Molecular structure of LSD.

The molecular configuration of lysergic acid diethylamide (LSD) in crystals of the iodobenzoate has been determined by using x-ray diffraction techniques. The configuration shows strain and steric hindrance and the conformation is fixed. Some of the implications of this for the hallucinogenic activity of LSD are discussed.

Stress and inflammation as a detrimental combination for peri-implant bone loss.

The causes of peri-implant bone loss continue to be controversial. To determine the impact of biomechanical stress and inflammation, we investigated a total of 80 interforaminal implants in situ for more than 10 years. Two stress groups, with 14 patients each, were established: a low-stress situation with single-standing implants, and an increased-stress situation with splinted implants. To categorize inflammation, we introduced a Composite Inflammation Score using 4 inflammatory parameters. Peri-implant bone loss was calculated from digital panoramic radiographs. To differentiate between the effects of stress and inflammation, we compared bone loss in both stress groups at equivalent levels of inflammation. With greater Composite Inflammation Score values, a clear discrepancy between single-standing and splinted implants was evident (p = 0.117/0.000, regression analysis; p = 0.135/0.000, analysis of variance; p = 0.002, t tests). While stress and inflammation alone may not necessarily be detrimental factors, the presence of stress heightens peri-implant bone loss significantly as inflammation increases.

Composite Replacement of Amalgam Restoration Versus Freshly Cut Dentin: An In Vitro Microleakage Comparison.

OBJECTIVE: The aim of this study was to evaluate the microleakage of the composite restorations when bonded to tooth structure previously restored with amalgam material compared with that of freshly cut dentin. METHODS AND MATERIALS: Thirty intact, extracted intact human molars were mounted in autopolymerizing acrylic resin. Class II box preparations were prepared on the occluso-proximal surfaces of each tooth (4-mm bucco-lingual width and 2-mm mesio-distal depth) with the gingival cavosurface margin 1 mm above the CEJ. Each cavity was then restored using high copper amalgam restoration (Disperalloy, Dentsply) and then thermocycled for 10,000 thermal cycles. Twenty-five of the amalgam restorations were then carefully removed and replaced with Filtek Supreme Ultra Universal (3M ESPE); the remaining five were used for scanning electron microscopy and energy dispersive x-ray spectroscopy analysis. A preparation of the same dimensions was performed on the opposite surface of the tooth and restored with composite resin and thermocycled for 5000 thermal cycles. Twenty samples were randomly selected for dye penetration testing using silver nitrate staining to detect the microleakage. The specimens were analyzed with a stereomicroscope at a magnification of 20×. All of the measurements were done in micrometers; two readings were taken for each cavity at the occlusal and proximal margins. Two measurements were taken using a 0-3 scale and the percentage measurements. RESULTS: Corrosion products were not detected in either group (fresh cut dentin and teeth previously restored with amalgam). No statistically significant difference was found between the microleakage of the two groups using a 0-3 scale at the occlusal margins (McNemar test, p=0.727) or proximal margins (Wilcoxon signed-rank test, p=0.174). No significance difference was found between the two groups using the percentage measurements and a Wilcoxon signed-rank test at either the occlusal (p=0.675) or proximal (p=0.513) margins. However, marginal microleakage was statistically significant between the proximal and occlusal margins (p<0.001). CONCLUSION: Within the limitations of this in vitro study, no significant difference was found between the microleakage of nondiscolored dentin in teeth that were previously restored with amalgam compared with freshly cut dentin. However, marginal microleakage in the proximal surface was higher than that in the occlusal surface.

Design and synthesis of a rapamycin-based high affinity binding FKBP12 ligand.

