Physiological and pathological significance of human telomerase reverse transcriptase splice variants.

Human telomerase reverse transcriptase (hTERT) is tightly regulated at various transcriptional and post-transcriptional levels. Alternative splicing of hTERT has been shown in many human tissues and cell lines regardless of telomerase status and may play a role in regulation of telomerase activity and other cellular functions. Catalytically inactive splice variants make up a substantial proportion of total hTERT mRNA and are at least partly translated into protein. Shifts in splicing patterns occur in development, tumorigenesis and in response to exogenous stimuli in a tissue- and cell type-specific manner. This review focuses on prevalence, patterns and regulation of hTERT alternative splicing, describes associations with telomerase activity and telomere length, and discusses the potential significance of hTERT alternative splice variants in cancer as well as possible telomere-independent functions.

Telomerase inhibition may contribute to accelerated mitochondrial aging induced by anti-retroviral HIV treatment.

HIV-infected individuals undergoing long-term anti-retroviral treatment tend to show premature senescence. Accelerated mitochondrial aging induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been implicated as a part of this phenomenon. Traditionally, this has been attributed to inhibition of mtDNA polymerase γ by these drugs, but alternative explanations have been proposed. It is known that NRTIs can not only inhibit viral reverse transcriptase, but also human telomerase. A number of extratelomeric roles of telomerase, including protection of mitochondrial DNA and function, have emerged recently. In this paper, I propose that inhibition of mitochondrial telomerase activity by NRTI drugs contributes to the mitochondrial toxicity and premature aging seen in treated HIV patients, and discuss objections and experimental testing of the hypothesis.

Rheumatic autoimmune diseases: proposed elimination of autoreactive B-cells with magnetic nanoparticle-linked antigens.

Although the pathogenesis of rheumatoid arthritis and other rheumatic diseases is still not fully understood, it has become clear that in many cases autoimmune responses with production of autoantibodies against physiological targets play a significant and causal role. Current immunosuppressive and immunomodulatory approaches such as bone marrow transplantation or the therapeutic antibody rituximab are effective, but unspecific and have serious side effects. Here, a method for targeted elimination of specific autoreactive B-cells which are essential for autoantibody production and maintenance of the autoimmune response is proposed. By binding to their receptive antigens linked to magnetic nanoparticles, the autoreactive B-cells can be separated from the rest of the blood in an extracorporeal filtration process, reducing the number of autoimmune cells and autoantibodies in the blood. The method can be adapted for use in different autoimmune diseases provided some key aspects of pathogenesis are known, and can be repeated if necessary. Evidence for feasibility and safety of this method is briefly reviewed, and potential limitations and hurdles to overcome are discussed.

The many faces of telomerase: emerging extratelomeric effects.

Telomeres, the ends of chromosomes, shorten with each cell division. To expand their replicative potential, various cell types use the ribonucleoprotein telomerase, which lengthens telomeres by its reverse transcriptase activity. Because of its ability to immortalize cancer cells, telomerase also plays a significant role in tumor growth. However, in recent years, a wide variety of non-canonical effects of telomerase that are independent of telomere lengthening have been discovered, and even the notion that telomerase is restricted to very few cell types has been questioned. These effects also seem to be important in carcinogenesis and might explain the tumor-promoting effects of telomerase independently of telomere elongation. Here, the current understanding of the extratelomeric roles of telomerase and their physiological and pathological significance is reviewed.

Targeting ALT: the role of alternative lengthening of telomeres in pathogenesis and prevention of cancer.

Telomere shortening in the course of cell divisions plays an important role in both suppression and pathogenesis of cancer. Telomere maintenance mechanisms such as telomerase and alternative lengthening of telomeres (ALT) are essential for long-term tumor growth. Consequently, interdiction of telomere lengthening has been proposed as an anti-cancer treatment but requires insight in the genes and pathways involved. In this article, the molecular and functional details of ALT are reviewed, and proposed next steps towards a therapy aimed at preventing ALT in human cancers are described.

A model of metabolic changes in respiration-deficient human cells.

