Crystal Structure of Human TWEAK in Complex with the Fab Fragment of a Neutralizing Antibody Reveals Insights into Receptor Binding.

The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases

Psychological profile and self-administered relaxation in patients with craniofacial pain: a prospective in-office study

Introduction: The objective of this study was to evaluate the psychological profile of craniofacial pain sufferers and the impact of patient subtype classification on the short-time effectiveness of a self-administered relaxation training. Methods: One hundred unselected in-office patients (67% females) suffering from chronic facial pain and/or headache with the presumptive diagnose of temporo-mandibular disorder (TMD) completed a questionnaire battery comprising craniofacial pain perception, somatic complaints, irrational beliefs, and pain behavior and were classified into subtypes using cluster analysis. They underwent a self-administered progressive relaxation training and were re-evaluated for pain perception after 3 months. Results: Pain was mild to moderate in the majority of patients. Symptom domains comprised parafunctional activities, temporo-mandibular pain and dysfunction, fronto-temporal headache, head/neck and neck/back pain. Three patient subtypes were identified regarding symptom/dysfunction level: (i) low burden (mild/moderate), (ii) psychosocial dysfunction (moderate/high), (iii) adaptive coping (moderate/mild). Self-rated adherence to the recommended relaxation training was moderate throughout the sample, but self-rated relief was significantly different between clusters. At follow-up, pain intensity was significantly decreased in all patients, whereas pain-related interference was improved only in dysfunctional and adaptive patients. Improvement of symptom domains varied between clusters and was most comprehensive in adaptive patients. Conclusions: In conclusion, craniofacial pain sufferers can be divided in meaningful subtypes based on their pain perception, irrational beliefs, and pain behaviour. A self-administered relaxation training generally yielded positive effects on pain perception, however the benefit may be greater in patients with more marked symptom impact (both dysfunctional and adaptive).<br

Mandibular prognathism caused by acromegaly – a surgical orthodontic case

A 22-year-old man presented for orthodontic surgery because of mandibular prognathism. Clinical symptoms suggested acromegaly, and diagnosis was verified by an endocrinologist as well as by radiograph. Bilateral mandibular prognathism often represents the first and most striking physical characteristic of acromegaly; usually, it is also the main reason why patients seek help from orthodontists or maxillo-facial surgeons. This case report recapitulates the clinical and histopathological findings in pituitary growth hormone (GH) adenomas and emphasises their importance in surgical orthodontic planning. Mandibular prognatism, macroglossia and abnormal growth of hands and feet represent strong indicators for the diagnosis of acromegaly. This disease and its complications not only affect the entire body but increase mortality if the pituitary gland tumour remains untreated

Housekeeping gene validation for RT-qPCR studies on synovial fibroblasts derived from healthy and osteoarthritic patients with focus on mechanical loading

Selection of appropriate housekeeping genes is essential for the validity of data normalization in reverse transcription quantitative PCR (RT-qPCR). Synovial fibroblasts (SF) play a mediating role in the development and progression of osteoarthritis (OA) pathogenesis, but there is no information on reliable housekeeping genes available. Therefore the goal of this study was to identify a set of reliable housekeeping genes suitable for studies of mechanical loading on SF from healthy and OA patients. Nine genes were evaluated towards expression stability and ranked according their relative stability determined by four different mathematical procedures (geNorm, NormFinder, BestKeeper and comparative ΔCq). We observed that RPLP0 (ribosomal protein, large, P0) and EEF1A1 (eukaryotic translation elongation factor 1 alpha 1) turned out to be the genes with the most stable expression in SF from non-OA or OA patients treated with or without mechanical loading. According to geNorm two genes are sufficient for normalization throughout. Expression of one tested target gene varied considerably, if normalized to different candidate housekeeping genes. Our study provides a tool for accurate and valid housekeeping gene selection in gene expression experiments on SF from healthy and OA patients with and without mechanical loading in consistent with the MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines and additionally demonstrates the impact of proper housekeeping gene selection on the expression of the gene of interest