BACKGROUND: The immunosuppressants rapamycin, ascomycin, FK506, and cyclosporin act by binding to a class of cytosolic proteins, the immunophilins. In the case of FK506, ascomycin and cyclosporin, the target of the immunophilin-immunosuppressant complex is calcineurin; in the case of rapamycin, the target is FRAP (TOR/RAFT1). Rapamycin, ascomycin and FK506 have a common domain responsible for binding to FKBP12, their cellular receptor, and different effector domains that determine the target of the complex. Both domains are necessary for signal transduction and biological activity. RESULTS: A hybrid molecule containing the rapamycin-FK506-ascomycin binding domain and a peptide tether has been designed, synthesized and biologically evaluated. The designed compound binds to FKBP12 with high affinity but has no biological activity, as expected from its lack of an effector domain. CONCLUSIONS: The designed rapamycin-based FKBP12 ligand exhibits powerful binding properties but, unlike rapamycin, shows no activity in IL-6 dependent B-cell proliferation and, in contrast to FK506, shows no activity in the IL-2 reporter assay. The modular nature of this designed molecule should make it possible to generate a series of compounds with effector domains for targeting either calcineurin or FRAP (TOR/RAFT1) or both, as potential biological tools and immunosuppressive agents.

The lack of effect of chronic metabolic acidosis on 25-OH-vitamin D metabolism and serum parathyroid hormone in humans.

We evaluated the turnover of the plasma 25-OH-vitamin D pool, acid, and mineral balances in paired balance studies of 6 normal subjects during normal acid base conditions and during stable chronic metabolic acidosis induced by NH4Cl. Positive acid balances and negative Ca balances due to hypercalciuria were observed as previously reported. Plasma 25-OH-D pool turnover averaged 6.1+/-0.4 nmol/day during control and did not change during acidosis (6.5 +/- 0.5 nmol/day) nor were any significant increments in net intestinal absorption of Ca, PO4, or Mg, the physiological expression of vitamin D action, observed during acidosis. In 3 other subjects, repetitive measurements of serum iPTH during 7 control days and 24 days of stable NH4Cl acidosis showed no changes. We interpret the data to support the hypothesis that neither PTH nor vitamin D and its metabolites mediates the increase in net bone resorption that must accompany chronic metabolic acidosis.

The 3D-structure of a natural inhibitor of cell adhesion molecule expression.

The three-dimensional structure of cyclopeptolide HUN-7293, a naturally-occurring inhibitor of cell adhesion molecule expression, has been determined from nuclear magnetic resonance data recorded in solution and from X-ray diffraction analysis of single crystals. The backbone conformation of HUN-7293 is characterized by two cis-peptide bonds in both the solution and crystalline state. Differences between the solution and crystal structure are visible for the orientation of some side chains and the strength of two transannular hydrogen bonds. Such structural information helps to provide insight into the molecular architecture of HUN-7293 on the atomic level and opens the way for structure-based modifications of this novel inhibitor of cell adhesion molecule expression.

Cyclosporin A-cyclophilin complex formation. A model based on X-ray and NMR data.

The previously determined 3D NMR solution structure of cyclophilin-bound cyclosporin A (CsA) was docked onto the X-ray crystal structure of cyclophilin. Intermolecular nuclear Overhauser effects (NOE) between CsA and cyclophilin were used as constraints in a restrained energy minimization to generate a model of the complex which satisfied all the NOE distance constraints. The model shows that the residues 9 to 11 and 1 to 5 of the cyclic CsA molecule are in contact with cyclophilin. Comparing the model of the CsA-cyclophilin complex to the X-ray crystal structure of a complex of cyclophilin with a substrate for peptidyl-proline cis-trans isomerase activity, i.e. the linear tetrapeptide substrate ac-Ala-Ala-Pro-Ala-amc (ac, acetyl; amc, amidomethylcoumarin), one notices that the contacting peptide segments in the two ligands are oriented in opposite directions, and that the side chain of MeVal-11 of CsA superposes rather precisely with the position of the prolyl residue in ac-Ala-Ala-Pro-Ala-amc.

Centrally acting alpha 1-adrenoceptor agonists based on hexahydronaphth[2,3-b]-1,4-oxazines and octahydrobenzo[g]quinolines.