Cells lacking aerobic metabolism because of damaged mtDNA accumulate in many postmitotic tissues in the course aging. Although being only a small fraction of cells, they might play a major role in oxidative stress affecting the whole body. However, it remains unclear how such cells, which are under normal circumstances dependent on aerobic metabolism, are able to survive for decades in vivo. Here a new model is presented that proposes a coexistence of anaerobic glycolysis and a partly reversed TCA cycle. Succinate plays a key role in the changed metabolic pathways because it has to be exported by the cell. This hypothesis supports the view that some respiration-deficient cells are able to survive permanently within the body and contribute to human aging.

[Investigation of influencing variables on the computer-aided simulation of contacts in dynamic occlusion based on optically digitized plaster casts]. / Untersuchungen zu den Einflussgrössen auf die computergestützte Simulation von Kontakten in der dynamischen Okklusion anhand optisch digitalisierter Situationsmodelle.

In dentistry, mechanical articulators with which mandibular movements can be reproduced in dentals casts play a major role. Commonly used semiadjustable articulators, however, have major limitations: On the one hand, the movement of the mandible is not reproduced exactly, on the other, they do not provide time-related information on jaw movement. Both problems can be solved by replacing the mechanical articulator by a digital simulation ("virtual articulator") based on digitized plaster casts and electronically recorded masticatory movements. We present a system for the 3D measurement of plaster casts in a skull-related, anatomical coordinate system using the fringe projection technique, and electronically recorded condylar movements. Using numerical algorithms, the contacts between upper and low jaw, and the angle of rotation of the temporomandibular joint can be computed for each movement in dynamic occlusion. Taking the data recorded from a patient as an example, the influence of the accuracy of the digitization of plaster casts on the computation of the rotation of the temporomandibular joint is discussed in relation to the anatomy of the masticatory apparatus.

[Computer-assisted development of epitheses after optical recording of facial defects]. / Rechnergestützte Gestaltung von Epithesen nach optischer Abformung von Gesichtsdefekten.

A major drawback of conventional impression techniques used for customizing facial prostheses is the fact that pressure applied deforms soft tissue, thus reducing accuracy and causing patient discomfort. A possible solution is the use of optical 3-D coordinate measuring techniques, such as the fringe projection technique, which enables precise and contact-free recording of facial surfaces. The application of this method is demonstrated on a patient who lost his left eye and part of the jaw bone during surgery for cancer. 3-D CAD software that supports the construction of a facial prosthesis from the data obtained has been developed. For this purpose, spline functions are used to define border curves, and the intact half of the face is used as a model for the prosthetic surface. The resulting digital data are used to construct first a model made of synthetic resin, and then a final wax model with the aid of rapid prototyping techniques.

Technical implementation of an Internet address database with online maintenance module.

The article describes the technical implementation and management of the Internet address database of the center for ZMK (University of Münster, Dental School) Münster, which is integrated in the "ZMK-Web" website. The editorially maintained system guarantees its topicality primarily due to the electronically organized division of work with the aid of an online maintenance module programmed in JavaScript/PHP, as well as a database-related feedback function for the visitor to the website through configuration-independent direct mail windows programmed in JavaScript/PHP.

The influence of maxillary central incisor position in complete dentures on /s/ sound production.

STATEMENT OF PROBLEM: The insertion of prosthodontic restorations often leads to speech defects, most of which are transient but nevertheless a source of concern to the patient. For the dental practitioner, there are few guidelines on designing a prosthetic restoration with maximum phonetic success. PURPOSE: This study investigated the effect of different maxillary central incisor positions on phonetic patterns. MATERIAL AND METHODS: The inclination angle of central incisor blocks in duplicate complete maxillary dentures was changed in a range of -30 degrees to +30 degrees from the original position (0 degrees). Test words and sentences were acoustically analyzed. Spectral parameters such as first peak, noise band (defined by upper and lower limits of the most intensively blackened frequency area), Fast Fourier Transformation power spectrum, energy spectrum, and time were investigated. Influences of oral stereognosis, hearing, and age as cofactors on /s/ articulation were also taken into account. RESULTS: The change of incisor block angle in both directions usually caused a poorer execution of the /s/ sound. The labial angulation seemed to have a greater effect than the palatal angulation. The most significant changes were those in the noise band and energy spectrum. CONCLUSION: Immediate phonetic adaptation of prosthetic restorations in the maxillary incisor region can be achieved only if the original position of the natural teeth is transferred to the denture. Although these misarticulations are, in most cases, likely to disappear within a few weeks, they may persist and even lead to psychosocial problems. A better understanding of the causes of misarticulation and the limits of adaptation according to certain morphologic parameters of dentures is important.

