuclease I activity in patient urine with an oligonucleotide probe exhibited substantially higher sensitivity for urinary tract infections than that reported for rapid urinalysis methods. The 3 hr turnaround time is much shorter than that of culture-based methods, thereby providing a means for expedited administration of appropriate antimicrobial therapy. We suggest this approach could address various unmet needs for rapid detection of E. coli.

Objective To analyse the craniofacial growth of a long-term semi-longitudinal sample of Caucasian subjects with untreated Class III malocclusion. Setting and sample population A total of 144 Caucasian subjects (of North American and Italian origin) with untreated Class III malocclusion. Materials and methods Subjects aged 2 years and 9 months up to 21 years and 7 months were selected. A multilevel model was used to calculate growth curves for ten variables for both each individual subject and for the whole sample. Results There was a statistically significant increase for total mandibular length (Co-Gn. T2-T1 = 8.4 mm), midfacial length (Co-A. T2-T1 = 3.4 mm) and lower anterior facial height (ANS-Me. T2-T1 = 3.8 mm). The multilevel analysis showed two points of acceleration of growth (about 3-5 years of age and 11-15 years of age) for seven out of ten variables. For Co-Gn and Co-A variables, males presented points of maximum growth delayed by 1 year in comparison with females, with a greater duration (1 year longer) and a greater total growth of about 5 mm. Active mandibular growth continued for a long time after the pubertal spurt: increases in mandibular length ended at about 17 years of age in females and at 21 years and 7 months in males. Conclusions Untreated Class III malocclusion showed a specific growth curve, especially for the mandible, whose excesses added up over time. In males, the amounts of mandibular and midfacial growth during the whole observation time were greater and lasted longer than in females.

OBJECTIVES: To determine the treatment effects produced in Class II patients by the Carriere(®) Motion 3D™ appliance (CMA) followed by full fixed appliances (FFA). MATERIALS AND METHODS: This retrospective study evaluated 34 adolescents at three time points: T1 (pretreatment), T2 (removal of CMA), and T3 (posttreatment). The comparison group comprised 22 untreated Class II subjects analyzed at T1 and T3. Serial cephalograms were traced and digitized, and 12 skeletal and 6 dentoalveolar measures were compared. RESULTS: Phase I with CMA lasted 5.2 ± 2.8 months; phase II with FFA lasted 13.0 ± 4.2 months. CMA treatment restricted the forward movement of the maxilla at point A. There was minimal effect on the sagittal position of the chin at pogonion. The Wits appraisal improved toward Class I by 2.1 mm during the CMA phase but not during FFA. Lower anterior facial height increased twice as much in the treatment group as in controls. A clockwise rotation (3.9°) of the functional occlusal plane in the treatment group occurred during phase I; a substantial rebound (−3.6°) occurred during phase II. Overjet and overbite improved during treatment, as did molar relationship; the lower incisors proclined (4.2°). CONCLUSIONS: The CMA appliance is an efficient and effective way of correcting Class II malocclusion. The changes were mainly dentoalveolar in nature, but some skeletal changes also occurred, particularly in the sagittal position of the maxilla and in the vertical dimension.

Traumatic brain injury (TBI) and status epilepticus (SE) have both been linked to development of human epilepsy. Although distinct etiologies, current research has suggested the convergence of molecular mechanisms underlying epileptogenesis following these insults. One such mechanism involves the neurotrophin brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin related kinase B (TrkB). In this review, we focus on currently available data regarding the pathophysiologic role of BDNF/TrkB signaling in epilepsy development. We specifically examine the axonal injury and SE epilepsy models, two animal models that recapitulate many aspects of TBI- and SE-induced epilepsy in humans respectively. Thereafter, we discuss aspiring strategies for targeting BDNF/TrkB signaling so as to prevent epilepsy following an insult or suppress its expression once developed. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