Centrally acting alpha 1-agonists may be of therapeutic value in dementias and other CNS disorders characterized by symptoms of noradrenergic insufficiency. Therefore, on the basis of known peripherally acting alpha 1-agonists two new groups of centrally acting alpha 1-agonists with improved lipophilicity, the hexahydronaphth[2,3-b]-1,4-oxazines type A and the octahydrobenzo[g]quinolines type B were designed. The N-methylated derivatives 14 and 33 demonstrate potent, direct agonistic activity at postjunctional alpha 1-receptors. Ring substituent alterations in compounds of type A and B change the potency of compounds on the rabbit ear artery by over 3 orders of magnitude (pD2 = 5.35-8.40). The efficacy of these compounds varies from 42 to 110%. Those alpha 1-agonists which were selective in the pithed rat increase vigilance in rats. Compound 14 was found to be a centrally acting alpha 1-agonist with good tolerability in different animal species and in healthy volunteers. Furthermore, 14 selectively stimulates the breakdown of phosphatidylinositol in rat cerebral cortex slices. In vivo, the compound reverses behavioral deficits in animals which received noradrenergic lesions following DDC or DPS4 treatment. Oxazine 14 and its close derivatives are by far more lipophilic than commonly known alpha 1-agonists. This is demonstrated in a ClogP-PROBIS plot.

Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations.

T-cell immunosuppressant-based therapies efficiently control early graft rejection in allotransplantation settings. They fail, however, to prevent those rejection events which are mediated by transplant-induced antibody (Ab) responses such as those involved in xenograft and chronic allograft rejection. This is mainly due to their inability to block T-cell-independent Ab production against the transplanted organs. The bioactive metabolite 2(Z) of leflunomide (1) inhibits the formation of such Ab, but the drug has pharmacokinetic properties and a therapeutic window incompatible with transplantation indications. Pyrazole 3, a constrained analogue of 2(Z), was designed and shown to be conformationally and biologically similar to 2(Z). Further investigations with derivatives of 3 demonstrated that the pyrazoles had very tight structure-activity relationships, the only equipotent compound being 3o. However, in contrast to 2(Z), both 3 and 3o were inactive in vivo due to short half-life and drug concentrations lower than the in vitro obtained IC50 values. Compound 3o inhibits T-cell-independent Ab production by a different biochemical mechanism from that of 2(Z) and 3 and may therefore represent a valuable tool for the identification of new targets for B-cell inhibition.

Light and transmission electron microscopy of the intact interfaces between non-submerged titanium-coated epoxy resin implants and bone or gingiva.

This experiment was aimed at studying the intact tissue/implant interface of non-submerged dental implants with a titanium surface. Epoxy-resin replicas were fabricated from 3.05 x 8 mm cylindrical titanium implants with a plasma-sprayed apical portion and a smooth coronal collar. The replicas were coated with a 90-120-nm-thick layer of pure titanium and autoclaved. The coated replicas were inserted as non-submerged endosseous implants in the edentulous premolar region of dog mandibles and allowed to heal for three months. Jaw sections containing the implants were processed for light and electron microscopic study of the intact tissue/implant interface with and without prior demineralization. Gingival connective tissue fibers were closely adapted to the titanium layer, in an orientation more or less parallel to the implant surface. There was no evidence of any fiber insertions into the surface irregularities of the smooth or rough titanium surface. Undemineralized bone was intimately adapted to the titanium surface without any intervening space. In demineralized sections, the collagen fibers of the bone matrix tended to be somewhat thinner and occasionally less densely packed in the vicinity of the implant surface. However, they extended all the way to the titanium surface, without any intervening fibril-free layer.

Side-Firing Fiber Device for Underwater Tissue Ablation with Ho:YAG and Er:YAG Laser Radiation.

A side-firing fiber device for arthroscopic Ho:YAG (λ=2.12 µm) and Er:YAG (λ=2.94 µm) laser applications was designed and constructed. The fiber delivery instrument consisted of a zirconium fluoride (ZrF4) fiber equipped with a coaxially mounted short end-piece of low OH- quartz fiber polished at an angle of 30 deg. The dynamics and depth of the vapor channel in water and the amplitude of pressure transients associated with the collapse of the vapor channel were measured for pulse energies up to 1 J (Ho:YAG) and 200 mJ for the Er:YAG laser (pulse duration τ=400 µs), respectively. To assess the feasibility of the side-firing fiber delivery instrument, the ablation efficiency and laser-induced damage in poly(acylamide) and meniscal tissue were determined after Ho:YAG and Er:YAG laser ablation. © 1998 Society of Photo-Optical Instrumentation Engineers.