Three-dimensional quantification of color-marked occlusal paths on anatomically oriented casts.

STATEMENT OF PROBLEM: The analysis of occlusal contacts on mounted diagnostic casts is an important task in prosthetic diagnostics. However, it is still restricted mainly to qualitative aspects because existing measuring techniques fail to provide 3-dimensional data for more than a few single points in acceptable time. PURPOSE: The aim of this study was to develop a method for quantifying occlusal contacts and paths by using anatomically oriented diagnostic casts and to design the method to allow fast acquisition of digital 3-dimensional coordinates. MATERIAL AND METHODS: Plaster casts with color-marked contacts were digitized optically with a profilometric system based on the fringe projection technique. Digital camera images taken simultaneously were used to define the contact areas by marking them either manually or automatically with the help of image-processing routines. Three-dimensional coordinates were determined by finding the corresponding points within the profilometric data set. RESULTS: Color-marked contact areas on diagnostic casts were successfully digitized with a computer-controlled, automatic setup in approximately 30 seconds. The accuracy of the acquired 3-dimensional data was estimated to be better than 60 microm in lateral and 30 microm in height resolution. The data set was visualized and evaluated in a skull related coordinate system. SUMMARY: This study verified the use of a new tool to quantify color-marked occlusal contacts on diagnostic casts in terms of spatial coordinates. The resulting digital data may be stored easily and analyzed numerically as well as visualized 3-dimensionally with computer graphic equipment. Because the anatomic orientation of the casts is maintained throughout the measurement process, it is possible to compare the data with electronically registered condyle paths and therefore to investigate, for example, their relation to the corresponding guidance paths of the frontal teeth and the canines in dynamic occlusion.

A pivoting appliance for intracavitary brachytherapy in patients with reduced mouth opening.

PURPOSE: The risks of radiotherapy to normal tissues are well known. In many cases, a tumor patient suffering a relapse cannot undergo radiotherapy a second time. One exception may be the local application of brachytherapy. Afterloading devices allow the position of radiating materials near the site for treatment exactly according to three-dimensional treatment planning. This report shows the technical procedure for the fabrication of an intracavitary afterloading radiation device. MATERIALS AND METHODS: A 48-year-old woman who had received neutron radiotherapy and tumor surgery for adenoid cystic carcinoma had to be treated for relapse. The mouth opening was limited to 15 mm. The mixing tip of a silicone impression system was used as an axis for a pivoting appliance. RESULTS: Two years after reradiation, the patient was free of relapse symptoms, although an increased limitation of mouth opening was recorded. CONCLUSION: Even if the mouth opening is severely limited after tumor surgery and/or radiation, intracavitary brachytherapy still can be performed in edentulous patients using a pivoting device.

Clinical anatomy and palpability of the inferior lateral pterygoid muscle.

STATEMENT OF PROBLEM: The intraoral palpation technique of the inferior belly of the inferior lateral pterygoid (ILP) muscle is a standard diagnostic examination method for temporomandibular joint dysfunction syndrome, although different studies have revealed inconsistent results. PURPOSE: This study assessed the feasibility of the ILP muscle palpation by a simulated clinical setting. MATERIAL AND METHODS: Three dentists performed a bilateral palpation of the ILP muscle in 53 fresh and unfixed human cadavers and decided whether the muscle was palpable or unpalpable. In a second step, it was observed through the dissected infratemporal fossa, whether the examiner's finger did or did not touch the ILP muscle by simulating the performed palpation. Palpatory findings were supplemented by 1-dimensional measurements for determination of topographic relations of the ILP muscle within the infratemporal fossa. For statistical analysis, sensitivity, specificity, and negative and positive predictive values of the palpation technique were calculated. Interexaminer agreement was estimated with the kappa value. RESULTS: In 86 of 106 dissected specimens, a superficial fascicle of the medial pterygoid muscle was found in direct proximity to the ILP muscle. In these cases, a residual distance of 7.8 +/- 3.2 mm remained between the ILP muscle and buccinator fascia indented by the tip of the examiner's finger. In 10 of 20 specimens with an absent superficial fascicle, the finger was able to reach the ILP muscle. CONCLUSION: It is recommended that the ILP muscle palpation technique should no longer be considered as a standard clinical procedure because it is nearly impossible to palpate the ILP muscle anatomically and because the risk of false-positive findings (by palpation of the medial pterygoid muscle) is high.

