The importance of sex hormones for pre-speech development in early infancy

Geschlechtsspezifische Differenzen in Hirnorganisation und –funktion sowie deren Entstehung sind gegenwärtig Gegenstand intensiver Forschung. Neben genetischen und epigenetischen Faktoren rückt dabei der potenzielle Einfluss von Sexualhormonen auf die frühkindliche Gehirnentwicklung und Hemisphärenlateralisierung zunehmend in den Fokus. Die vorliegende Arbeit widmete sich dieser aktuellen Thematik durch die zeitgleiche Untersuchung der postnatalen Aktivierung der Hypothalamus-Hypophysen-Gonaden-Achse, auch als „Minipubertät“ bezeichnet, und frühkindlichen Sprachentwicklungsindikatoren. Sie entstand im Rahmen des Teilprojekts „Hormonstudie“ innerhalb der interdisziplinären Längsschnittstudie „GLaD-Study“ (Deutsche Sprachentwicklungsstudie) unter der Leitung von Prof. Dr. Kathleen Wermke am Zentrum für vorsprachliche Entwicklung und Entwicklungsstörungen (ZVES) der Poliklinik für Kieferorthopädie der Universität Würzburg. Erstmals wurde der Einfluss postnataler Sexualhormonkonzentrationen, d.h. der Östradiol- und Testosteronkonzentration, auf frühkindliche stimm- und sprachphysiologische Kenngrößen wie den artikulatorischen Entwicklungsstand, die Variablen der Grundfrequenz und die Lautlänge von marginalen Babbellauten im Alter von fünf Lebensmonaten analysiert. Hierfür wurden insgesamt über 2700 spontan geäußerte Vokalisationen von sechzehn Probanden (männlich: 7, weiblich: 9; Alter: 145 ± 7 Tage) nach der am ZVES vorgeschriebenen Routine mit Hilfe spezifischer Analysemethoden (CSL, PRAAT, CDAP) im Signalanalyselabor objektiv untersucht. Nach einer audiovisuellen Voranalyse unter Eliminierung sämtlicher Wein- und Schreilaute wurde ein altersadäquates, repräsentatives Lautspektrum von 911 marginalen Babbellauten ausgewählt und in melodischen und spektralen Analysen untersucht. Die daraus berechnete artikulatorische Leistung, die Melodiekomplexität, die Variablen der Grundfrequenz und die Lautlänge wurden mit den freien, bioaktiven Sexualhormonkonzentrationen sowie den Hormongesamtkonzentrationen korreliert. Eine multiple, hierarchische Regressionsanalyse identifizierte einen robusten, statistisch signifikanten positiven Zusammenhang zwischen der freien Östradiolkonzentration im Alter von vier Lebenswochen und den artikulatorischen Fähigkeiten der Säuglinge. Im Gegensatz dazu zeigte sich zwischen der logarithmierten freien Testosteronkonzentration der zwanzigsten Lebenswoche und den artikulatorischen Fähigkeiten eine statistisch signifikante, negative Korrelation. Darüberhinaus zeigten sich Korrelationen auf stimmphysiologischer Ebene. Die freie Östradiolkonzentration im Alter von zwanzig Wochen zeigte einen signifikanten, positiven Zusammenhang mit der minimalen Grundfrequenz. Die logarithmierte, freie Testosteronkonzentration zum Zeitpunkt der zwanzigsten Lebenswoche korrelierte negativ mit der Lautlänge. Diese Ergebnisse stützen die Annahme einer sprachfunktionellen Relevanz der „Minipubertät“. In einem hormonspezifischen Zeitfenster scheinen Sexualhormone die vorsprachliche Entwicklung von Säuglingen sowohl auf laryngealer als auch auf zerebraler Ebene zu beeinflussen. Dem Geschlecht per se fällt weniger Bedeutung zu als dem individuellen Verlauf der Sexualhormonkonzentrationen. Trotz zahlreicher offener Fragen bezüglich des Wirkmechanismus der Sexualhormone, könnte die postnatale Messung von freien Östradiol- bzw. Testosteronkonzentrationen zukünftig zur Identifikation potenzieller „Risikokinder“ dienen und eine frühzeitig einsetzende Sprachförderung dieser Kinder ermöglichen. Sollte sich dieser Ansatz bestätigen, wäre dies ein Durchbruch für die Frühdiagnostik von Sprachentwicklungsstörungen. Weiterführende Längsschnittstudien mit größerem Probandenkollektiv sind notwendig um die Generalisierbarkeit der Ergebnisse zu prüfen und die langfristige Auswirkung der „Minipubertät“ auf den Spracherwerb zu belegen.Gender-dependent differences in brain organisation and function as well as their development are subject of recent research. In addition to genetic and epigenetic factors, the potential influence of sex hormones on early brain development and hemispheric lateralization is gaining momentum. The present study focused on this topic by investigation of the postnatal sex hormone surge, also referred to as “minipuberty”, and properties of pre-speech babbling at the same time. It was embedded in the subproject "Hormone Study" within the interdisciplinary longitudinal study "GLaD-Study" (German Language Development Study) under the direction of Prof. Dr. Kathleen Wermke at the Center for Pre-Speech Development and Developmental Disorders (ZVES) at the Department of Orthodontics at the University of Würzburg. As far as we know, this is the first study to investigate the possible correlation between postnatal sex hormones, i.e. estradiol and testosterone, and early pre-speech characteristics like articulatory skills, fundamental frequency and duration of vocalisations in infants at the age of five months. In total, more than 2700 spontaneous vocalisations of sixteen infants (male: 7, female: 9, age: 145 ± 7 days) were analysed using specific software (CSL, PRAAT, CDAP) in the baby lab. By audiovisual pre-analysis cry utterances were excluded. An age-appropriate, representative sound spectrum of 911 comfort vocalisations remained and melodic and spectral analysis were performed. Individual articulatory skills, melody complexity, fundamental frequency parameters and duration of vocalisation were correlated to the unbound, bioactive fraction of sex hormones as well as to total hormone concentrations. A multiple, hierarchical regression approach revealed a robust, statistically significant, positive correlation between the free estradiol concentration at the age of four weeks and articulatory skills of the infants. In contrast, a statistically significant, negative correlation between the logarithmic free testosterone concentration at twenty weeks of life and articulatory skills was observed. In addition, voice parameters correlated with sex hormone concentrations. The free estradiol concentration at the age of twenty weeks showed a significant, positive correlation with the lowest fundamental frequency recorded for each infant. The logarithmic, free testosterone concentration at twenty weeks correlated negatively with the duration of the vocalisations. These findings support the assumption of the importance of sex hormones for vocal development and early communication in infants. During an early postnatal period, sex hormones seem to influence pre-speech development by changes in the viscoelastic properties of the vocal folds as well as by organisation of neuronal circuitries. Still, there are numerous open questions concerning the molecular mechanism of these hormone effects. Further studies with larger sample size and longitudinal design beyond the period of “mini-puberty” are required