OBJECTIVES: To compare three-dimensional (3D) skeletal and dentoalveolar effects of the Herbst and Pendulum appliances followed by fixed orthodontic treatment in growing patients. SETTING AND SAMPLE POPULATION: A sample of 35 adolescents with cone-beam computed tomography scans obtained prior to Herbst and Pendulum treatment (T1) and immediately after fixed appliance treatment (T2). MATERIALS AND METHODS: Patients with Class II malocclusion was assessed retrospectively and divided into two treatment groups: Herbst group (n = 17, age: 12.0 ± 1.6 years) and Pendulum group (n = 18, age: 12.1 ± 1.5 years), with a mean treatment duration of 2.8 ± 0.8 years and 2.5 ± 0.7 years, respectively. Reconstructions of the maxillomandibular and dentoalveolar regions and data in 3D were obtained relative to cranial base, maxillary and mandibular regional superimpositions. Treatment outcomes (T2-T1) were compared between both groups using t tests for independent samples (P

Objectives To perform a three-dimensional evaluation of the position of the condyles in patients treated with Herbst appliance (HA) in two stages of cervical vertebral maturation. Setting and sample population Retrospective case-control study. Pubertal Herbst group (PHG; n = 24, mean age 14.5 years, CS 3 and CS 4) and pre-pubertal Herbst group (PPHG; n = 17, mean age 9.9 years, CS 1 and CS 2) were contrasted with comparison groups of non-orthopaedically treated Class II patients in pubertal (PCG; n = 17, mean age 13.9 years) and pre-pubertal maturational stages (PPCG; n = 18, mean age 10.6 years). Materials and methods Cone-beam computer tomography scans were taken before treatment (T0) and at T1 after 8 to 12 months. Point-to-point measurements of the displacement of the condyles between T0 and T1, relative to the glenoid fossae, were performed in the X, Y, Z and 3D perspectives. Qualitative assessments using semi-transparent overlays and colour mapping also were produced. Results The displacement of the condyles within the glenoid fossae in the treated groups was small ( .05). Relative to the glenoid fossa, condylar position at T1 was similar to T0 in pre-pubertal and pubertal groups (P > .05). Similar condylar rotations from T0 to T1 were observed in Herbst and comparison groups, and no significant difference was found between pre-pubertal and pubertal patients. Conclusions Regardless the stage of skeletal maturation, HA treatment did not change the condyle-glenoid fossa relationship.

The Board of Trustees of the American Association of Orthodontists asked a panel of medical and dental experts in sleep medicine and dental sleep medicine to create a document designed to offer guidance to practicing orthodontists on the suggested role of the specialty of orthodontics in the management of obstructive sleep apnea. This White Paper presents a summary of the Task Force's findings and recommendations.

Summary The COVID-19 pandemic has brought humanity’s strained relationship with nature into sharp focus, with calls for cessation of wild meat trade and consumption, to protect public health and biodiversity.1,2 However, the importance of wild meat for human nutrition, and its tele-couplings to other food production systems, mean that the complete removal of wild meat from diets and markets would represent a shock to global food systems.3, 4, 5, 6 The negative consequences of this shock deserve consideration in policy responses to COVID-19. We demonstrate that the sudden policy-induced loss of wild meat from food systems could have negative consequences for people and nature. Loss of wild meat from diets could lead to food insecurity, due to reduced protein and nutrition, and/or drive land-use change to replace lost nutrients with animal agriculture, which could increase biodiversity loss and emerging infectious disease risk. We estimate the magnitude of these consequences for 83 countries, and qualitatively explore how prohibitions might play out in 10 case study places. Results indicate that risks are greatest for food-insecure developing nations, where feasible, sustainable, and socially desirable wild meat alternatives are limited. Some developed nations would also face shocks, and while high-capacity food systems could more easily adapt, certain places and people would be disproportionately impacted. We urge decision-makers to consider potential unintended consequences of policy-induced shocks amidst COVID-19; and take holistic approach to wildlife trade interventions, which acknowledge the interconnectivity of global food systems and nature, and include safeguards for vulnerable people., Graphical abstract, Highlights • 15 countries identified as at risk of food insecurity from wild meat prohibitions • Extra agricultural land to replace wild meat protein with livestock is ∼124,000 km2 • This land-use change could drive >260 species toward extinction, globally • Context-specific factors moderate risks of food insecurity and biodiversity loss, The COVID-19 pandemic has led to calls to prohibit wild meat consumption, to protect public health and biodiversity. However, Booth et al. demonstrate that the sudden removal of wild meat from food systems could negatively impact people and nature. Wildlife trade policy interventions need to consider tele-couplings between food systems and nature.

