Epidemiological trends, predictive factors, and projection of tooth loss in Germany 1997-2030: part I. missing teeth in adults and seniors.

OBJECTIVE: This is the first part of a report on tooth loss in Germany 1997-2030. Here, we describe trends in the prevalence of tooth loss in adults and seniors 1997-2014, assess predictive factors for tooth loss and projected it into 2030. MATERIAL AND METHODS: Data of the cross-sectional, multi-center, nationally representative German Oral Health Studies of 1997, 2005, and 2014 were used. Age, sex, educational level, smoking status, and the cohort were used for ordinary least square regression to assess the association of predictors with tooth loss (missing teeth, MT). The yielded regression coefficients were used to predict tooth loss in 2030. RESULTS: Compared with 1997, the mean MT in adults (35-44 years old) in 2030 was predicted to decrease by two-thirds to 1.3. The prevalence of tooth loss (MT > 0) will decrease by 72% from 1997 to 2030. In 2030, half of the population of adults will not exhibit any tooth loss. Compared with 1997, the mean MT among seniors (65-74 years old) will decline to 5.6 teeth (i. e. two-thirds reduction) until 2030. Prevalence of tooth loss will be halved by 2030, and approximately one-third of this age group will not exhibit any tooth loss. CONCLUSIONS: Based on the model used, the trend of a robust decline in tooth loss will become more dynamic by the year 2030. As a result, every second adult will have experienced no tooth loss at all in 2030, and seniors will possess more teeth than they have previously lost. CLINICAL RELEVANCE: This study presents the trends of tooth loss in Germany for a period of three decades. It provides clinically relevant data for health care planning by 2030.

Rasagiline derivatives combined with histamine H3 receptor properties.

The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson's disease. The combination of this established drug to recently developed histamine H3 receptor (H3R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC50 = 256 nM; hH3R Ki = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H1, H4, dopamine D2, D3 receptors or acetyl-/butyrylcholinesterases.

PEKK-made indirect temporary crowns and bridges: a clinical pilot study.

OBJECTIVES: The aim of the present study was to find out whether the high-performance polymer PEKK is an equivalent alternative compared to cobalt chrome (CoCr)-made restorations, regarding to biocompatibility, stability, and comfort. MATERIALS AND METHODS: Twenty-two patients (m, 10; f, 12) who were indicated for a long-term temporary-fixed restoration were included. They were randomized through a lottery procedure into two groups: the first group was restored with veneered PEKK-made crowns and bridges (Pekkton ivory), while the second group was restored with veneered CoCr crowns. Clinical parameters (plaque index (PI), probing depth (PD), fracture, and chipping) were documented in a period of 3-5 months from the insertion of restoration. Furthermore, every patient completed the OHIP-14 questionnaire. An exchange of the restorations from the first to the alternative material was performed after a period of 3-5 months. RESULTS: All patients showed an improvement of the oral hygiene and probing depth after insertion of the temporary restorations. However, there were no significant differences between PEKK and CoCr-made restorations (P > 0.05). There was no chipping after 5 months for both kinds of materials. There was a noticeable reduction of pain and discomfort of patients after insertion of temporary restorations. However, there were no significant differences between the two materials (P > 0.05). CONCLUSIONS: PEKK-made temporary restorations offer a good and stable alternative to CoCr-made restorations. They have a high aesthetical advantage over CoCr restoration. CLINICAL RELEVANCE: Esthetic and price-efficient temporary crowns can be offered for the patient during periodontal therapy to improve its success, in particular by improving the oral hygiene.

[Injury patterns in interstitial lung diseases]. / Schädigungsmuster interstitieller Lungenerkrankungen.

Interstitial lung diseases (ILD) consist of a complex group of hundreds of non-neoplastic pulmonary diseases with divergent clinical presentation, morphology and progression tendency. This great number of clinical entities contrasts with a limited number of injury patterns. By definition, an adequate classification requires a synopsis of the clinical, radiological and morphological findings. The ATS/ERS (American Thoracic Society/ European Respiratory Society) guidelines recommend an open lung biopsy if high-resolution computed tomography does not provide conclusive results. Due to the focal nature and overlapping features of injury patterns, microscopic categorization is not always possible. In order to broaden the diagnostic criteria by using molecular patterns the Lung Research Working Group of the Institute of Pathology of Hannover Medical School, Europe's leading transplant center, is working up fresh explanted human lungs in a standardized manner. These fresh specimens are used for translational research by means of functional, morphological and molecular techniques in order to identify disease-specific regulatory processes and to make them usable diagnostically and therapeutically.