The adult orthodontic patient over 40 years of age: association between periodontal bone loss, incisor irregularity, and increased orthodontic treatment need

Objectives!#!Adult orthodontic treatment, especially in patients over 40 years, is steadily increasing. One causal factor for the treatment need in this age group is periodontal breakdown. The aim of this study was to detect correlations between periodontal problems and orthodontic parameters in interdisciplinary patients.!##!Methods!#!This observational, cross-sectional study included 118 patients over 40 years (51 men/67 women; mean age, 58.03 years) classified into three groups according to periodontal breakdown (group I, controls; group II, moderate periodontitis; group III, severe periodontitis). Clinical periodontal and orthodontic parameters as well as the index of orthodontic treatment need (IOTN) were assessed and compared between the groups.!##!Results!#!A gradual deterioration of all periodontal and orthodontic parameters according to periodontal bone loss (lowest values in group I; highest values in group III) was observed. Especially groups I and III differed significantly regarding the overjet (p < 0.001) and the little indices of the maxilla (p < 0.001) and mandible (p < 0.010). The IOTN was highest in group III: 90% of the patients with severe periodontitis were classified to have moderate to very great treatment need.!##!Conclusions!#!The higher the degree of periodontal breakdown was, the more severe were overjet, overbite, irregularity of the anterior teeth, and the orthodontic treatment need.!##!Clinical relevance!#!Adult patients over 40 years represent a challenge for an orthodontic/periodontal treatment approach with high incidence of pathologic tooth migration, orthodontic treatment need, and periodontal breakdown. Therefore, this special patient collective requires a focus in clinical orthodontics and research

General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC.

The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable

Predictability of maxillary positioning: a 3D comparison of virtual and conventional orthognathic surgery planning

Background!#!Virtual surgery planning (VSP) is believed to reduce inaccuracies in maxillary positioning compared to conventional surgery planning (CSP) due to the elimination of face-bow transfer and laboratory steps. However, there is still a lack of comparative studies for the accuracy of splint-based maxillary positioning in CSP versus VSP. Therefore, the objective of this retrospective, observational study was to compare if splints produced by VSP and CSP reach postoperative outcomes within clinically acceptable limits.!##!Methods!#!The planned and actual postoperative results of 52 patients (VSP: n = 26; CSP: n = 26) with a mean age of 24.4 ± 6.2 years were investigated by three-dimensional (3D) alignment with planning software. The conventional treatment plan was digitized, so that the evaluation of both methods was performed in the same manner using the same coordinate system. Inaccuracies were measured by sagittal, vertical and transversal deviations of the upper central incisors and the inclination of the maxillary occlusal plane between the planned and achieved maxillary positions.!##!Results!#!Both methods demonstrated significant differences between the planned and actual outcome. The highest inaccuracies were observed in vertical impaction and midline correction. No significant differences between CSP and VSP were observed in any dimension. Errors in vertical and sagittal dimension intensified each other.!##!Conclusions!#!In conclusion, splint-based surgeries reached similar results regardless of the applied planning method and splint production

Two-stage palatal repair in non-syndromic CLP patients using anterior to posterior closure is associated with minimal need for secondary palatal surgery