The Rho GTPase proteins Rac1, RhoA and Cdc42 have a central role in regulating the actin cytoskeleton in dendritic spines1, thereby exerting control over the structural and functional plasticity of spines2, 3, 4, 5 and, ultimately, learning and memory6, 7, 8. Although previous work has shown that precise spatiotemporal coordination of these GTPases is crucial for some forms of cell morphogenesis9, the nature of such coordination during structural spine plasticity is unclear. Here we describe a three-molecule model of structural long-term potentiation (sLTP) of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA and Cdc42 as a causal signal of sLTP. This model posits that complete tripartite signal overlap in spines confers sLTP, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during sLTP, we find that such spatiotemporal signal complementation simultaneously explains three integral features of plasticity: the facilitation of plasticity by brain-derived neurotrophic factor (BDNF), the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of sLTP, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity. Thus, we present a form of biochemical computation in dendrites involving the controlled complementation of three molecules that simultaneously ensures signal specificity and primes the system for plasticity.

Introduction The aims of this study were to evaluate the differences between 2 regions of maxillary voxel-based registration and to test the reproducibility of the registration. Methods Three-dimensional models were built for before-treatment (T1) and after-treatment (T2) based on cone-beam computed tomography images from 16 growing subjects. Landmarks were labeled in all T2 models of the maxilla, and voxel-based registrations were performed independently by 2 observers at 2 times using 2 reference regions. The first region, the maxillary region, included the maxillary bone clipped inferiorly at the dentoalveolar processes, superiorly at the plane passing through the right and left orbitale points, laterally at the zygomatic processes through the orbitale point, and posteriorly at a plane passing through the distal surface of the second molars. In the second region, the palate and infrazygomatic region had different posterior and anterior limits (at the plane passing through the distal aspects of the first molars and the canines, respectively). The differences between the registration regions were measured by comparing the distances between corresponding landmarks in the T2 registered models and comparing the corresponding x, y, and z coordinates from corresponding landmarks. Statistical analysis of the differences between the T2 surface models was performed by evaluating the means and standard deviations of the distances between landmarks and by testing the agreement between coordinates from corresponding landmarks (intraclass correlation coefficient and Bland-Altman method). Results The means of the differences between landmarks from the palate and infrazygomatic region to the maxillary region 3-dimensional surface models at T2 for all regions of reference, times of registrations, and observer combinations were smaller than 0.5 mm. The intraclass correlation coefficient and the Bland-Altman plots indicated adequate concordance. Conclusions The 2 regions of regional maxillary registration showed similar results and adequate intraobserver and interobserver reproducibility values.

The aim of the study was to investigate how to improve the forecasting of craniofacial unbalance risk during growth among patients affected by Class III malocclusion. To this purpose we used computational methodologies such as Transductive Learning (TL), Boosting (B), and Feature Engineering (FE) instead of the traditional statistical analysis based on Classification trees and logistic models. Such techniques have been applied to cephalometric data from 728 cross-sectional untreated Class III subjects (6–14 years of age) and from 91 untreated Class III subjects followed longitudinally during the growth process. A cephalometric analysis comprising 11 variables has also been performed. The subjects followed longitudinally were divided into two subgroups: favourable and unfavourable growth, in comparison with normal craniofacial growth. With respect to traditional statistical predictive analytics, TL increased the accuracy in identifying subjects at risk of unfavourable growth. TL algorithm was useful in diffusion of information from longitudinal to cross-sectional subjects. The accuracy in identifying high-risk subjects to growth worsening increased from 63% to 78%. Finally, a further increase in identification accuracy, up to 83%, was produced by FE. A ranking of important variables in identifying subjects at risk of growth worsening, therefore, has been obtained.

