Two versus three magnesium screws for osteosynthesis of mandibular condylar head fractures: a finite element analysis.

OBJECTIVES: Previous finite element analyses (FEA) have shown promising results for using two titanium screws in treating mandibular condylar head fractures but limited mechanical stability of a two-screw osteosynthesis with magnesium screws. Given the potential benefits of magnesium screws in terms of biocompatibility and resorption, this study aimed to compare two- and three-screw osteosynthesis solutions for a right condylar head fracture (AO CMF type p) with magnesium screws with a FEA. MATERIALS AND METHODS: A previously validated finite element model simulating a 350 N bite on the contralateral molars was used to analyze von Mises stress within the screws, fragment deformation, and fracture displacement. All screws were modeled with uniform geometric specifications mirroring the design of Medartis MODUS® Mandible Hexadrive cortical screws. RESULTS: The three-screw configuration demonstrated lower values for all three parameters compared to the two-screw scenario. There was a 30% reduction in maximum von Mises stress for the top screw and a 46% reduction for the bottom screw. CONCLUSIONS: Fracture treatment with three magnesium screws could be a valuable and sufficiently stable alternative to the established treatment with titanium screws. Further studies on screw geometry could help improve material stability under mechanical loading, enhancing the performance of magnesium screws in clinical applications. CLINICAL RELEVANCE: The use of magnesium screws for osteosynthesis of mandibular condylar head fractures offers the benefit of reducing the need for second surgery for hardware removal. Clinical data is needed to determine whether the advantages of resorbable screw materials outweigh potential drawbacks in condylar head fracture treatment.

Interdisciplinary strategies for diagnosis and treatment of trigeminal neuralgia.

Temporary, sudden, shooting and recurrent unilateral facial pain in the supply area of one or more trigeminal nerve branches characterises trigeminal neuralgia. Innocuous stimuli trigger the pain, e.g. chewing, speaking or brushing teeth. In some patients, paroxysms superimpose on continuous pain. In aetiological terms, idiopathic, classic (due to neurovascular compression) and secondary trigeminal neuralgia (e.g. due to multiple sclerosis, brainstem ischaemia and space-occupying lesions) are defined. Many drugs may be efficacious, with carbamazepine being first-choice therapy. However, non-pharmacological and invasive procedures may also help. To reach the correct diagnosis and determine the best therapeutic measures, adequate pain characterisation and interdisciplinary collaboration are essential. We hereby present our experience of an interdisciplinary approach for the diagnosis and treatment of trigeminal neuralgia.

Two-screw osteosynthesis of the mandibular condylar head with different screw materials: a finite element analysis.

This study compared the biomechanical behavior of titanium, magnesium, and polylactic acid screws for two-screw osteosynthesis of mandibular condylar head fractures using finite element analysis. Von Mises stress distribution, fracture displacement, and fragment deformation were evaluated. Titanium screws performed the best in terms of carrying the highest load, resulting in the least fracture displacement and fragment deformation. Magnesium screws showed intermediate results, while PLA screws were found to be unsuitable with stress values exceeding their tensile strength. These findings suggest that magnesium alloys could be considered a suitable alternative to titanium screws in mandibular condylar head osteosynthesis.

Two-versus three-screw osteosynthesis of the mandibular condylar head: A finite element analysis.

Titanium screws are commonly used for osteosynthesis of mandibular condylar head fractures. Evidence suggests that the insertion of three screws may result in better fracture stability. Two screws only, on the other hand, could reduce adverse effects, mainly bone resorption. This study aimed to investigate the biomechanical differences in mandibular condylar head osteosynthesis with two versus three titanium screws using finite element analysis. A finite element model of the mandible with a right type P condylar head fracture fixed with two or three titanium screws was analyzed in ANSYS Mechanical. The geometry of the model assembly was constructed in ANSYS Spaceclaim. Biomechanical load boundary conditions were obtained from a validated musculoskeletal model in AnyBody Modeling System™. The preprocessing of the finite element model and mapping of the obtained boundary conditions was done in docq VIT. Fracture displacement, fragment deformation, von Mises stress distribution, and reaction forces within the screws were evaluated in ANSYS for three different loading scenarios. Finite element analysis showed similar results when comparing osteosynthesis with two versus three titanium screws for all three loading scenarios. Contralateral molar loading resulted in the highest stress on both the fracture and the screws with the maximum von Mises stress being found at the condylar neck. Stress concentration within the screws was found in the fracture gap and was higher in the lateral fragment. In all scenarios, maximum von Mises stress values were smaller when forces were distributed among three screws. However, stability was also adequate when two screws were used. Mandibular condylar head osteosynthesis with two titanium screws appears to provide sufficient fracture stability. Further clinical studies are needed to clarify the implications of these results.