Anatomical observations of the subarachnoid cisterns of the brain during surgery.

Subarachnoid cisterns and their contents are described briefly in the light of observations made during microsurgical explorations. The concept of intracranial surgery in terms of moving from one cistern to another is presented here with particular emphasis on the cisterns in surgical approaches to intracranial vessels and nerves for the treatment of aneurysms, arteriovenous malformations, and for surgery of basal tumors.

Temporal backward projection of optoacoustic pressure transients using fourier transform methods.

In medical imaging different techniques have been developed to gain information from inside a tissue. Optoacoustics is a method to generate tomography pictures of tissue using Q-switched laser pulses. Due to thermal and pressure confinement, a short light pulse generates a pressure distribution inside tissue, which mirrors absorbing structures and can be measured outside the tissue. Using a temporal back-projection method, the pressure distribution measured on the tissue surface allows us to gain a tomography picture of the absorbing structures inside tissue. This study presents a novel computational algorithm, which, at least in principle, yields an exact reconstruction of the absorbing structures in three-dimensional space inside the tissue. The reconstruction is based on 2D pressure distributions captured outside at different delay times. The algorithm is tested in a simulation and back-projection of pressure transients of a small absorber and a single point source.

Transcatheter laser atrial septostomy in rabbits.

The feasibility of percutaneous transluminal catheter-directed laser (Argon multiline 488/514 nm) atrial septostomy under echocardiographic guidance was studied in eight rabbits. In five animals the interatrial septum was exposed to laser energy for 30 s (n = 1) or for 10 s (n = 4) by using the continuous wave (cw) mode of irradiation. In the other three animals chopped mode of irradiation was applied for 10 s at 7 W. Echocardiography allowed visualization of both atrial cavities and the interatrial septum, the tip of the catheter including the optical fiber tip as well as the flow direction of contrast echoes during the laser firing. Blood clotting with thrombus formation was present following the cw mode of irradiation. The defects created in the interatrial septa of < or = 0.3 mm in diameter had irregular black borders and, histopathologically, were surrounded by a zone of coagulation necrosis of < or = 0.2 mm and vacuolization (vacuoles of < 0.1 mm in diameter). After 30 s of lasering a huge defect was conspicuous in the interatrial septum which extended up to the right and left atrial roof. The chopped mode of irradiation induced less blood clotting and narrow channels of < or = 0.08 mm through the interatrial septa with a small zone of coagulation necrosis of < or = 0.05 mm and without carbonization and vacuolization. This study demonstrates that laser atrial septostomy is technically feasible. However, prior to the extension of the method to humans, further investigation especially considering other laser power sources, possibly more suitable for this application such as Neodymium-YAG or Excimer lasers is warranted.

A time-dependent healing function for immediate loaded implants.

Current interest in immediate dental implant loading has grown due to a number of clinical advantages this treatment modality offers. To obtain a deeper insight into the changing mechanical properties during the healing phase, results from removal torque tests are used in a biomechanical model. The ultimate removal torques, which depend on healing time, are described by a time-dependent healing function. The bone behavior is modeled using an elastic law with damage. The evolution of damage is represented with an incremental equation with an initial damage value and two material parameters. The nonlinear relationship between the torque and the angle of rotation up to the ultimate torque can be calculated. By changing the elastic parameter in the elastic damage law, the remodeling process can be characterized. In a further step, the elastic parameters and the limits for shear stress from the biomechanical model for the removal torque will be used in an FE analysis in order to obtain information on the axial loading limits of a dental implant at different healing times.

Postnatal development of tubular phosphate reabsorption.