Objectives The aim of this study was to evaluate the reliability of 3-dimensional maxillary dental changes using two methods of digital model superimposition. Setting and sample population The Department of Orthodontics of Bauru Dental School, University of Sao Paulo and University of Michigan Craniofacial Growth Center. Fifteen subjects with normal occlusion. Material & methods The sample was composed of digital study models of 15 normal occlusion subjects taken at 13 (T1), 18 (T2) and 60 years of age (T3). Using the software SlicerCMF 3.1, superimposition (registration) was conducted using 9 landmarks placed on the incisive papilla, second and third palatal rugae and 10 mm distal to the third palatal rugae. Two registration methods were compared: landmarks (LA) and regions of interest (ROI). Three-dimensional changes of landmarks on the buccal cusp tip of posterior teeth bilaterally and the incisal edge of the right central incisor were measured by three examiners. Intraclass correlation coefficients and Bland-Altman method evaluated intra- and inter-examiner agreements. Results Good or excellent intra-examiner agreement was found for T1-T2 and T2-T3 measurements using both registration methods. Inter-examiner agreements were good to excellent for T1-T2 measurements and poor to fair for most T2-T3 measurements. Mean T1-T2 differences were less than 0.5 mm for most measurements. Conclusion Maxillary digital dental models of patients with normal occlusion superimposed on palatal rugae showed an adequate reliability for a 5-year interval comparison using landmarks or regions of interest. Lower than acceptable reproducibility using both superimposition methods was found for a 40-year interval comparison.

The Myosin Binding Protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cardiac MyBP-C is limited to the heart, and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow and fast, in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. This review characterizes MyBP-C as a whole and points out knowledge gaps that still remain with respect to skeletal MyBP-C.

Objectives To compare the three-dimensional maxillary dentoskeletal effects of a modified alternate rapid maxillary expansion and constriction facemask protocol (Alt-RAMEC/FM) with the traditional rapid maxillary expansion facemask protocol (RME/FM) performed in deciduous or early mixed dentition Class III patients. Setting and sample population Orthodontic Clinic of the Section of Dentistry of the Department of Surgery and Translational Medicine of the University of Florence. Thirty-four Class III patients were enrolled and allocated by alternating assignment to either Alt-RAMEC/FM or RME/FM therapy. Materials and methods Prior to treatment, all patients were evaluated, and a cone beam computed tomography (CBCT) scan was acquired. After completion of the orthopaedic therapy (average interval 1.2 years), a follow-up CBCT scan was obtained. Anatomic landmark identification on the CBCTs and subsequent quantification of the changes were performed. The primary outcome variable was the anteroposterior displacement of the anterior nasal spine (ANS AP). The treatment groups were compared with independent samples t tests. Results The patients in the two treatment groups showed a similar degree of compliance. No statistically significant differences were recorded for any variable when comparing the Alt-RAMEC/FM and RME/FM groups. In particular, the between-group difference for ANS AP was 0.0 mm (95%CI: -0.6;0.7, P = 0.933). Conclusions Both Alt-RAMEC/FM and RME/FM produced favourable orthopaedic changes in Class III growing patients. Neither protocol was superior to the other in terms of maxillary protraction effectiveness.