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions.

Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model.

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.

Gross tumour volume variations in primary non-small-cell lung cancer during the course of treatment with stereotactic body radiation therapy.

INTRODUCTION: We aim to quantify the variations in the gross tumour volume (GTV) during a course of stereotactic body radiotherapy (SBRT) and determine its impact on dosimetric coverage of the GTV. METHODS: The GTVs and dose coverage for 14 patients with 16 primary non-small-cell lung tumours treated with SBRT were investigated. Initial GTVs were calculated from treatment planning CT scans. The prescribed doses ranged from 48 to 60 Gy in three to five fractions. Before each treatment, patients underwent a CBCT scan. For each CBCT scan, the GTV and the dose received by the GTV were determined and followed during the course of therapy. RESULTS: There was considerable variation in the measured GTVs during the course of therapy. Increases of up to 63.3% of volume measured by initial CBCT were detected during the first few fractions, after which GTV tended to decrease. Dose coverage (V95) for any given fraction deviated no more than 5% from optimised coverage obtained in the initial treatment plan. In the long term, all patients with follow-up scans demonstrated tumour shrinkage with no radiographic evidence of tumour recurrence. CONCLUSION: GTV, as evaluated in this study, demonstrates an initial increase in volume followed by a subsequent decrease. This volume change needs to be considered in the design of treatment plans and assignment of treatment margins.

The relative timing of syntactic and semantic processes in sentence comprehension.

The functional primacy of syntactic over semantic processes was put to test in an auditory event-related brain potentials study using sentences in which the final words were semantically and/or syntactically incongruent with the prior context. Crucially, these words encoded the syntactically relevant word category information in the suffix, available only after the word stem which carried the semantic information. Semantic violations elicited an N400 and syntactic violations a biphasic LAN-P600 pattern. Words that were semantically and syntactically incongruent with the context evoked a biphasic LAN-P600 ERP pattern, but no N400. The similarity of the ERP pattern for the pure syntactic and the double violation condition provides strong evidence for a functional primacy of initial syntactic over lexical-semantic processes.

Dissociable brain mechanisms for inhibitory control: effects of interference content and working memory capacity.

In this study, event-related fMRI was used to examine whether the resolution of interference arising from two different information contents activates the same or different neuronal circuitries. In addition, we examined the extent to which these inhibitory control mechanisms are modulated by individual differences in working memory capacity. Two groups of participants with high and low working memory capacity [high span (HS) and low span (LS) participants, respectively] performed two versions of an item recognition task with familiar letters and abstract objects as stimulus materials. Interference costs were examined by means of the recent negative probe technique with otherwise identical testing conditions across both tasks. While the behavioral interference costs were of similar magnitude in both tasks, the underlying brain activation pattern differed between tasks: The object task interference-effects (higher activation in interference trials than in control trials) were restricted to the anterior intraparietal sulcus (IPS). Interference effects for familiar letters were obtained in the anterior IPS, the left postero-ventral and the right dorsolateral prefrontal cortex (PFC) as well as the precuneus. As the letters were more discernible than the objects, the results suggest that the critical feature for PFC and precuneus involvement in interference resolution is the saliency of stimulus-response mappings. The interference effects in the letter task were modulated by working memory capacity: LS participants showed enhanced activation for interference trials only, whereas for HS participants, who showed better performance and also lower interference costs in the letter task, the above-mentioned neuronal circuitry was activated for interference and control trials, thereby attenuating the interference effects. The latter results support the view that HS individuals allocate more attentional resources for the maintenance of task goals in the face of interfering information from preceding trials with familiar stimulus materials.

[Effects of shaft length of finger joint prostheses on tension distribution in the bone]. / Auswirkung der Schaftlänge von Fingergelenkprothesen auf die Spannungsverteilung im Knochen.

In order to investigate the influence of stem length in finger joint prostheses on stress in the surrounding bone area, finite element (FEM) calculations of finger bones before and after prosthetic replacement of metacarpophalangeal joints with cementless implants of different stem length were performed. CT scans of the metacarpal bone and proximal phalanx before and after implantation of a prototype of a noncemented semiconstrained implant for the MP joint, which has been developed to replace metacarpophalangeal joints destroyed by rheumatoid arthritis, were analysed. The FEM calculations showed comparatively decreased differences of the von-Mises stress after implantation of intramedullary stems reaching the middle of the diaphysis. At the metaphysis of the metacarpal head we found an increase of the von-Mises stress of 1.3 MPa (Mega Pascal = 10(6) Pa), an increase of 18.9 MPa around the shortest prosthesis and a decrease of 21.4 MPa around the prosthesis with the longest stem.