In 51 infants (0.5-12 months) and 143 children (1-15 years), the postnatal development of renal phosphate handling could be studied by short term clearance investigations. The infants demonstrated significantly higher values of plasma phosphate (Pp), urinary phosphate excretion and endogenous phosphate clearance than the children. Net tubular phosphate reabsorption (Tp) was low infancy due to low glomerular filtration rate (CIn). The fractional phosphate reabsorption (Tp/CIn), however, was significantly higher in infancy than in childhood. There was a close correlation between fractional phosphate reabsorption and plasma phosphate for both children and infants. When the regression lines of Pp to Tp/CIn were analyzed separately for children and infants, a parallel shift was recognized, which means that at each level of Tp/CIn infants had higher plasma phosphate concentrations than children. Evaluation of available data suggests that the shift was very probably related to low CIn in the young infants which may lead to further retention of phosphate.

Guided bone regeneration utilizing expanded polytetrafluoroethylene membranes in combination with submerged and nonsubmerged dental implants in beagle dogs.

Treatment of partial and total edentulism with submerged and nonsubmerged dental implants which follows the concept of osseointegration has become an accepted treatment modality. With compromised implant sites, practitioners have begun to combine one-stage implants with established techniques including guided bone regeneration. However, the clinical evaluation of this technique is limited. Therefore, the purpose of this study was to evaluate osseointegration and bone regeneration around nonsubmerged or submerged implants placed directly into surgically created osseous defects with or without expanded polytetrafluoroethylene (ePTFE) membranes. A total of 24 implants were placed in the mandibles of 4 beagle dogs and randomly assigned to 1 of 3 treatment groups. In group A, nonsubmerged implants were placed into osseous defects and treated with a poncho style ePTFE membrane. These membranes had a hole punched into the center and were slipped over the nonsubmerged implants. In group B, nonsubmerged implants were placed into osseous defects without an ePTFE membrane. In group C, submerged implants were placed into osseous defects and covered with an ePTFE membrane. Histometric measurements of each treatment group were made to determine percent bone gain or loss along the implant surface. Although a number of membrane removals occurred during the healing period, histological analysis indicated osseous ingrowth and osseointegration around nonsubmerged and submerged implants. An overall comparison of the treatment groups with ANOVA revealed that there were no significant differences between treatment groups, P > or = 0.05. However, when the data were stratified into sites which retained or lost the ePTFE membrane, the percent of bone regeneration was reduced in group A. Therefore, it may be recommended that nonsubmerged implants be placed with a submerged or "semi-submerged" protocol when utilized in conjunction with ePTFE membranes.

Soft tissue reactions to non-submerged unloaded titanium implants in beagle dogs.

The soft tissue reactions to non-submerged unloaded titanium implants were examined. A total of 24 implants were placed in 6 beagle dogs. The implants differed in their crestal area by having either a rough sandblasted, a fine sandblasted, or a polished surface. After 3 months, all implants were firmly anchored in the bone and had no clinical signs of peri-implant inflammation. Undecalcified histologic sections demonstrated that all implants achieved osseointegration with direct bone contact. The epithelial structures showed a peri-implant sulcus with a non-keratinized sulcular epithelium and a junctional epithelium. None of the sections exhibited epithelial downgrowth to the alveolar crest. In the supracrestal area, a direct connective tissue contact to the implant post was observed. An approximately 50 to 100 microns wide zone of dense circular fibers was found close to the implant surface. It was free of blood vessels and resembled closely an inflammation-free scar tissue formation. This zone was surrounded by a looser connective tissue with a 3-dimensional network of collagen fibers running in different directions. No significant differences concerning soft tissue reactions were found between the 3 implant surfaces. In particular, the length of direct connective tissue contact was similar. Concerning bone reactions, a significantly shorter distance from the top of the implant to the most coronal bone-implant contact was observed for rough surfaces. It is concluded that non-submerged unloaded titanium implants achieved a complication-free tissue integration with a dense connective tissue in direct contact to the implant surface in the supracrestal area, and epithelial structures similar to those around natural teeth. The different surface textures did not influence the healing pattern of the soft tissues, but had an influence on the location of the most coronal bone-implant contact.