The aim of this 2-arm parallel trial was to compare the dentoskeletal effects of the expander with differential opening (EDO) and the Hyrax expander in the mixed dentition.Patients aged 7-11 years with maxillary dental arch constriction and Class I or Class II sagittal relationships were randomly allocated into 2 study groups. The experimental group comprised 22 patients (10 males, 12 females) with a mean age of 8.46 years treated with the EDO. The comparison group was composed of 24 patients (6 males, 18 females), mean age of 8.92 years treated with the conventional Hyrax expander. One complete turn per day for 6 days was performed for the posterior screw of the EDO and for the Hyrax expander. The anterior screw of the EDO was activated 1 complete turn per day for 10 days. The primary outcomes were the anterior opening of the midpalatal suture, changes on the interincisal diastema width, maxillary dental arch widths, arch perimeter, arch length, palatal depth, inclination of maxillary posterior teeth and on dental arch shape, and the amount of differential expansion in the anterior region compared with the posterior region of the maxillary dental arch. Computer-generated randomization was used. Allocation was concealed with sequentially, numbered, sealed, and opaque envelopes. Blinding was applicable for outcome assessment only. Occlusal radiographs of the maxilla were obtained at the end of the active expansion phase (T2). Intraoral photographs were obtained immediately pre-expansion (T1) and at T2. Digital dental models were obtained at T1 and 6 months after the active expansion period (T3). Intergroup comparisons of T1-T2 changes were performed using multiple linear regression analysis (P 0.05). The independent variables were both treatment and the starting forms. Bonferroni correction for multiple tests was applied.The experimental group showed a significantly greater opening of the anterior region of the midpalatal suture, a greater increase of the interincisal diastema width, and greater increases of the intercanine distance and inter-first deciduous molar distance than the Hyrax expander. The experimental group showed a significant differential expansion between the anterior and posterior regions, whereas the Hyrax group produced a similar expansion in the canine and molar regions. Serious harm was not observed.The EDO was capable of promoting greater orthopedic and dental changes in the anterior region of the maxilla than the conventional Hyrax expander. Similarity between the 2 expanders was observed for changes in the posterior region width, arch perimeter, arch length, palatal depth, and posterior teeth inclination.

Aim: To evaluate maxillary and mandibular dental arch changes induced by a passive self-ligating system by analysing digital dental casts. Subjects and methods: A sample of 25 growing patients (16 females and 9 males, mean age 12.8 years) treated with passive self-ligating brackets was compared to a sample of 25 untreated controls (15 females and 10 males, mean age 13.4 years). Sixty three-dimensional points were digitised on the maxillary and mandibular pre- and post-treatment virtual models to evaluate differences in the transverse and antero-posterior arch dimensions and in the torque values of representative anterior and posterior teeth. Statistical comparisons were performed with independent sample t -tests with Holm-Bonferroni correction for multiple tests. Results: The greatest increments in arch widths were found at the maxillary and mandibular premolar level (ranging from 2.0 to 2.2mm) and they were associated with significant increases in maxillary and mandibular arch perimeters (2.3 and 2.5mm, respectively), and in buccal crown torque of the upper premolars (with adequate torque control of all other teeth). Conclusions: The passive self-ligating system produced a modest but statistically significant widening of both maxillary and mandibular dental arches that were associated with significant net gains in maxillary and mandibular arch perimeters.

Introduction The aim of this study was to analyze the diagnostic performance of the cervical vertebral maturation (CVM) method in estimating accurately the stages of maturation of the midpalatal suture. Methods Cone-beam computed tomography (CBCT) images from 142 subjects (84 female, 58 male; mean age, 14.8 ± 9.7 years) were analyzed by 2 calibrated examiners to define, by visual analysis, the maturational stages of the cervical vertebrae and the midpalatal suture. These CBCT images were required by orthodontists and surgeons for diagnosis and treatment purposes. Positive likelihood ratios (LHRs) were calculated to evaluate the diagnostic performance of the CVM stages in identifying the maturational stages of the midpalatal suture. Results Positive LHRs greater than 10 were found for several cervical vertebral stages (CSs), including CS1 and CS2 for the identification of midpalatal suture stages A and B, CS3 for the diagnosis of midpalatal suture stage C, and CS5 for the assessment of midpalatal suture stages D and E. These positive LHRs indicated large and often conclusive increases in the likelihood that the CVM stages were associated with specific stages of midpalatal suture maturation. At CS4, there were a moderate positive LHR for stage C and low positive LHRs for stages D and E. Conclusions Most CVM stages can be used for the diagnosis of the stages of maturation of the midpalatal suture, so that CBCT imaging may not be necessary in these patients. In the postpubertal period, however, an assessment of the midpalatal suture maturation using CBCT images may be indicated in deciding between conventional rapid maxillary expansion and surgically assisted rapid maxillary expansion. On the other hand, if the CVM stage cannot be assessed, chronologic age may be a viable alternative to predict some midpalatal suture stages (particularly the early stages).