Three-dimensional visualization and quantification of the mandibular articular surface by optical profilometry.

The aim of this study was to introduce a nondestructive optical technique for the quantitative assessment of natural biological surfaces as demonstrated with the example of the articular surface of the human temporomandibular joint. The computer-assisted quantitative evaluation of the surface is realized by the acquisition of three-dimensional images via the optical technique of phase measuring profilometry. After mathematical processing of the data set the resulting image can be visualized as three-dimensional object surface reconstructions or as grid surfaces from which arbitrary sections may easily be extracted. From such single sections we can calculate a value that represents the degree of height deviations of the section profile and can be regarded as a parameter for the surface roughness. Further quantitative information about the surface topography is provided by the Fourier transform analysis of the profiles. The Fourier spectrum contains information about the spatial distribution of roughness-causing protuberances along the overall surface. As an example one healthy condyle and one remodeled condyle from macerated cadaver mandibles were investigated. For the two samples evaluated we calculated a mean surface roughness of the entire articular surface with a value of 0.03 +/- 0.005 mm for the healthy condyle with its smooth surface and a value of 0.14 +/- 0.009 mm for the remodeled condyle. We recommend optical profilometry as a sophisticated technique for a more objective and quantitative pathological classification of articular surfaces and similar objects.

[Effect of dental prosthesis on the voice]. / Der Einfluss der Zahnprothese auf die Stimme.

It is well known that alterations to the oral cavity caused by dental prostheses may affect speech articulation, although influences on the voice are not assumed. In addition to the vocal fundamental frequency, vibrations of the vocal chords generate overtones. Through the shape of the larynx and the upper airway, resonances and antiresonances are formed, and in this way overtones are amplified to a variable extent. Nozzle changes caused by a dental prosthesis in the oral cavity may possibly influence overtones but influences on the vocal fundamental frequency seem unlikely. The influence of dental prostheses on the voice is demonstrated in a patient who owned two different dental prostheses. The fundamental frequency rose by up to five semitones during speech and his vocal range increased by up to four semitones when a thin denture was used instead of a normal denture. When the position of the mandible was checked by intraoral needle point placement, a more rostral position of the mandible was recorded with the thin denture than with the normal denture. Sagittal magnetic resonance tomography imaging also showed that the larynx was in a more cranial position. This change was presumed to be due to an upward movement of the larynx induced by the tongue, which itself was found to be in a more cranial position with the thin denture. In this situation, increased tension of the laryngeal muscles were believed to induce a rise in fundamental frequency, shifting the voice range toward higher frequencies. These findings show that dental prostheses can cause vocal changes in individual cases. The etiology of this occurrence is still not clear. Its consequences, however, should be known to the dentist, ENT surgeon and phoniatrist if patients notice changes in their voice after having altered or replaced their dentures.

Zahnklinik Munster im Internet--Datenbankgestutzte Internetprasentation des Zentrums fur Zahn-, Mund- und Kieferheilkunde Munster (http:/(/)medweb.uni-muenster.de/institute/zmk/).

Since February 1997 the Departments of Dentistry and Oral & Maxillofacial Surgery of the University of Munster, Germany, can be visited on the Internet on more than 1400 HTML pages. These Web pages have been organized using an especially designed database which ensures standardized layout of the presented information and systematic navigation. A various amount of the Web pages are created fully automatically from a database (e.g. lectures, list of resources (URLs)); manually created pages are automatically adjusted concerning layout, integrated in the overall structure and given uniform navigation elements. Among other things, the database generates an interactive Web-site index (like a tree view), which facilitates search.

Can dental prostheses influence vocal parameters?