Differentiating ERAN and MMN: an ERP study.

In the present study, the early right-anterior negativity (ERAN) elicited by harmonically inappropriate chords during listening to music was compared to the frequency mismatch negativity (MMN) and the abstract-feature MMN. Results revealed that the amplitude of the ERAN, in contrast to the MMN, is specifically dependent on the degree of harmonic appropriateness. Thus, the ERAN is correlated with the cognitive processing of complex rule-based information, i.e. with the application of music-syntactic rules. Moreover, results showed that the ERAN, compared to the abstract-feature MMN, had both a longer latency, and a larger amplitude. The combined findings indicate that ERAN and MMN reflect different mechanisms of pre-attentive irregularity detection, and that, although both components have several features in common, the ERAN does not easily fit into the classical MMN framework. The present ERPs thus provide evidence for a differentiation of cognitive processes underlying the fast and pre-attentive processing of auditory information.

Musical syntax is processed in Broca's area: an MEG study.

The present experiment was designed to localize the neural substrates that process music-syntactic incongruities, using magnetoencephalography (MEG). Electrically, such processing has been proposed to be indicated by early right-anterior negativity (ERAN), which is elicited by harmonically inappropriate chords occurring within a major-minor tonal context. In the present experiment, such chords elicited an early effect, taken as the magnetic equivalent of the ERAN (termed mERAN). The source of mERAN activity was localized in Broca's area and its right-hemisphere homologue, areas involved in syntactic analysis during auditory language comprehension. We find that these areas are also responsible for an analysis of incoming harmonic sequences, indicating that these regions process syntactic information that is less language-specific than previously believed.

Working memory constraints on syntactic processing: an electrophysiological investigation.

Event-related potentials (ERPs) and reaction times (RTs) were used to study how the processing of sentences with morphosyntactic violations is constrained by working memory (WM) capacity. The available WM capacity was varied by three orthogonal manipulations: (1) syntactic complexity; (2) additional WM load; and (3) verbal WM span. The processing of the morphosyntactic violations was reflected in longer RTs in ungrammatical compared with grammatical sentences, and in an anterior negativity and a centroparietal positivity in the ERPs. While the behavioral grammaticality effect was not influenced by the WM manipulations, the ERP effects were. The amplitude of the anterior negativity was modulated by the combination of complexity and load, and by WM span. The onset of the centroparietal positivity was delayed in the high-load condition, and for the low-span group. ERPs over the course of the sentences showed a frontal negative slow wave under high WM load, largest for the low-span group. The finding that online syntactic processing is related to WM span and to additional WM load does not support the theory that there is a WM capacity specific for syntactic processing.

The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria.

A mechanism of Ca(2+) uptake, capable of sequestering significant amounts of Ca(2+) from cytosolic Ca(2+) pulses, has previously been identified in liver mitochondria. This mechanism, the Rapid Mode of Ca(2+) uptake (RaM), was shown to sequester Ca(2+) very rapidly at the beginning of each pulse in a sequence [Sparagna et al. (1995) J. Biol. Chem. 270, 27510-27515]. The existence and properties of RaM in heart mitochondria, however, are unknown and are the basis for this study. We show that RaM functions in heart mitochondria with some of the characteristics of RaM in liver, but its activation and inhibition are quite different. It is feasible that these differences represent different physiological adaptations in these two tissues. In both tissues, RaM is highly conductive at the beginning of a Ca(2+) pulse, but is inhibited by the rising [Ca(2+)] of the pulse itself. In heart mitochondria, the time required at low [Ca(2+)] to reestablish high Ca(2+) conductivity via RaM i.e. the 'resetting time' of RaM is much longer than in liver. RaM in liver mitochondria is strongly activated by spermine, activated by ATP or GTP and unaffected by ADP and AMP. In heart, RaM is activated much less strongly by spermine and unaffected by ATP or GTP. RaM in heart is strongly inhibited by AMP and has a biphasic response to ADP; it is activated at low concentrations and inhibited at high concentrations. Finally, an hypothesis consistent with the data and characteristics of liver and heart is presented to explain how RaM may function to control the rate of oxidative phosphorylation in each tissue. Under this hypothesis, RaM functions to create a brief, high free Ca(2+) concentration inside mitochondria which may activate intramitochondrial metabolic reactions with relatively small amounts of Ca(2+) uptake. This hypothesis is consistent with the view that intramitochondrial [Ca(2+)] may be used to control the rate of ADP phosphorylation in such a way as to minimize the probability of activating the Ca(2+)-induced mitochondrial membrane permeability transition (MPT).