Successful treatment of multiple bilateral impactions - a case report

Background: Successful treatment of patients with multiple bilateral impactions can be an orthodontic challenge, but few reports on treatment planning and execution exist. Case presentation: In this case report, we describe the successful orthodontic treatment of a 16.3-year old female patient without systemic or genetic disease with initially nine persisting deciduous and nine impacted permanent teeth with complete root formation and closed apices in both jaws. After extraction of the deciduous and surgical exposure of the impacted permanent teeth, the Easy-Way-Coil (TM) system was used in conjunction with a skeletal anchorage (maxilla, BENEfit (TM) system) to guide the eruption of all impacted teeth. After a total treatment time of only 22.8 months all impacted teeth could be aligned successfully and a stable and functional class I occlusion was achieved. In addition, there were no adverse treatment effects such as anchorage loss, root resorptions or periodontal problems and an esthetic result could be achieved. Conclusions: The presented treatment approach thus proved to be highly effective in cases with multiple bilateral impactions with minimal side effects and considerably reduced treatment time

Association of dentoskeletal morphology with incisor inclination in angle class II patients: a retrospective cephalometric study

Introduction: The purpose of this study was to identify possible dentoskeletal parameters associated with variation of anterior tooth inclination in Angle Class II subdivisions. Methods: Pre-treatment lateral radiographs of 144 Class II patients (68 males, 76 females) aged 9 to 17 years were classified for upper incisor inclination into three groups (proclined, normally inclined, retroclined) homogeneous for gender and skeletal jaw relationship. The effect of age on the 22 cephalometric variables was controlled by covariance analysis. Results: Multivariate analysis of the cephalometric parameters indicated significant inter-group differences. Systematic associations with incisor inclination were revealed using rank correlation: Lower incisor proclination, Wits appraisal and gonial angle significantly decreased (0.04 ≥ p ≥ 0.002), while intercisal angle, mandibular total and corpus length and nasolabial angle increased (0.04 ≥ p ≥ 0.001) with decreasing incisor proclination. Conclusions: Clear-cut classification criteria and control of confounding effects may clarify conflicting previous findings on dentoskeletal differences between Class II subdivisions in the mixed dentition. Only minor dentoskeletal differences appear to be associated with incisor inclination. The increased interincisal and nasolabial angle in Class II division 2 subjects are due to reclination of both upper and lower incisors. Jaw positions and chin prominence are not significantly different between the subdivisions. However, Wits appraisal is decreased in Class II division 2. The increased mandibular length observed in Class II division 2 requires further scrutinization.<br

Ideal treatment timing of orthodontic anomalies—a German clinical S3 practice guideline

Purpose Ideal treatment timing in orthodontics is controversially discussed depending on the type and extent of the dysgnathia and malocclusion present, especially with regard to efficiency, patient burden and treatment efforts of early compared to regular or late treatment. This German clinical practice guideline aims to clarify, at which time points an orthodontic anomaly can be effectively treated and how treatment efficiency differs depending on treatment timing. Methods A systematic literature search was performed in various guideline databases and databases PROSPERO, MEDLINE (PubMed), Cochrane Library, Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform according to a predefined PICO (Population, Intervention, Comparison and Outcomes with added qualitative search terms) search algorithm and strategy. Appraisal of scientific evidence of the individual studies checked for eligibility was carried out according to SIGN (Scottish Intercollegiate Guidelines Network), AMSTAR II (Assessing the Methodological Quality of Systemic Reviews), and AXIS (Appraisal Tool to Assess the Quality of Cross-sectional Studies) tools. Only controlled studies with a high, acceptable or moderate quality (and thus an acceptable risk of bias) were considered. Results A total of 309 studies of over 11,000 sources screened were identified to be eligible for inclusion and critically appraised for study quality and risk-of-bias. No relevant guidelines relating to the aims of the present guideline were found. Elected delegates of in total 21 German scientific societies and organizations agreed upon a total of 19 evidence-based statements and recommendations based on a nominal consensus process. Conclusions Although most malocclusions can be effectively treated both in the early, late mixed, and permanent dentition, evidence suggests that therapy of a pronounced skeletal or dental class II anomaly can be started early to reduce the risk of dental anterior tooth trauma, whereas in a moderate class II anomaly, therapy can preferably be carried out before or during the pubertal growth peak. Therapy of a skeletal or dental class III anomaly should be started early, as this also reduces the need for later surgery to correct the anomaly. The treatment of a pronounced skeletal or dental transverse anomaly should be started early in the upper jaw in order to utilize the high adaptivity of the maxillary structures in young patients