Structural Characterization and Photochemical Properties of Mono- and Bimetallic Cu-Mabiq Complexes.

We present a series of monometallic ([Cu(Mabiq)OTf] (1) and [Cu(Mabiq)] (2)) and bimetallic copper-Mabiq complexes ([Cu2(Mabiq)(PPh3)2(OTf)2] (3) and [Cu2(Mabiq)(PPh3)2]PF6 (4)). The latter compounds contain an additional CuI center that binds in a tetrahedral fashion to the external bipyrimidine nitrogens of the macrocyclic ligand. Compounds 3 and 4 represent the first examples of bimetallic transition metal Mabiq complexes, stable both in solution and in the solid state. The structural and electronic properties of compounds 1-4 were analyzed by means of X-ray crystallography, cyclic voltammetry, and spectroscopic methods. One-electron reduced 2 and 4 consist of a CuII ion coordinated by a Mabiq ligand radical, [CuII(Mabiq•)]. Thus, both bimetallic compounds are mixed-valent with respect to the copper oxidation states. Complexes 2 and 4 can be generated photochemically, upon irradiation of 1 or 3 with visible light in the presence of a sacrificial electron donor.

Coherently combined 16-channel multicore fiber laser system.

We present a coherently combined laser amplifier with 16 channels from a multicore fiber in a proof-of-principle demonstration. Filled-aperture beam splitting and combination, together with temporal phasing, is realized in a compact and low-component-count setup. Combined average power of up to 70 W with 40 ps pulses is achieved with combination efficiencies around 80%.

Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition.

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H1R - H4R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H1R, H2R and H3R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H4R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H4 receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H1 receptor inhibits heart dilatation but does not prolong the life.

Finite element analysis of different loading conditions for implant-supported overdentures supported by conventional or mini implants.

The effect of implants' number on overdenture stability and stress distribution in edentulous mandible, implants and overdenture was numerically investigated for implant-supported overdentures. Three models were constructed. Overdentures were connected to implants by means of ball head abutments and rubber ring. In model 1, the overdenture was retained by two conventional implants; in model 2, by four conventional implants; and in model 3, by five mini implants. The overdenture was subjected to a symmetrical load at an angle of 20 degrees to the overdenture at the canine regions and vertically at the first molars. Four different loading conditions with two total forces (120, 300 N) were considered for the numerical analysis. The overdenture displacement was about 2.2 times higher when five mini implants were used rather than four conventional implants. The lowest stress in bone bed was observed with four conventional implants. Stresses in bone were reduced by 61% in model 2 and by 6% in model 3 in comparison to model 1. The highest stress was observed with five mini implants. Stresses in implants were reduced by 76% in model 2 and 89% increased in model 3 compared to model 1. The highest implant displacement was observed with five mini implants. Implant displacements were reduced by 29% in model 2, and increased by 273% in model 3 compared to model 1. Conventional implants proved better stability for overdenture than mini implants. Regardless the type and number of implants, the stress within the bone and implants are below the critical limits.

Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B.

Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer's disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.

Active Brownian motion of emulsion droplets: Coarsening dynamics at the interface and rotational diffusion.

A micron-sized droplet of bromine water immersed in a surfactant-laden oil phase can swim (S. Thutupalli, R. Seemann, S. Herminghaus, New J. Phys. 13 073021 (2011). The bromine reacts with the surfactant at the droplet interface and generates a surfactant mixture. It can spontaneously phase-separate due to solutocapillary Marangoni flow, which propels the droplet. We model the system by a diffusion-advection-reaction equation for the mixture order parameter at the interface including thermal noise and couple it to fluid flow. Going beyond previous work, we illustrate the coarsening dynamics of the surfactant mixture towards phase separation in the axisymmetric swimming state. Coarsening proceeds in two steps: an initially slow growth of domain size followed by a nearly ballistic regime. On larger time scales thermal fluctuations in the local surfactant composition initiates random changes in the swimming direction and the droplet performs a persistent random walk, as observed in experiments. Numerical solutions show that the rotational correlation time scales with the square of the inverse noise strength. We confirm this scaling by a perturbation theory for the fluctuations in the mixture order parameter and thereby identify the active emulsion droplet as an active Brownian particle.

Polypharmacology of dopamine receptor ligands.

Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsons disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.

Human basophil chemotaxis and activation are regulated via the histamine H4 receptor.