A radiographic evaluation of bone healing around submerged and non-submerged dental implants in beagle dogs.

BACKGROUND: The rehabilitation of the oral cavity with dental implants has become a predictable treatment modality. However, there have been only a few direct comparisons evaluating the submerged and nonsubmerged placement techniques. The purpose of this study was to characterize radiographic peri-implant bone changes following the insertion of submerged and nonsubmerged implants in the beagle dog. METHODS: At the end of the extraction healing phase, 19 submerged and 19 nonsubmerged implants were randomly placed in a split-mouth study design and observed over an 18-week period. For submerged implants, a second stage surgery and transmucosal abutment attachment was performed at week 12. Standardized dental radiographs taken at baseline, week 12, and week 18 were used to measure peri-implant bone changes. The radiographs were analyzed with a simple computer assisted method. RESULTS: A total of 43 standardized radiographs were exposed to evaluate the 38 implants. During the study period, all submerged and nonsubmerged implants demonstrated peri-implant bone loss. At baseline, both submerged and nonsubmerged implants had similar bone levels (P > or = 0.05). When the mean peri-implant bone levels for submerged and nonsubmerged implants were compared from baseline to week 12, nonsubmerged implants had a significantly greater amount and rate of bone resorption than submerged implants (P < or = 0.05). Following week 12, the initially submerged implant had a significantly higher rate and amount of peri-implant bone loss than the nonsubmerged implants (P < or = 0.05). However, by the end of the study period, week 18, both submerged and nonsubmerged implants had comparable bone levels (P > or = 0.05). CONCLUSIONS: The study indicates that, although the temporal patterns of peri-implant bone resorption differed, there were no differences between submerged and nonsubmerged implants in the overall amount and rate of peri-implant bone loss.

Microbiota of successful osseointegrated dental implants.

BACKGROUND: The long-term survival of dental implants depends, in part, on control of bacterial infection in the peri-implant region. Periodontal pathogens colonized implants symptomatic through infection, whereas the microbiota of successful implants was similar to that of periodontal health. This study examined the impact on the peri-implant microbiota of crown restorations; implant type; length of time of loading; history of implant or periodontal infections; and whether implants replaced single or multiple teeth. It was of particular interest to evaluate implant colonization by species in a newly described red complex of periodontal pathogens, Porphyromonas gingivalis and Bacteroides forsythus. METHODS: This study sampled 43 partially edentulous subjects with successfully osseointegrated titanium root-form dental implants. Eighty-one (81) non-submerged and 20 submerged asymptomatic implants, 83 crowned, and 36 uncrowned teeth were sampled from peri-implant or subgingival sites. The microbiota of samples was evaluated using whole genomic DNA probes in a checkerboard assay to 23 subgingival species. RESULTS: Implants were colonized principally by oral streptococci, capnocytophagae, Veillonella parvula, Peptostreptococcus micros, and Fusobacterium nucleatum. The periodontal species, P. gingivalis, B. forsythus, Prevotella intermedia, Prevotella nigrescens, and Campylobacter rectus were detected in a few subjects. The microbiota around crowned implants and crowned teeth was similar. Streptococcus oralis, P. intermedia, and Selenomonas noxia were elevated in samples from uncrowned teeth compared to crowned teeth and implants. Microbial complexity increased as loading time increased, but colonization by periodontal pathogens, including red complex species, was higher in subjects with previous periodontal disease. No differences were observed in the microbiota of 1- and 2-stage implants, or between implants supporting single or multiple restorations. CONCLUSIONS: While presence of crowns had only a minor impact on the peri-implant microbiota, microbial changes were observed the longer the implants had been in function and in those patients with a history of periodontal or peri-implant infections. A history of periodontitis had a greater impact on the peri-implant microbiota than implant loading time. The major influence on the peri-implant microbiota was, however, the microbiota on remaining teeth. P. gingivalis and B. forsythus, red complex periodontal pathogens, colonized several implants, although all implants were successfully osseointegrated.