Number and localization of occlusal contact areas on natural posterior teeth without dental findings - evaluations of the regional baseline study (SHIP-1) with the Greifswald Digital Analyzing System (GEDAS).

Sufficient occlusion is a basic prerequisite for the functional efficiency of the occlusal surfaces. Exactly where and in what number the occlusal contacts in the posterior region should be present for this purpose is controversial. The present study investigated the number and location of occlusal contacts on posterior teeth without dental findings, ie, without caries or restorative restorations such as fillings, crowns, etc. Such natural posterior teeth were present in 709 subjects (males (m) = 446: 48.9 ± 13.04 years, females (f) = 283: 52.4 ± 14.23 years) of a subject collective of 1223 subjects (m = 648, f = 575) of the regional baseline study 'Study of Health in Pomerania 1' (SHIP-1). Silicone bite registrations in habitual intercuspation (IP) were evaluated, whereby the test persons were asked to fix the bite block with biting force without biting firmly. The registrations were scanned with a document scanner in incident and transmitted light; a calibration strip was used to determine the transparency threshold of a layer thickness of 20 µm, below and equal to which the transparent zone was considered as a contact or contact area. The Greifswald Digital Analyzing System 2 (GEDAS 2) software was used to determine the number and location of occlusal contact areas tooth by tooth. To define the localization of the contacts, a cross with two concentric circles symmetric to the longitudinal fissure was superimposed on the occlusal surface; this resulted in four inner and four outer quadrants. Thus, the number of pixels in occlusal contact areas per inner and outer quadrant could be determined. The image resolution was 300 dpi. On average (median), the premolars had two occlusal contacts each, the posterior teeth had four to five, and tooth 46 had six contacts. The right and left teeth did not differ in the frequency of occlusal contacts in the Mann-Whitney U test for independent samples. In the maxillary premolars, frequent contact areas were primarily located mesially on the inner and outer slopes of the palatal cusp. In the maxillary molars, the palatal slope of the distopalatal cusp and the inner slopes of the mesiopalatal and distopalatal cusps were frequently affected. On the mandibular premolars, the inner slopes of the buccal cusps and the buccal slope of the distobuccal cusp were particularly frequently addressed; in teeth 35 and 45, the buccal slope of the mesiobuccal cusp was also somewhat more frequently addressed. Teeth 36 and 46 frequently had contact areas on the buccal slope of the distobuccal cusp as well as on the inner slopes of the distal cusps (distobuccal and distolingual), whereas teeth 37 and 47 tended to behave similarly. Epidemiologically, the focus of the frequent contact areas on the respective supporting cusps of the maxillary and mandibular posterior teeth and a distribution of contacts stabilizing the tooth in its position in the dental arch through the interlocking were confirmed. It makes sense to take this into account when designing occlusal surfaces in the posterior region.

5-year randomized multicenter clinical trial on single dental implants placed in the midline of the edentulous mandible.

OBJECTIVES: This multicenter randomized controlled clinical trial was conducted to investigate whether the loading protocol of single dental implants placed in the midline of edentulous mandibles will influence the implant survival or prosthetic maintenance. MATERIALS AND METHODS: In total, 158 patients were randomly assigned either to the immediate loading group (n = 81) or to the delayed loading group (n = 77). All implants were loaded with an overdenture retained by a ball attachment. RESULTS: After 5 years, 102 patients attended the follow-up investigation. Immediately loaded single implants in the midline of the edentulous mandible revealed a statistically significant lower survival rate than implants loaded conventionally over an observation period of 5 years. In the immediate loading group, 9 implants failed within the first three months of implant loading. No further implant loss was recorded for this group. Two implants failed in the delayed loading group, whereas one implant had to be removed during second-stage surgery and the second five years after implant loading. Non-inferiority of the survival rate of the midline implant of the immediate loading group, compared with the delayed loading group, could not be shown (p = .79, CI immediate loading: 74.9%; 100.0%, CI delayed loading: 73.0%; 100.0%). The observed difference in implant survival between the two treatment groups over time was statistically significant. CONCLUSIONS: The results of the present study indicate that immediate loading of a single mandibular implant in the edentulous mandible should be considered only in exceptional cases.

