Is sleep bruxism in obstructive sleep apnea only an oral health related problem?

BACKGROUND: The etiology of sleep bruxism in obstructive sleep apnea (OSA) patients is not yet fully clarified. This prospective clinical study aimed to investigate the connection between probable sleep bruxism, electromyographic muscle tone, and respiratory sleep patterns recorded during polysomnography. METHODS: 106 patients with OSA (74 males, 31 females, mean age: 56.1 ± 11.4 years) were divided into two groups (sleep bruxism: SB; no sleep bruxism: NSB). Probable SB were based on the AASM criteria: self-report of clenching/grinding, orofacial symptoms upon awakening, abnormal tooth wear and hypertrophy of the masseter muscle. Both groups underwent clinical examination for painful muscle symptoms aligned with Temporomandibular Disorders Diagnostic Criteria (DC/TMD), such as myalgia, myofascial pain, and headache attributed to temporomandibular disorder. Additionally, non-complaint positive muscle palpation and orofacial-related limitations (Jaw Functional Limited Scale-20: JFLS-20) were assessed. A one-night polysomnography with electromyographic masseter muscle tone (EMG) measurement was performed. Descriptive data, inter-group comparisons and multivariate logistic regression were calculated. RESULTS: OSA patients had a 37.1% prevalence of SB. EMG muscle tone (N1-N3, REM; P = 0.001) and the number of hypopneas (P = 0.042) were significantly higher in the sleep bruxism group. While measures like apnea-hypopnea-index (AHI), respiratory-disturbance-index (RDI), apnea index (AI), hypopnea-index (HI), number of arousals, and heart rate (1/min) were elevated in sleep bruxers, the differences were not statistically significant. There was no difference in sleep efficiency (SE; P = 0.403). Non-complaint masseter muscle palpation (61.5%; P = 0.015) and myalgia (41%; P = 0.010) were significant higher in SB patients. Multivariate logistic regression showed a significant contribution of EMG muscle tone and JFLS-20 to bruxism risk. CONCLUSION: Increased EMG muscle tone and orofacial limitations can predict sleep bruxism in OSA patients. Besides, SB patients suffer more from sleep disorder breathing. Thus, sleep bruxism seems to be not only an oral health related problem in obstructive apnea. Consequently, interdisciplinary interventions are crucial for effectively treating these patients. TRIAL REGISTRATION: The study was approved by the Ethics Committee of Philipps-University Marburg (reg. no. 13/22-2022) and registered at the "German Clinical Trial Register, DRKS" (DRKS0002959).

Remineralisation capability of silver diamine fluoride in artificial enamel lesions on smooth surfaces using quantitative light-induced fluorescence measurements in-vitro.

Enamel demineralisation can develop on smooth surfaces as an undesirable side effect during orthodontic treatment with fixed appliances. This study aimed to evaluate the ability of 38% silver diamine fluoride in remineralisation (as estimated by fluorescence gain) of artificial initial lesions in smooth surfaces of human enamel. The smooth surfaces of 50 human tooth samples were artificially demineralised and 45 samples were allocated randomly into three groups receiving a single treatment with a varnish: group I: Riva Star (silver diamine fluoride, SDF), group II: Bifluorid 12 (NaF, CaF2), and group III: Cervitec F (CHX, CPC, NH4F). Five samples were assigned as a negative control group without treatment. All samples were exposed to pH-cycling for 28 days. Fluorescence behavior was measured using Quantitative light-induced fluorescence before and after demineralisation and up to four weeks on a weekly basis. Analysis of variance (ANOVA) with Tukey-Kramer post-hoc tests and repeated measures ANOVA were used for statistical evaluation (α = 0.05). After demineralisation, all samples showed mean ΔF of - 16.22% ± 4.35, without significance differences between the fluorescence behaviour of the samples (p = 0.251). After 28 days group comparison showed a statistically significant difference (p = 0.034) for ΔF values: the lowest fluorescence values were found in group I (SDF, mean ΔF - 16.47 ± 6.08) with a significant difference compared to group III (Cervitec F, mean ΔF - 11.71 ± 4.83). In group II (Bifluorid 12) mean ΔF value was - 15.55 ± 2.15) without statistically significant differences to groups I and III. The fluorescence behaviour of SDF varnish on smooth surfaces with artificial initial enamel lesions was significantly lower compared to Cervitec F varnish after short time use.

Impact of self-assembling peptides in remineralisation of artificial early enamel lesions adjacent to orthodontic brackets.