BACKGROUND: IgE-mediated cross-linking of FcεRI results in the release of mediators stored in basophil granules, such as histamine and proteases, and in the de novo synthesis of sulfidoleukotrienes. OBJECTIVE: In this study, we investigated the role of the histamine receptors, in particular that of the histamine H4 receptor (H4R), in modulating human basophil function. METHODS: The mRNA expression of the histamine receptors was measured by real-time PCR. Migration of basophils was assessed using the modified Boyden chamber technique. The expression levels of CD63 and CD203c on the cell surface and the sulfidoleukotriene release were determined by flow cytometry and ELISA, respectively. RESULTS: We could show that highly purified basophils express the H1R, H2R, and H4R but not the H3R mRNA. Human basophils expressed higher H4R mRNA levels as compared to the expression levels of the H1R (P < 0.01). Histamine and the H4R agonist ST-1006 initiated active migration of basophils (P < 0.001). A significant reduction in FcεRI cross-linking-mediated surface expression of CD63 and CD203c was observed on basophils after pre-incubation with histamine or the specific H4R agonist ST-1006 (P < 0.01). The synthesis and release of sulfidoleukotrienes from basophils after activation with different stimuli, by FcεRI cross-linking or by stimulation with hymenoptera venom allergens, were significantly reduced by histamine or the H4R agonist ST-1006 (P < 0.05-0.001). CONCLUSION: These data imply that the H4R regulates IgE-dependent processes in human basophils and provides a novel function of the H4R preventing an overwhelming immune reaction by engagement of a negative feedback loop.

Viscoelastic properties of marginal networks in a solvent.

Polymer networks at the margins of mechanical stability are known to be highly sensitive to applied forces and fields and to exhibit an anomalously large resistance to deformation. In this paper, we study the effects of hydrodynamic interactions on the behavior of marginal networks using a hybrid molecular dynamics and multiparticle collision dynamics simulation technique. We examine how the filament and solvent properties affect the response of marginal networks to shear. We find that the stiffening of the network shows a stronger dependence on the shear frequency when hydrodynamic interactions are present than when they are not. The network shear modulus scales as G'∼ω(α(c)), with a critical stiffening exponent α(c) that can be controlled by varying the relative concentrations of the network and the solvent. Our results show that this arises due to the solvent aiding the relaxation of the network and suppressing the network nonaffinity, with the system deforming more affinely when hydrodynamic interactions are maximized.

Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice.

Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

The effect of implant splinting on the load distribution in bone bed around implant-supported fixed prosthesis with different framework materials: A finite element study.

Analysing the influence of implant splinting and its relation to different framework materials is a complex issue. The stiffness of framework materials and the overload of the implant system directly affect the final transferred load of the bone around implants. A finite element model of a long-span cementable implant-supported fixed prosthesis was created. Three materials were analysed for the framework: Titanium, gold alloy, and zirconia. The connection screws were first preloaded with 200 N. Two loading conditions were studied: The implant at the molar region was first loaded without splinting to the framework, and in the second condition, the implant was splinted to the framework. A total force of 500 N and 1000 N in 30° from the long axis of the framework were applied in buccal or distal direction on the implant system. The stresses and strains within the framework materials, implant system, and bone bed around the supporting implants were analysed. Loading the implant distally was associated with high stresses within the implant system in comparison to buccal loading. By splinting the implant, the stress in the implant system was reduced from 5393 MPa to 2942 MPa. Buccal loading of the implant was more critical than the distal loading. In the splinted condition of the implant, the stresses in the cortical bone were reduced from 570 MPa to 275 MPa.

Histamine H4 receptor in oral lichen planus.

OBJECTIVES: Oral lichen planus (OLP) is an autoimmune disease characterized by a band-like T-cell infiltrate below the apoptotic epithelial cells and degenerated basement membrane. We tested the hypothesis that the high-affinity histamine H4 receptors (H4 Rs) are downregulated in OLP by high histamine concentrations and proinflammatory T-cell cytokines. MATERIALS AND METHODS: Immunohistochemistry and immunofluorescence staining, image analysis and quantitative real-time polymerase chain reaction of tissue samples and cytokine-stimulated cultured SCC-25 and primary human oral keratinocytes. RESULTS: H4 R immunoreactivity was weak in OLP and characterized by mast cell (MC) hyperplasia and degranulation. In contrast to controls, H4 R immunostaining and MC counts were negatively correlated in OLP (P = 0.003). H4 R agonist at nanomolar levels led to a rapid internalization of H4 Rs, whereas high histamine concentration and interferon-γ decreased HRH4 -gene transcripts. CONCLUSION: Healthy oral epithelial cells are equipped with H4 R, which displays a uniform staining pattern in a MC-independent fashion. In contrast, in OLP, increased numbers of activated MCs associate with increasing loss of epithelial H4 R. Cell culture experiments suggest a rapid H4 R stimulation-dependent receptor internalization and a slow cytokine-driven decrease in H4 R synthesis. H4 R may be involved in the maintenance of healthy oral mucosa. In OLP, this maintenance might be impaired by MC degranulation and inflammatory cytokines.