We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability.

The mechanisms by which truncating mutations in

Background Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration–approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium‐dependent effects on myocyte contractility. Methods and Results The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single‐center, double‐blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6‐minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo −1.7±1.0% ( P =0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E′ by −2.95±1.21 versus 1.32±1.21 in comparison to placebo ( P =0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm 2 , P P Conclusions Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01814319.

Rapid maxillary expansion and facial mask (RME/FM) therapy typically is indicated for treatment of Class III malocclusion associated with maxillary skeletal retrusion.1–4 The effects produced by this treatment protocol include more convexity of the facial profile5 due to forward displacement of the maxilla,4 clockwise rotation of the mandible,5 proclination of the maxillary incisors6 and a counterclockwise rotation of the palatal plane.7 To produce greater skeletal effects, early RME/FM treatment has been advocated. However, different chronological ages have been proposed as the best timing for initiating the RME/FM protocol. While some authors have recommended treatment up to 8 years,8 9 years9 and 10 years of age10,11 or before puberty,12 others did not identify any differences in response according to chronological age.2,13,14 Great individual variability in the amount of maxillary protraction has been demonstrated also in patients treated with bone-anchored maxillary protraction (BAMP).15 BAMP is initiated in the late mixed dentition or early permanent dentition. De Clerck and co-workers state that the placement of the miniplates typically should be delayed until after 10 years of age because the zygomatic plates tend to fail more often in younger patients.16 The amount of maxillary protraction is dependent on the maturation of the circummaxillary sutures, including the transverse palatine suture, the frontomaxillary sutures and the zygomaticomaxillary sutures (ZMSs). Kambara17 demonstrated that the ZMSs presented similar histological findings, or even greater complexity of interdigitations, compared to other circummaxillary sutures in young (mixed dentition phase) and older (permanent dentition phase) monkeys. The ZMSs are the longest and thickest circummaxillary sutures.18–20 They are oriented along the direction of the applied force system used in maxillary protraction.21 Individual assessment of the maturation of ZMSs, therefore, may represent an indicator of the response to orthopaedic maxillary protraction. In Part 1 of this investigation,22 we presented a classification of the maturational stages of the ZMSs. The aim of this study was to evaluate the influence of the maturational stages of the ZMSs on the amount of maxillary protraction produced by RME/FM and BAMP protocols in growing patients with Class III malocclusion. The differences between the two protocols were of secondary interest because the main goal of this study was to evaluate an adequate sample of children who underwent maxillary protraction at the three earliest stages of ZMS maturation and for whom CBCT data were available.

Objectives Three-dimensional evaluation of skeletal mandibular changes following Herbst appliance treatment. Setting and Sample Population Retrospective case–control study, based on a sample size calculation. Twenty-five pubertal patients treated with Herbst appliance (HAG), and 25 matched Class II patients who received other non-orthopaedic dental treatments (CG). Material and Methods Three-dimensional models were generated from pre-treatment (T0) and post-treatment (T1) cone beam computed tomograms. Volumetric registration on the cranial base was used to assess mandibular displacement; volumetric regional registration was performed to evaluate mandibular growth. Quantitative measurements of X, Y, Z and 3D Euclidian changes, and also qualitative visualization by colour-mapping and semi-transparent overlays were obtained. Results Downward displacement of the mandible was observed in both HAG and CG (2.4 mm and 1.5 mm, respectively). Significant forward displacement of the mandible was observed in the HAG (1.7 mm). HAG showed greater 3D superior and posterior condylar growth than the CG (3.5 mm and 2.0 mm, respectively). Greater posterior growth of the ramus was noted in the HAG than in CG. Conclusions Immediately after Herbst therapy, a significant mandibular forward displacement was achieved, due to increased bone remodelling of the condyles and rami compared to a comparison group. Three-dimensional changes in the direction and magnitude of condylar growth were observed in Herbst patients.

