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

Individual dental and skeletal age assessment according to Demirjian and Baccetti: Updated norm values for Central-European patients

Purpose Chronological age often differs from dental and skeletal age. With orthopantomograms and lateral cephalograms, dental and skeletal development can be determined according to the methods published by Demirjian et al. and Baccetti et al. However, gender and skeletal class as possible confounders were frequently not considered and available norm values are not up-to-date. This retrospective cross-sectional study thus aimed to evaluate effects of skeletal class and gender on dental and skeletal age of growing patients and to generate updated norm values for contemporary Central-European patients. Methods A total of 551 patients were included in the dental and 733 in the skeletal age assessment, respectively. Dental analysis was based on tooth mineralisation stages in orthopantomograms (Demirjian) and skeletal age was defined by cervical vertebrae maturation stages (CVMS) in lateral cephalograms (Baccetti). Skeletal class was determined by the individualised ANB angle of Panagiotidis/Witt. With nonlinear regression analysis a formula for determining dental age was established. Effects of gender and skeletal class were evaluated and updated norm values generated. Results Inter- and intrarater reliability tests revealed at least substantial measurement concordance for tooth mineralisation and CVMS. Demirjian stages and CVMS significantly depended on gender with girls developing earlier. Skeletal class significantly affected skeletal age only, but without clinical relevance. Updated norm values for dental age differed significantly from the original values of Demirjian and the values for skeletal age differed from those published by Baccetti. Conclusion Optimised norms, separated by gender, increase precision in determining individual dental and skeletal age during orthodontic treatment planning. Further studies analysing the effect of skeletal class on dental and skeletal development are needed

Validation of a mathematical–geometrical model to calculate the length of an individual anterior arch

Purpose For resolving anterior dental crowding or spacing, it is of key interest in personalised orthodontic diagnostics and treatment planning to predict the extent of space gained or lost in the anterior dental arch by changing incisor inclination or position. To facilitate the determination of anterior arch length (AL) and to predict its alterations following tooth movements, a mathematical–geometrical model, based on a third-degree parabola, was established. The aim of this study was to validate this model and assess its diagnostic precision. Methods This retrospective diagnostic study evaluated 50 randomly chosen dental casts taken before (T0) and after (T1) orthodontic treatment with fixed appliances. Plaster models were digitally photographed, allowing two-dimensional digital measurements of arch width, depth and length. A computer programme based on the mathematical–geometrical model to be validated was created to calculate AL for any given arch width and depth. Mean differences and correlation coefficients as well as Bland–Altman plots were used to compare the measured and the calculated (predicted) AL, evaluating the precision of the model. Results Inter- and intrarater reliability tests showed reliable measurements of arch width, depth and length. Measured and calculated (predicted) AL revealed high concordance according to concordance correlation coefficient (CCC), intraclass correlation coefficient (ICC), and Bland–Altman analyses and negligible differences between the mean values. Conclusions The mathematical–geometrical model calculated anterior AL without significant difference to the measured AL, indicating its validity. The model can thus be used clinically for predicting alterations of AL following therapeutic changes of incisor inclination/position

Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

BACKGROUND: Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. METHODS: Mice were held either at normoxia (N; 21% O(2)) or at hypobaric hypoxia (H; 0.5 atm; ~10% O(2)). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy. RESULTS: Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H ± RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined. CONCLUSION: Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension

Comparative treatment outcomes after bilateral extractions of maxillary second molars or first premolars in patients with class II malocclusion: a retrospective study

Background This retrospective cohort study aimed to compare treatment results between bilateral extraction of upper second molars (M2) and first premolars (P1) in terms of treatment timing, cephalometry, upper third molar alignment and relapse in the long-term. Methods Fifty-three consecutively treated Caucasian patients with a brachyfacial pattern, skeletal class I and dental class II requiring extraction in the maxilla due to crowding were retrospectively divided into group I (M2 extracted; N = 31) and II (P1 extracted; N = 22). Fixed appliances were inserted after extraction and after distalisation of the first molars in group I. Post-treatment lateral cephalograms were digitally analysed and compared between groups. Six to seven years later relapse and success of upper third molar alignment were clinically evaluated as well as orthodontic treatment duration, pre-treatment age and gender recorded. Results After debonding patients with second molar extraction showed significantly smaller values for the Wits-appraisal, but higher values for index and facial axis. Extracting first premolars caused significantly more retroinclination/−position of anterior teeth and an increased profile concavity, more relapse and less successful alignment of upper third molars. Orthodontic treatment duration, pre-treatment age and gender were not significantly different between groups. Conclusions Bilateral extraction of upper first premolars or second molars may solve dental crowding in skeletal class I dental class II patients with a brachyfacial growth pattern. Upper second molar extraction seems to affect maxillary third molar alignment, long-term stability and dental and soft-tissue cephalometric parameters positively, but no intervention proved to be clearly superior