Computerized occlusal analysis - innovative approaches for a practice-oriented procedure.

A hands-on method for instrument-based occlusal analysis with digital technology is presented using a patient case example. The method is based on new software for digital occlusal analysis that includes a new measuring system for recording mandibular function (Jaw Motion Analyser Optic System/oJMA). With the new system, occlusal contact patterns in the real movement function of the mandible are captured and analyzed digitally with regard to occlusal interferences or a suitable therapeutic position of the mandible. For this purpose, scans of both jaws are brought together with the movement recordings by means of a special coupling tray and then visualized together as one complete image. Since the movement paths of the temporomandibular joints (TMJs) are also captured, the new system makes it possible to define a suitable therapeutic position specifically aimed at relieving the TMJs, and a therapeutic change in the jaw relation can be adjusted, for instance, by using an occlusal splint. Dedicated software modules provide a layer-by-layer analysis of the intercuspation relationship and the generation of 'envelopes' for occlusal gliding movements. This system is used to gain a deeper and more comprehensive understanding of the relationship between the structure and function of the occlusion. Interfaces to CAD software have also been established.

Crystal structure of Brucella abortus deoxyxylulose-5-phosphate reductoisomerase-like (DRL) enzyme involved in isoprenoid biosynthesis.

Most bacteria use the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the synthesis of their essential isoprenoid precursors. The absence of the MEP pathway in humans makes it a promising new target for the development of much needed new and safe antimicrobial drugs. However, bacteria show a remarkable metabolic plasticity for isoprenoid production. For example, the NADPH-dependent production of MEP from 1-deoxy-D-xylulose 5-phosphate in the first committed step of the MEP pathway is catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in most bacteria, whereas an unrelated DXR-like (DRL) protein was recently found to catalyze the same reaction in some organisms, including the emerging human and animal pathogens Bartonella and Brucella. Here, we report the x-ray crystal structures of the Brucella abortus DRL enzyme in its apo form and in complex with the broad-spectrum antibiotic fosmidomycin solved to 1.5 and 1.8 Å resolution, respectively. DRL is a dimer, with each polypeptide folding into three distinct domains starting with the NADPH-binding domain, in resemblance to the structure of bacterial DXR enzymes. Other than that, DRL and DXR show a low structural relationship, with a different disposition of the domains and a topologically unrelated C-terminal domain. In particular, the active site of DRL presents a unique arrangement, suggesting that the design of drugs that would selectively inhibit DRL-harboring pathogens without affecting beneficial or innocuous bacteria harboring DXR should be feasible. As a proof of concept, we identified two strong DXR inhibitors that have virtually no effect on DRL activity.

Distribution patterns of occlusal contact areas on natural posterior teeth - Evaluations of a cross-sectional population-based study with the Greifswald Digital Analyzing System (GEDAS).