Enamel demineralisation can occur as a side effect during orthodontic treatment with fixed appliances. This study aimed to evaluate the efficacy of the self-assembling peptide P11-4 for remineralisation combined with fluorides, compared to application of fluoride varnish alone. De- and remineralisation was assessed by Quantitative light-induced fluorescence (QLF). Orthodontic brackets were bonded on 108 human enamel samples and white spot lesions were created. The samples were allocated randomly into three groups: Group I received no treatment, group II had a single application of fluoride varnish (22,600 ppm), and group III was treated with P11-4 following a single application of fluoride varnish. Quantitative light-induced fluorescence (QLF) measurements were performed at baseline, after demineralisation and after storage in remineralisation solution for 7 and 30 days. Non-parametric tests (Kruskal-Wallis test and Friedman test) were used for further analysis. After demineralisation, all samples showed a median ΔF -9.38% ± 2.79. After 30 days median ΔF values were as followed: group I = -9.04% ± 2.51, group II = -7.89 ± 2.07, group III = -6.08% ± 2.79). The median ΔF values differed significantly between all groups at all investigation times (p < 0.00001). Application of P11-4 with fluoride varnish was superior to the use of fluorides alone for remineralisation of enamel adjacent to brackets.

Large magnetic gap at the Dirac point in Bi2Te3/MnBi2Te4 heterostructures.

Magnetically doped topological insulators enable the quantum anomalous Hall effect (QAHE), which provides quantized edge states for lossless charge-transport applications1-8. The edge states are hosted by a magnetic energy gap at the Dirac point2, but hitherto all attempts to observe this gap directly have been unsuccessful. Observing the gap is considered to be essential to overcoming the limitations of the QAHE, which so far occurs only at temperatures that are one to two orders of magnitude below the ferromagnetic Curie temperature, TC (ref. 8). Here we use low-temperature photoelectron spectroscopy to unambiguously reveal the magnetic gap of Mn-doped Bi2Te3, which displays ferromagnetic out-of-plane spin texture and opens up only below TC. Surprisingly, our analysis reveals large gap sizes at 1 kelvin of up to 90 millielectronvolts, which is five times larger than theoretically predicted9. Using multiscale analysis we show that this enhancement is due to a remarkable structure modification induced by Mn doping: instead of a disordered impurity system, a self-organized alternating sequence of MnBi2Te4 septuple and Bi2Te3 quintuple layers is formed. This enhances the wavefunction overlap and size of the magnetic gap10. Mn-doped Bi2Se3 (ref. 11) and Mn-doped Sb2Te3 form similar heterostructures, but for Bi2Se3 only a nonmagnetic gap is formed and the magnetization is in the surface plane. This is explained by the smaller spin-orbit interaction by comparison with Mn-doped Bi2Te3. Our findings provide insights that will be crucial in pushing lossless transport in topological insulators towards room-temperature applications.

Randomised in situ clinical trial investigating self-assembling peptide matrix P11-4 in the prevention of artificial caries lesions.

The aim was to investigate the ability of self-assembling Peptide P11-4 Matrix (SAPM) to remineralize artificial initial caries lesions compared to the use of fluoride varnish. Volunteers were recruited for this randomised, cross-over in situ trial. Bovine specimens, half including orthodontic brackets, were recessed on the buccal aspects of mandibular appliances. Specimens included internal sound enamel control, a demineralised control and a part exposed during the in situ phase. Each phase lasted four weeks, followed by a one-week washout. Treatment groups were: A: negative control, no treatment,B: positive control, 22,600 ppm fluoride varnish,C: test group, 1,000 ppm SAPM. Laser fluorescence values (LF) were measured before/after demineralisation, and after the in situ period. Micro-CT analysis was used to assess mineral changes within the specimens after the in situ phase. In specimens without brackets, ΔLF values after in situ phase were: A: +5.28, B: +0.85, C: -2.89. Corresponding ΔLF for specimens with brackets were: A: +5.77, B: +1.30, C: -3.15. LF-values between groups significantly differed from each other (p < 0.0001) after the in situ phase. Micro-CT analysis yielded no significant difference among groups for specimens without brackets. For specimens with brackets, the test group showed significantly more remineralisation than the negative (p = 0.01) and positive control (p = 0.003). Within the limitations of the study, SAPM showed prevention of caries and remineralisation of enamel around orthodontic brackets.

A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo.

Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (⩾18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2-ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.

Analyzing Amyloid-ß Peptide Modulation Profiles and Binding Sites of γ-Secretase Modulators.

γ-Secretase is a key player in the pathogenesis of Alzheimer's disease (AD). The intramembrane-cleaving enzyme initially cleaves a C-terminal fragment of the amyloid precursor protein (APP) at the ɛ-site within its transmembrane domain to release the APP intracellular domain. Subsequent stepwise carboxy-terminal trimming cleavages eventually release amyloid-ß (Aß) peptides of 37-43 amino acids into the extracellular space. Aß42 as well as the much less abundant Aß43 species are highly aggregation prone and can deposit as plaques in the brains of affected patients, which are widely believed to be causative of AD. Disappointingly, due to lack of efficacy and side effects likely attributable to the inhibition of the crucial substrate Notch, inhibitors of γ-secretase that lower Aß generation failed in clinical trials of AD. There is hope, however, that recently developed potent γ-secretase modulators (GSMs) provide a safer approach for disease modification. These compounds have the unique property of primarily shifting the generation of Aß42 toward that of shorter peptides without affecting the ɛ-site cleavage of Notch and other substrates. In this chapter, we describe methods to investigate how GSMs affect the activity of the enzyme as well as how their molecular targets are identified.