Dopamine D3 receptor agonists as pharmacological tools.

Dysregulation of the dopaminergic innervation in the central nervous system plays a key role in different neurological disorders like Parkinson´s disease, restless legs syndrome, schizophrenia etc. Although dopamine D3 receptors have been recognized as an important target in these diseases, their full pharmacological properties need further investigations. With focus on dopamine D3 receptor full agonists, this review has divided the ergoline and non-ergoline ligands in dissimilar chemical subclasses describing their pharmacodynamic properties on different related receptors, on species differences and their functional properties on different signaling mechanism. This is combined with a short description of structure-activity relationships for each class. Therefore, this overview should support the rational choice for the optimal compound selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies.

Modulation of IL-33/ST2-TIR and TLR signalling pathway by fingolimod and analogues in immune cells.

For the immune modulatory drug fingolimod (FTY720), lymphocyte sequestration has been extensively studied and accepted as mode of action. Further, direct effects on immune cell signalling are incompletely understood. Herein, we used the parent drug and newly synthesized analogues to investigate their effects on dendritic cell (DC) calcium signalling and on Th1, Th2 and Th17 responses. DC calcium signalling was determined with a single cell-based confocal assay and IL-33/ST2-TIR Th2-like response with ST2-transduced EL4-6.1 thymoma cells. The Th1/Th17 responses were examined with a LPS/TLR-enhanced antigen presentation assay with OVA-TCRtg CD4 and CD8 spleen cells. Our results revealed a comparable influence of fingolimod and S1P on intracellular calcium level in DC, while an oxy-derivative of fingolimod exhibited an EC50 of 3.3 nm, being 14 times more potent than FTY720-P. The IL-33/ST2-TIR Th2-like response in ST2-EL4 cells was inhibited by fingolimod and analogues at varying degrees. Using the OVA-TCRtg LPS/TLR-enhanced spleen cell assay, we found that fingolimod inhibited both IL-17 and IFN-γ production. In contrast, fingolimod phosphate failed to decrease Th1 cytokines. Interestingly, the effects of the parent compound fingolimod were modulated by the PP2A inhibitor okadaic acid, thus suggesting PP2A as relevant intracellular target. These studies describe detailed immune-modulating properties of fingolimod, including interference with a prototypical Th2 response via IL-33/ST2-TIR. Moreover, differential effects of fingolimod versus its phosphorylated derivative on TLR-activated and antigen-dependent Th1 activation suggest PP2A as an additional target of fingolimod immune therapy. Together with the analogues tested, these data may guide the development of more specific fingolimod derivatives.

Unique immunomodulatory effects of azelastine on dendritic cells in vitro.

Allergic contact dermatitis and atopic dermatitis are among the most common inflammatory skin diseases in western countries, and antigen-presenting cells like dendritic cells (DC) are key players in their pathophysiology. Histamine, an important mediator of allergic reactions, influences DC maturation and cytokine secretion, which led us to investigate the immunomodulatory potential of the well-known histamine H1 receptor antagonists: azelastine, olopatadine, cetirizine, and pyrilamine. Unlike other H1 antihistamines, azelastine decreased lipopolysaccharide-induced tumor necrosis factor α and interleukin-12 secretion from murine bone marrow-derived DC. This effect was independent of histamine receptors H1, H2, or H4 and may be linked to inhibition of the nuclear factor kappa B pathway. Moreover, only azelastine reduced proliferation of allogenic T cells in a mixed leukocyte reaction. We then tested topical application of the H1 antihistamines on mice sensitized against toluene-2,4-diisocyanate, a model of Th2-mediated allergic contact dermatitis. In contrast to the in vitro results, all investigated substances were efficacious in reducing allergic ear swelling. Azelastine has unique effects on dendritic cells and T cell interaction in vitro. However, this did not translate into superior in vivo efficacy for Th2-mediated allergic dermatitis, possibly due to the effects of the antihistamines on other cell types involved in skin inflammation. Future research will have to clarify whether these properties are relevant to in vivo models of allergic inflammation with a different T cell polarization.