STATEMENT OF THE PROBLEM: Alterations to the oral cavity caused by dental prostheses can affect speech articulation, whereas the influence of dental prostheses on the voice is unknown. For 1 patient, the fundamental frequency rose by up to 5 semitones during speech and his voice range was enlarged by up to 4 semitones when a thin denture was used instead of his normal denture. In this patient, intraoral needlepoint registration revealed a more rostral position of the mandible with the thin denture when compared with the normal denture. PURPOSE: This study evaluated the effects of such changes on phonation by varying the dentures of 20 subjects in line with those of the first patient. MATERIAL AND METHODS: The volumes of the test dentures were reduced and the vertical and horizontal dimensions of occlusion were varied. The influences of these changed dentures on speaking fundamental frequency, voice range (in semitones), and lowest and highest frequencies of the voice range were examined with a Homoth phonomat. RESULTS: A statistically significant influence of the different dentures on the investigated voice parameters was not proven; however, audible changes to the voice parameters for persons were documented. CONCLUSIONS: Variations of thickness and or volume of dentures and of the vertical and horizontal dimension of occlusion may result in unpredictable audible changes to the voice. Patients should be informed about possible effects of modified or new dentures on their voice.

Three-dimensional acquisition and visualization of dental arch features from optically digitized models.

A method for the acquisition and evaluation of 3D coordinates from anatomically oriented plaster casts is presented, which is based on optical phase shifting profilometry (a fringe projection technique). With the computer-controlled setup, measurements from different views can be combined to obtain a complete three dimensional reconstruction of the model surface. To allow faster evaluation, the result is converted into a range image. From this digital data set the characteristic features like cusp tips can be identified and located semi-automatically. Based on these marks, quantitative values for differences between situation models like local displacements, e.g. during orthodontic treatment, can be determined. The results are visualized as interactively controllable 3D computer graphics, which helps to make spatial relations clearer.

Computer-aided axiography of asymptomatic individuals with Class II/2.

UNLABELLED: The condylar axiographic tracings of 23 asymptomatic adult volunteers (Helkimo-index DiO) with Class II/2 axiography relationships were compared to tracings of an analogous group (DiO; n = 30) with normal occlusion. The obtained measurements were evaluated statistically and discussed with respect to possible recording errors. RESULTS: The open-close movement proceeded uncharacteristically, differences existed only in protrusion, mediotrusion and their combined rotation component. In Class II/2 cases an approximately 7 degrees higher angle of the condylar path inclination (CPI) was measured. The Class II/2 group rotated to a significantly higher angle in protrusive and mediotrusive movements and showed longer condylar path lengths than the control group. Another significant difference was found in the location of maximum CPI values and maximum rotation angles within the condylar path, because in no case was isolated rotation or translation of the hinge axis observed. CONCLUSION: The temporomandibular joint of Class II/2 individuals shows a wider range of motion than joints of subjects with normal occlusion. The reduced capacity of motion which was assumed to exist in a so-called hack-bite could not be backed up for Class II/2 deep bite cases. The investigated differences cannot be seen as pathomechanisms, because all participants were clinically free of dysfunction. The neuromuscular engram to overcome the overbite controls a complex spatial motion pattern which cannot be described by a simplified mechanical abstraction of motion in the sagittal plane. The temporomandibular joint with its complex pattern of movement is able to create physiological mechanisms of compensation to react to different dental and skeletal features.

Computer-aided automated landmarking of cephalograms.

The computer-aided method presented is able to interpret and measure radiological structures automatically and reproducibly on a large number of randomly selected lateral head films of different film quality. For example the hard and soft tissue expression of the profile is used to discuss method, application and disadvantages. The performance of the system depends on image quality. The algorithm cannot be influenced by opacifications due to metal structure. In 90% of all cases the contours are identified correctly. Even if the image quality is poor, the recognition rate is about 84%. The selected cephalometric landmarks are placed in the right way in 85% of all cases. The constraint mathematical conditions and the high reproducibility improve the quality process of the cephalometric analysis. Recognition rates of 84% to 90% justify even nowadays the routine use of semi-automatic systems in PC-based analysis. With advancing digital radiography and improved computer performance, image interpreting systems will certainly become established.