Quality Requirements for the early Fetal Ultrasound Assessment at 11-13+6 Weeks of Gestation (DEGUM Levels II and III).

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

Nonmagnetic band gap at the Dirac point of the magnetic topological insulator (Bi(1-x)Mn(x))2Se3.

Magnetic doping is expected to open a band gap at the Dirac point of topological insulators by breaking time-reversal symmetry and to enable novel topological phases. Epitaxial (Bi(1-x)Mn(x))2Se3 is a prototypical magnetic topological insulator with a pronounced surface band gap of ∼100 meV. We show that this gap is neither due to ferromagnetic order in the bulk or at the surface nor to the local magnetic moment of the Mn, making the system unsuitable for realizing the novel phases. We further show that Mn doping does not affect the inverted bulk band gap and the system remains topologically nontrivial. We suggest that strong resonant scattering processes cause the gap at the Dirac point and support this by the observation of in-gap states using resonant photoemission. Our findings establish a mechanism for gap opening in topological surface states which challenges the currently known conditions for topological protection.

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

Effects of therapeutic horse riding on gait cycle parameters and some aspects of behavior of children with autism.

We studied effects of therapeutic riding on the development of children with autism. Experiments in walking is appropriate for assessing the coordination of movement and for following the changes. We found that therapeutic riding should be considered as a new form of rehabilitation. Twenty-six pupils (12 boys and 14 girls) of a special needs school participated in therapeutic riding. We analyzed walking twice during a school-term: full body analyses each time before and after one-month therapy. The research included a non-riding control group. All together 104 analyses were performed. We measured mental skills using Pedagogical Analysis and Curriculum (PAC) test consisting of four parts being communication, self care, motor skills and socialization. The Gait Cycle Analysis consists of the time-series analysis, the analysis of part of the gait cycle and the measurement of joint angles in each plane. We found significant differences between before and after the therapy in the length of the gait cycle that became more stable in the sagital plane and concluded that our results proved that horse therapy may be successfully used as an additional therapy for children with autism, and it may be a form of rehabilitation in cases when other therapies are not successful.

Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.

In a positron-emission tomography (PET) study with the ß-amyloid (Aß) tracer [(18)F]-florbetaben, we previously showed that Aß deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aß42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aß-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aß-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aß were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aß42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aß-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics.

Intramembrane proteolysis - cleavage of proteins within the plane of a membrane - is a widespread phenomenon that can contribute to the functional activation of substrates and is involved in several diseases. Although different families of intramembrane proteases have been discovered and characterized, we currently do not know how these enzymes discriminate between substrates and non-substrates, how site-specific cleavage is achieved, or which factors determine the rate of proteolysis. Focusing on γ-secretase and rhomboid proteases, we argue that answers to these questions may emerge from connecting experimental readouts, such as reaction kinetics and the determination of cleavage sites, to the structures and the conformational dynamics of substrates and enzymes.

Novel lingual retainer created using CAD/CAM technology: evaluation of its positioning accuracy.

OBJECTIVES: Permanent retention is currently the method of choice to stabilize orthodontic treatment results. Frequently, permanent retention schemes are adopted to prevent posttreatment changes in the esthetic zone of the anterior teeth. With increasingly prolonged times of intraoral device use, and retention to be provided in the maxilla despite limited space, the demands placed on well-planned and precise retainer positioning are becoming more exacting. The aim of the present study was to analyze the intraoral precision of lingual retainers made using computer-aided design and machining (CAD/CAM). MATERIALS AND METHODS: A custom manufacturer (Retaintechnology; Cologne, Germany) employing innovative CAD/CAM technology was commissioned to fabricate 16 lingual retainers. Following intraoral insertion using the manufacturer's recommended transfer system, impressions of the intraoral situations were taken and scanned for digitization. On this basis, the intraoral retainer positions were compared to the preceding virtual setups by superimposition with the manufacturer's datasets. Three-dimensional processing software (Geomagic Qualify 2012; Geomagic) was used to analyze the retainers, based on a total of 80 interproximal sites, for deviations from their planned positions along the horizontal (x-), sagittal (y-), and vertical (z-) axes. These deviations of the achieved from the intended positions were considered clinically relevant if ≥ 0.5 mm and, based on this premise, were subjected to a t-test with statistical software (Prism; GraphPad). RESULTS: The intraoral retainer positions were found to correlate closely with the preceding virtual setups (i.e., the positions as they had been planned by the custom manufacturer). Positional deviations were significantly less than 0.5 mm. They were very small in the horizontal and sagittal planes and moderately larger in the vertical plane. CONCLUSION: Highly precise intraoral results may be achieved by transferring three-dimensional virtual setups for lingual retainers to the actual patients. This CAD/CAM strategy of making retainers can offer high predictability even in anatomically demanding regions and in the presence of limited space.

Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization.

Induction of mucosal immunoglobulin-A (IgA) capable of providing a first line of defense against bacterial and viral pathogens remains a major goal of needle-free vaccines given via mucosal routes. Innate immune cells are known to play a central role in induction of IgA responses by mucosal vaccines, but the relative contribution of myeloid cell subsets to these responses has not firmly been established. Using an in vivo model of sublingual vaccination with Bacillus anthracis edema toxin (EdTx) as adjuvant, we examined the role of myeloid cell subsets for mucosal secretory IgA responses. Sublingual immunization of wild-type mice resulted in a transient increase of neutrophils in sublingual tissues and cervical lymph nodes. These mice later developed Ag-specific serum IgG responses, but not serum or mucosal IgA. Interestingly, EdTx failed to increase neutrophils in sublingual tissues and cervical lymph nodes of IKKß(ΔMye) mice, and these mice developed IgA responses. Partial depletion of neutrophils before immunization of wild-type mice allowed the development of both mucosal and serum IgA responses. Finally, co-culture of B cells with neutrophils from either wild-type or IKKß(ΔMye) mice suppressed secretion of IgA, but not IgM or IgG. These results identify a new role for neutrophils as negative regulators of IgA responses.

Neural effects of cognitive-behavioural therapy on dysfunctional attitudes in depression.

BACKGROUND: Dysfunctional attitudes are a feature of depression that has been correlated with receptor binding abnormalities in limbic and cortical regions. We sought to investigate the functional neuroanatomy of dysfunctional attitudes in major depressive disorder (MDD) and the effects of treatment with cognitive-behavioural therapy (CBT). METHOD: Participants were 16 patients with unipolar depression in an acute depressive episode (mean age 40.0 years) and 16 matched healthy controls (mean age 39.9 years). Patients were medication free and received a course of treatment with CBT. All participants underwent functional magnetic resonance imaging (fMRI) scans at baseline and at week 16, prior to the initiation of therapy and following the course of CBT for patients. During each fMRI scan, participants indicated their attributions to statements from a modified Dysfunctional Attitudes Scale (mDAS-48). RESULTS: MDD patients in an acute depressive episode endorsed a greater number of extreme responses to DAS statements, which normalized following CBT treatment. Extreme attributions were associated with greater activation in the left hippocampal region, inferior parietal lobe and precuneus in MDD patients as compared with healthy controls as a main effect of group. An interaction effect was found in the left parahippocampal region, which showed less attenuation in MDD patients at the follow-up scan relative to healthy controls. CONCLUSIONS: Attenuation of activity in the parahippocampal region may be indicative of an improvement in dysfunctional thinking following CBT treatment in depression, while persistent engagement of regions involved in attentional processing and memory retrieval with extreme attributions reflects a trait feature of depression.

[Management of postpartum hemorrhage (PPH): algorithm of the interdisciplinary D-A-CH consensus group PPH (Germany - Austria - Switzerland)]. / Management der postpartalen Blutung (PPH): Algorithmus der Interdisziplinären D-A-CH-Konsensusgruppe PPH (Deutschland - Österreich - Schweiz).

Postpartum hemorrhage (PPH) is one of the main causes of maternal deaths even in industrialized countries. It represents an emergency situation which necessitates a rapid decision and in particular an exact diagnosis and root cause analysis in order to initiate the correct therapeutic measures in an interdisciplinary cooperation. In addition to established guidelines, the benefits of standardized therapy algorithms have been demonstrated. A therapy algorithm for the obstetric emergency of postpartum hemorrhage in the German language is not yet available. The establishment of an international (Germany, Austria and Switzerland D-A-CH) "treatment algorithm for postpartum hemorrhage" was an interdisciplinary project based on the guidelines of the corresponding specialist societies (anesthesia and intensive care medicine and obstetrics) in the three countries as well as comparable international algorithms for therapy of PPH.The obstetrics and anesthesiology personnel must possess sufficient expertise for emergency situations despite lower case numbers. The rarity of occurrence for individual patients and the life-threatening situation necessitate a structured approach according to predetermined treatment algorithms. This can then be carried out according to the established algorithm. Furthermore, this algorithm presents the opportunity to train for emergency situations in an interdisciplinary team.

Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures.

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid ß-peptide (Aß), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.