Floating norms for individualising the ANB angle and the WITS appraisal in orthodontic cephalometric analysis based on guiding variables

Purpose The sagittal skeletal relationship of maxilla and mandible (skeletal class) can generally be determined via lateral cephalograms (ANB angle or Wits appraisal) by comparing measurements to empirical norms based on the respective population mean. However, values differing from these empirical norms also enable a therapeutically desired, normal class I occlusion depending on individual craniofacial pattern, thus requiring floating norms based on guiding variables. As available regression equations consider only few predictor variables and are not up-to-date regarding a contemporary patient collective, the aim of this study was to establish improved and extended regression equations for individualising the ANB angle and Wits appraisal. Methods This retrospective, cross-sectional multicentre study was based on 71 Caucasian male and female subjects of any age with normal dental occlusion. We cephalometrically analysed digitised pretreatment lateral radiographs and performed multiple linear regression analyses to identify suitable skeletal predictor variables for individualising the ANB angle and Wits appraisal. Results Inter- and intrarater reliability tests showed mostly perfect measurement concordance. Both original regression equations by Panagiotidis/Witt and Järvinen could be updated for a contemporary population with new regression coefficients. The equation for individualising the ANB could be further optimised in its prediction reliability by adding the skeletal predictor variables NL-NSL, NSBa, facial axis (Ricketts) and index (Hasund), whereas the recalculated Wits equation could not be further improved by additional guiding variables. Conclusions The improved regression formulae for individualising the ANB angle and Wits appraisal should help to improve the assessment of sagittal skeletal class in clinical orthodontic practice

Der Stellenwert von Leitlinien in der Zahnheilkunde und in der zahnmedizinischen Ausbildung

Im Rahmen von qualitätssichernden Maßnahmen spielen evidenzbasierte Handlungsempfehlungen in der Zahn- und Humanmedizin eine zunehmend bedeutendere Rolle. Die von Expertengremien methodenkritisch evaluierten Wissenschaftserkenntnisse werden dabei zu einfach verständlichen Leitlinien zusammengefasst. Entsprechend der Konsens- und Evidenzgewichtung des Erstellungsprozesses werden die Leitlinien in verschiedenen Entwicklungsstufen qualitativ bewertet. Seit der Gründung in den 1960er-Jahren erfolgen die Publikation von Leitlinien und die Koordination der Leitlinienerstellung durch die Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Zum aktuellen Zeitpunkt sind 44 zahnmedizinische Leitlinien verfügbar, die zum größten Teil mit der höchsten Entwicklungsstufe S3 bewertet sind. Dadurch sind Handlungskorridore für eine Vielzahl von Behandlungsmaßnahmen für zahnärztliches Personal der universitären Standorte und Praxen definiert, deren Implementierung in den klinischen Alltag wünschenswert ist. Mangelnde Akzeptanz von Leitlinien und ein hoher Ressourcenaufwand bei deren Erstellung sind wesentliche Limitationen im Ausbau der evidenzbasierten Zahnmedizin. Diese könnten durch Einführung der wissenschaftlichen Grundausbildung innerhalb des Zahnmedizinstudiums und verstärkte Förderung des wissenschaftlichen Nachwuchses überwunden werden, um hohe Behandlungsqualität und Ökonomie in der Zahnheilkunde auch zukünftig zu gewährleisten. Leitlinien können die zahnmedizinische Ausbildung unterstützen, indem sie Studierenden wissenschaftlich abgesicherte Handlungsschablonen bieten und den Lehrenden helfen, den hohen Anforderungen im Rahmen von praktischen Kursen gerecht zu werden