AIM: The aim of our investigations is to optimize the anatomical basis for the design of a sufficient occlusal relationship, especially in view of the innovative technologies by analyzing the occlusal contact point patterns at cusp structures according to A-, B-, C- localization tooth by tooth on the individual occlusal surfaces in the posterior region in static habitual occlusal position. MATERIALS AND METHODS: In 3300 subjects of the population-based Study of Health in Pomerania (SHIP 1) the interocclusal registration in habitual intercuspation using silicone registration was used and analyzed by using the special evaluation software Greifswald Digital Analyzing System (GEDAS II). Chi square test was used to investigate whether the distribution of contact areas differed in the group of premolars or molars - each considered separately for maxilla and mandible - on the basis of the probability of error p < 0.05. RESULTS: In 709 subjects (446 male with a mean age of 48.9 ± 13.04 years; 283 female with a mean age of 52.4 ± 14.23 years) the antagonistic situation was specifically considered on natural posterior teeth without conservative or restorative-prosthetic interventions, i.e. without caries, fillings, crowns or other restorations. On the basis of these subjects, the silicone registrations were analyzed using GEDAS II. For the first and second upper molars, the ABC contact distribution was the most frequent: 20.4 % for the first and 15.3 % for the second molar. The second most frequent contact area for maxillary molars was area 0. The upper molars had contact areas only at the maxillary palatal cusp (B-/C-contacts). This contact relationship was most frequent in the maxillary premolar (18.1-18.6 %). In mandibular premolars, with the buccal cusps areas A and B were frequently involved (15.4-16.7 %). Mandibular molars showed a frequent contact pattern involving all A-, B-, C- and 0- contact areas (13.3-24.2 %). To capture the possible influence of the antagonistic dentition situation, the antagonistic situation was specifically considered and except for the mandibular premolars (p < 0.05) the contact distribution did not differ for molars and maxillary premolars regarding the dental status of the antagonistic teeth. Natural posterior teeth without occlusal contacts were observed from 20.0 % in the second lower molars to 9.7 % in the first upper molars. CONCLUSION: Our results suggest a clinically relevant due to the fact, that this study is the first population-based epidemiological study to analyze the occlusal contact point patterns at cusp structures according to A-, B-, C- localization tooth by tooth on the individual occlusal surfaces in the posterior region in static habitual occlusal position in order to optimize the anatomical basis for the design of a sufficient occlusal relationship.

Inhibition of the Yersinia pestis Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis by α-Phenyl-Substituted Reverse Fosmidomycin Analogues.

Fosmidomycin inhibits IspC (1-deoxy-d-xylulose 5-phosphate reductoisomerase), the first committed enzyme in the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis. The MEP pathway of isoprenoid biosynthesis is essential to the causative agent of the plague, Yersinia pestis, and is entirely distinct from the corresponding mammalian pathway. To further drug development, we established structure-activity relationships of fosmidomycin analogues by assessing a suite of 17 α-phenyl-substituted reverse derivatives of fosmidomycin against Y. pestis IspC. Several of these compounds showed increased potency over fosmidomycin with IC50 values in the nanomolar range. Additionally, we performed antimicrobial susceptibility testing with Y. pestis A1122 (YpA1122). The bacteria were susceptible to several compounds with minimal inhibitory concentration (MIC) values ranging from 128 to 512 µg/mL; a correlation between the IC50 and MIC values was observed.

Prodrugs of reverse fosmidomycin analogues.

Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.

Binding modes of reverse fosmidomycin analogs toward the antimalarial target IspC.

1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative 2c showed potent inhibition of PfIspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with PfIspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg(2+) were determined by X-ray structure analysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds.

IspC as target for antiinfective drug discovery: synthesis, enantiomeric separation, and structural biology of fosmidomycin thia isosters.

The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.

Reverse fosmidomycin derivatives against the antimalarial drug target IspC (Dxr).

Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.

gamma-Substituted bis(pivaloyloxymethyl)ester analogues of fosmidomycin and FR900098.

The synthesis and in-vitro antimalarial activity of gamma-substituted bis(pivaloyloxymethyl)ester analogues of the drug candidate fosmidomycin have been investigated. In contrast to the high antimalarial activity of alpha-aryl substituted fosmidomycin analogues like alpha-phenylfosmidomycin, gamma-substituted derivatives display only weak to moderate activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum.

Conformationally restrained aromatic analogues of fosmidomycin and FR900098.

The synthesis and in-vitro antimalarial activity of conformationally restrained bis(pivaloyloxymethyl) ester analogues of the natural product fosmidomycin is presented. In contrast to alpha-aryl-substituted analogues, conformationally restrained aromatic analogues exhibit only moderate in-vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The most active derivative displays an IC(50) value of 47 microM.