Abstract Objective The aim of the present study was to assess the need for secondary palatal corrective surgery in a concept of palate repair that uses a protocol of anterior to posterior closure of primary palate, hard palate and soft palate. Methods A data base of patients primarily operated between 2001 and 2021 at the Craniofacial and Cleft Care Center of the University Goettingen was evaluated. Cleft lips had been repaired using Tennison Randall and Veau-Cronin procedures in conjunction with alveolar cleft repair. Cleft palate repair in CLP patients was accomplished in two steps with repair of primary palate and hard palate first using vomer flaps at the age of 10–12 months and subsequent soft palate closure using Veau/two-flap procedures 3 months later. Isolated cleft palate repair was performed in a one-stage operation using Veau/two-flap procedures. Data on age, sex, type of cleft, date and type of surgery, occurrence and location of oronasal fistulae, date and type of secondary surgery performed for correction of oronasal fistula (ONF)and / or Velophyaryngeal Insufficiency (VPI) were extracted. The rate of skeletal corrective surgery was registered as a proxy for surgery induced facial growth disturbance. Results In the 195 patients with non-syndromic complete CLP evaluated, a total number of 446 operations had been performed for repair of alveolar cleft and cleft palate repair (Veau I through IV). In 1 patient (0,5%), an ONF occurred requiring secondary repair. Moreover, secondary surgery for correction of VPI was required in 1 patient (0,5%) resulting in an overall rate of 1% of secondary palatal surgery. Skeletal corrective surgery was indicated in 6 patients (19,3%) with complete CLP in the age group of 15 – 22 years (n = 31). Conclusions The presented data have shown that two-step sequential cleft palate closure of primary palate and hard palate first followed by soft palate closure has been associated with minimal rate of secondary corrective surgery for ONF and VPI at a relatively low need for surgical skeletal correction

Reliability of landmark identification for analysis of the temporomandibular joint in real-time MRI

Abstract Background Real-time magnetic resonance imaging (rtMRI) is essential for diagnosing and comprehending temporomandibular joint (TMJ) movements. Current methods for tracking and analysis require manual landmark placement on each acquisition frame. Therefore, our study aimed to assess the inter- and intra-rater reliability of placing cephalometric landmarks in frames from a dynamic real-time TMJ MRI. Material and methods Four real-time MRIs of the right TMJ were taken during mandibular movement at ten frames per second. Seven dentists identified ten landmarks on two frames (intercuspal position—ICP—and maximum mouth opening—MMO) twice at a two-week interval, yielding 112 tracings. Six typical cephalometric measurements (angles and distances) were derived from these landmarks. The reliabilities of landmarks and measurements were evaluated using distance-based (dbICC), linear mixed effect model intraclass correlation (lmeICC), and standard ICC. Results The average inter-rater reliability for the landmarks stood at 0.92 (dbICC) and 0.93 (lmeICC). The intra-rater reliability scores were 0.97 and 0.98. Over 80% of the landmarks showed an ICC greater than 0.98 (inter-rater) and over 0.99 (intra-rater). The lowest landmark ICC was observed for the orbitale and the oblique ridge of the mandibular ramus. However, the cephalometric angle and distance measurements derived from these landmarks showed only moderate to good reliability, whereas the reliability in the frames with ICP was better than those with MMO. Measurements performed in the ICP frame were more reliable than measurements in the MMO frame. Conclusion While dentists reliably localize isolated landmarks in real-time MRIs, the cephalometric measurements derived from them remain inconsistent. The better results in ICP than MMO are probably due to a more familiar jaw position. The higher error rate of the TMJ measurements in MMO could be associated with a lack of training in real-time MRI analysis in dentistry

Orthodontic incisor decompensation in orthognathic therapy—success and efficiency in three dimensions

Objectives!#!Sufficient dental decompensation is crucial for treatment success in combined orthodontic-surgical treatment. The study's objective was to determine the treatment success and efficiency in sagittal, vertical, and transversal decompensation.!##!Methods!#!This longitudinal, observational study enrolled 52 adult patients, who underwent orthodontic-surgical treatment. Incisor inclinations and positions as well as skeletal changes were assessed pre-treatment (T1), pre-surgical (T2), and post-surgical (T3) by lateral cephalograms and CBCT scans.!##!Results!#!Incisor decompensation was insufficient in all three dimensions. Sagittal: treatment efficiency did not differ between class II and III patients. Vertical: patients with open bite demonstrated pre-surgical bite deepening and insufficient surgical reduction of the maxillomandibular plane angle. Transversal: Dental midline deviations were not adapted to the skeletal asymmetry so that menton deviations were not properly corrected.!##!Conclusions!#!Incisor decompensation was not as successful as requested in all three dimensions and the treatment ideal was seldom achieved.!##!Clinical relevance!#!To improve the skeletal outcome, the orthodontist has to treat the patient with the desired surgical movements in mind and should critically evaluate the pre-surgical incisor decompensation before referral to the surgical team

TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis-

Abstract Background Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement. Patients/Methods 46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height. Results Patients were divided into groups (Group I – slightly affected, n = 36; Billiau severity 0–2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II – severely affected, N = 10; Billiau severity 3–4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I. Conclusions Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results