Summary Objective: To determine whether it is possible to predict Class III treatment outcomes on the basis of a model derived from a combination of computational analyses derived from complexity science, such as fuzzy clustering repartition and network analysis. Methods: Cephalometric data of 54 Class III patients (32 females, 22 males) tak en before (T1, mean age 8.2 ± 1.6 years) and after (T2, mean age 14.6 ± 1.8 years) early rapid maxillary expansion and facemask therapy followed by fixed appliances were analysed. Patients were classified at T1 on the basis of high membership grade into three main dentoskeletal fuzzy cluster phenotypes: hyperdivergent (HD), hypermandibular (HM), and balanced (Bal) phenotypes. The prevalence rate of successful and unsuccessful cases at T2 was calculated for the three clusters and compared by means of Fisher’s exact test corrected for multiple testing (Holm–Bonferroni method). Results: Unsuccessful cases were 9 out of 54 patients (16.7%). Once patients were framed into their cluster member ship, the individualized pre-treatment prediction of unsuccessful cases was largely differentiated: HD and HM patients showed a significantly greater prevalence rate of unsuccessful cases than Bal patients (0% in Bal cluster, 28.6% in HM cluster, and 33.3% in HD cluster). Network analysis captured some noticeable interdependencies of Class III patients, showing a more connected interactive structure of cephalometric data sets in HM and HD patients compared with Bal patients. The results were confirmed after minimizing the geometrical connections between cephalometric variables in the model. Conclusions: Fuzzy clustering repar tition can be usefully used to estimate an individualized risk of unsuccessful treatment outcome in Class III patients.

This study was a cephalometric evaluation of the growth changes in untreated subjects with minimal overbite at 4 time points during 4 developmental stages from the early mixed dentition to the permanent dentition, as well as from the prepubertal phase to young adulthood.A sample of 24 untreated subjects with minimal overbite (1.5 mm) was selected retrospectively from the University of Michigan Growth Study and the Denver Child Growth Study. The sample was followed longitudinally from about 9 years of age through 17 years of age. Dentofacial changes at the 4 times (T1-T4), defined by the cervical vertebral maturation method, were analyzed on lateral cephalograms. Nonparametric statistical analysis was used for comparisons.Overbite on average increased by 2.3 mm during the overall observation period. Improvement occurred during the prepubertal interval (T1-T2; 2.4 mm), whereas no significant changes occurred in the pubertal and postpubertal stages. From prepubertal ages to young adulthood, the open-bite tendency improved in 91% of the subjects, with self-correction in 75%. Logistic regression analysis on the cephalometric variables at T1 with the value of overbite at T4 did not show a statistically significant correlation.Subjects with an open-bite tendency show improvement of their occlusal condition during the prepubertal stage, but there is no significant improvement after this. These results provide useful indications for appropriate orthodontic treatment timing for patients with an open-bite tendency.

Introduction In this study, we present a novel classification method for individual assessment of midpalatal suture morphology. Methods Cone-beam computed tomography images from 140 subjects (ages, 5.6-58.4 years) were examined to define the radiographic stages of midpalatal suture maturation. Five stages of maturation of the midpalatal suture were identified and defined: stage A, straight high-density sutural line, with no or little interdigitation; stage B, scalloped appearance of the high-density sutural line; stage C, 2 parallel, scalloped, high-density lines that were close to each other, separated in some areas by small low-density spaces; stage D, fusion completed in the palatine bone, with no evidence of a suture; and stage E, fusion anteriorly in the maxilla. Intraexaminer and interexaminer agreements were evaluated by weighted kappa tests. Results Stages A and B typically were observed up to 13 years of age, whereas stage C was noted primarily from 11 to 17 years but occasionally in younger and older age groups. Fusion of the palatine (stage D) and maxillary (stage E) regions of the midpalatal suture was completed after 11 years only in girls. From 14 to 17 years, 3 of 13 (23%) boys showed fusion only in the palatine bone (stage D). Conclusions This new classification method has the potential to avoid the side effects of rapid maxillary expansion failure or unnecessary surgically assisted rapid maxillary expansion for late adolescents and young adults.