Measurements of intracellular free calcium concentration in biological systems.

Intracellular calcium plays a role in signaling and as a second messenger in many types of cells and its concentration is closely regulated in cells. Two techniques for measuring intracellular free calcium are using fluorescent ratiometric and nonratiometric probes are described in this unit: fluorescent spectroscopy to measure calcium concentrations in a suspension of cells and fluorescent digital imaging microscopy (FDIM) to measure calcium concentrations in plated cells.

Release of Ca2+ from mitochondria via the saturable mechanisms and the permeability transition.

The literature, reviewed in the previous article, supports three physiological roles for sequestration of calcium by mitochondria: 1) control of the rate of ATP production, 2) activation of the Ca2+-induced mitochondrial permeability transition (PT), and 3) modulation of cytosolic Ca2+ transients. Removal of Ca2+ from mitochondria permits rapid and efficient changes in the rate of ATP production to adapt to changing demands and can reverse the process of PT induction. Two separate, saturable mechanisms for facilitating Ca2+ efflux from mitochondria exist. In addition, the permeability transition or PT, which may also remove Ca2+ from the mitochondrial matrix, is intimately involved in other important functions such as apoptosis. Here we briefly review what is known about these important mitochondrial mechanisms and from their behavior speculate on their possible and probable functions.

Uptake of calcium by mitochondria: transport and possible function.

Vertebrate mitochondria contain a complex system for transport of Ca2+ and related ions, consisting of two saturable modes of Ca2+ influx and two separate, saturable mechanisms of Ca2+ efflux. The characteristics of the mechanisms of Ca2+ uptake, the uniporter and the RaM, are discussed here and suggestions are made about how the mechanisms may work together and separately to mediate the two physiological roles with which they are most commonly associated-control of the rate of cellular ATP production and induction of the permeability transition and apoptosis. It is argued that more subtlety of control of intramitochondrial free Ca2+ concentration ([Ca2+]m) must be used by the uniporter and the RaM to fulfill their physiological roles than has been commonly recognized. This is because an increase in [Ca2+]m is associated with both increased production of ATP which supports the continued life of the cell and with induction of the permeability transition and possibly apoptosis, which leads to cell death. The saturable mechanisms of mitochondrial Ca2+ efflux and the Ca2+-induced mitochondrial permeability transition, which can transport Ca2+ as well as other ions and molecules and is often considered as a Ca2+ transport mechanism, are being reviewed separately.

Mitochondrial calcium transport: mechanisms and functions.

Ca(2+)transport across the mitochondrial inner membrane is facilitated by transporters having four distinct sets of characteristics as well as through the Ca(2+)-induced mitochondrial permeability transition pore (PTP). There are two modes of inward transport, referred to as the Ca(2+)uniporter and the rapid mode or RaM. There are also two distinct mechanisms mediating outward transport, which are not associated with the PTP, referred to as the Na(+)-dependent and the Na(+)-independent Ca(2+)efflux mechanisms. Several important functions have been proposed for these mechanisms, including control of the metabolic rate for cellular energy (ATP) production, modulation of the amplitude and shape of cytosolic Ca(2+)transients, and induction of apoptosis through release of cytochrome c from the mitochondrial inter membrane space into the cytosolic space. The goals of this review are to survey the literature describing the characteristics of the mechanisms of mitochondrial Ca(2+)transport and their proposed physiological functions, emphasizing the more recent contributions, and to consider how the observed characteristics of the mitochondrial Ca(2+)transport mechanisms affect our understanding of their functions.

[Testing dental implants with an in vivo finite element model]. / Zahnimplantattestung am In-vivo-Finite-Elemente-Modell.

The finite element method (FEM) makes it possible to simulate biomechanical situations on a computer. In the present study the so-called voxel method [9, 14, 17, 18, 19] was used for the construction of the mandible model. For this, the relationship between the biological tissue (e.g. bone) and the corresponding attenuation coefficient of CT data (Hounsfield units = HU) were utilized. The CT data were obtained from an edentulous patient provided with a prosthesis borne on two titanium implants. In a parallel study, the bite forces of the same individual were measured. These were recorded digitally in three dimensions (cranio-caudal, anterior-posterior and left-right) The forces determined by a special program were then transferred to the FEM model implants. We were able to show that a bar joining the implants had a far greater effect on maximum equivalent stress than was expected from the measuring data alone. The highest stress at maximum occlusive force was lowered by 704% on using the connecting bar. On chewing, a stress reduction of 59.9% was observed. The reduction in stress achieved by the bar could, we believe, prolong the life of the implant.