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

Background: Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILIassociated lung permeability in vivo. Methodology/Principal Findings: Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxi

Impact of Leptin on the Expression Profile of Macrophages during Mechanical Strain In Vitro

Childhood obesity is a growing problem in industrial societies and associated with increased leptin levels in serum and salvia. Orthodontic treatment provokes pressure and tension zones within the periodontal ligament, where, in addition to fibroblasts, macrophages are exposed to these mechanical loadings. Given the increasing number of orthodontic patients with these conditions, insights into the effects of elevated leptin levels on the expression profile of macrophages during mechanical strain are of clinical interest. Therefore, the aim of this in vitro study was to assess the influence of leptin on the expression profile of macrophages during simulated orthodontic treatment. RAW264.7 macrophages were incubated with leptin and lipopolysaccharides (LPS) from Porphyromonas gingivalis (P. gingivalis) or with leptin and different types of mechanical strain (tensile, compressive strain). Expression of inflammatory mediators including tumor necrosis factor (TNF), Interleukin-1-B (IL1B), IL6, and prostaglandin endoperoxide synthase (PTGS2) was assessed by RT-qPCR, ELISAs, and immunoblot. Without additional mechanical loading, leptin increased Tnf, Il1b, Il6, and Ptgs2 mRNA in RAW264.7 macrophages by itself and after stimulation with LPS. However, in combination with tensile or compressive strain, leptin reduced the expression and secretion of these inflammatory factors. By itself and in combination with LPS from P. gingivalis, leptin has a pro-inflammatory effect. Both tensile and compressive strain lead to increased expression of inflammatory genes. In contrast to its effect under control conditions or after LPS treatment, leptin showed an anti-inflammatory phenotype after mechanical stres

protection by adrenomedullin

Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia. We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation. In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1-3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p<0.01; prevention of pulmonary restriction) and against VILI- induced liver and gut injury in pneumonia (91% reduction of AST levels p<0.05, 96% reduction of alanine aminotransaminase (ALT) levels p<0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut). MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia

Impact of Mechanical Strain and Nicotinamide on RUNX2-Deficient Osteoblast Mimicking Cleidocranial Dysplasia

Cleidocranial dysplasia (CCD) is a rare genetic defect caused by a heterozygous mutation of runt-related transcription factor 2 (RUNX2), which is important for osteoblast and skeletal development. RUNX2-deficiency causes extra- and intra-oral malformations that often require orthodontic treatment. Nicotinamide (NAM) affects bone remodelling processes. As these are crucial for orthodontic therapy, NAM could improve orthodontic treatment in CCD patients. This study investigates the effect of NAM in control and RUNX2-deficient osteoblasts under mechanical strain mimicking orthodontic treatment. First, the optimal NAM concentration and the differences in the expression profile of control and RUNX2-deficient osteoblasts were determined. Subsequently, osteoblasts were exposed to tensile and compressive strain with and without NAM, and the expression of genes critically involved in bone remodelling was investigated. NAM increased the expression of bone remodelling genes. RUNX2-deficient osteoblasts expressed more receptor activator of NFkB ligand (RANKL) and interleukin-6 (IL6), but less colony-stimulating factor-1 (CSF1). Most of the positive effects of NAM on bone remodelling genes were impaired by mechanical loading. In conclusion, NAM stimulated osteoblast differentiation by increasing the expression of RUNX2 and regulated the expression of osteoclastogenic factors. However, the positive effects of NAM on bone metabolism were impaired by mechanical loading and RUNX2 deficiency