Numerous studies of smile esthetics have used still photos. Photos, however, do not capture the dynamics of a smile, an element that can contribute to overall smile esthetics. In this study, we assessed the esthetics of dynamic smiles.Four facially balanced female dental students were trained to produce 8 distinct smiles using the facial action coding system. Videos of the models' whole faces were presented to 2 panels of raters: dental students and nondental undergraduate students. Smile attractiveness was rated using a Web-based survey.The smile that used 4 labial muscles was rated significantly better than the smile involving only the risorius muscle (P0.05). The orbicularis oculi improved smile attractiveness (P0.04), especially among smiles rated less favorably (P0.05). Visibility of the models' eyes, however, did not influence the ratings (P0.05), perhaps because orbicularis oculi activation altered activations in other muscles in such a way that smile attractiveness was increased in the lower face.Smile esthetics increased with increased recruitment of muscles involved in smile production. The results were robust across the models, suggesting that objective rating methods of smile-dynamic esthetics could become an important clinical tool.

The aim of this study was to analyze sagittal and vertical dentofacial dimensions in subjects with normal occlusions during the juvenile and adolescents age periods to establish age- and gender-specific lateral cephalometric standard values for Germans during their active growth period. The study group consisted of a sample of 32 untreated subjects with normal occlusions. Lateral cephalograms were analyzed at 11 consecutive stages, from 6-13 and from 15-17 years of age. A customized cephalometric analysis was used to measure 53 variables. Statistical comparisons of gender-specific differences were performed by means of Mann-Whitney U tests.Anterior and posterior cranial base lengths, midfacial length as well as mandibular length were recorded to be significantly larger in male subjects at the age of 6 years. For most of the linear measurements, significantly larger craniofacial distances were recorded in males from the age of 15 years onward. There were no statistically significant gender differences with regard to most angular measurements at subsequent age groups. Soft tissue analysis revealed flatter profiles in females than in males from the age of 10-11 years onward, while age-dependent changes in the soft tissue profile were similar in both genders.In untreated subjects with normal occlusion craniofacial development of the hard and soft tissues can be considered age- and gender-dependent. Therefore age- and gender-specific differences of linear craniofacial distances should be taken into account for diagnosis and treatment planning in children and adolescents. The present results can be used as reference values for children and adolescents of German origin.

The paucity of costimulation at the tumor site compromises the ability of tumor-specific T cells to eliminate the tumor. The recent U.S. Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. Nonetheless, systemic administration of immunomodulatory antibodies has been associated with dose-limiting autoimmune pathologies, conceivably reflecting also the activation of resident autoreactive T cells. Arguably, targeting immunomodulatory ligands to the disseminated tumor lesions of the patient would reduce such drug-associated toxicities. We have recently developed a new class of inhibitory (CTLA-4) and agonistic (4-1BB and OX-40) ligands composed of short oligonucleotide (ODN) aptamers that exhibited bioactivities comparable or superior to that of antibodies. To reduce toxicity, the immunomodulatory aptamers were targeted to the tumor by conjugation to a second aptamer that bound to a product expressed on the surface of the tumor cell, the targeting aptamer, generating a bispecific aptamer conjugate analogous to bispecific antibodies. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB–binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)–binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers. The cell-free chemically synthesized ODN aptamers offer significant advantages over antibodies in terms of synthesis, cost, as well as conjugation chemistry needed to generate bispecific ligand fusions. Clin Cancer Res; 19(5); 1054–62. ©2012 AACR.