Group 5 ITI Consensus Report: Digital technologies.

OBJECTIVES: Working Group 5 was assigned the task to review the current knowledge in the area of digital technologies. Focused questions on accuracy of linear measurements when using CBCT, digital vs. conventional implant planning, using digital vs. conventional impressions and assessing the accuracy of static computer-aided implant surgery (s-CAIS) and patient-related outcome measurements when using s-CAIS were addressed. MATERIALS AND METHODS: The literature was systematically searched, and in total, 232 articles were selected and critically reviewed following PRISMA guidelines. Four systematic reviews were produced in the four subject areas and amply discussed in the group. After emendation, they were presented to the plenary where after further modification, they were accepted. RESULTS: Static computer-aided surgery (s-CAIS), in terms of pain & discomfort, economics and intraoperative complications, is beneficial compared with conventional implant surgery. When using s-CAIS in partially edentulous cases, a higher level of accuracy can be achieved when compared to fully edentulous cases. When using an intraoral scanner in edentulous cases, the results are dependent on the protocol that has been followed. The accuracy of measurements on CBCT scans is software dependent. CONCLUSIONS: Because the precision intraoral scans and of measurements on CBCT scans and is not high enough to allow for the required accuracy, s-CAIS should be considered as an additional tool for comprehensive diagnosis, treatment planning, and surgical procedures. Flapless s-CAIS can lead to implant placement outside of the zone of keratinized mucosa and thus must be executed with utmost care.

Evolving maps in craniofacial development.

The shaping of the vertebrate head results from highly dynamic integrated processes involving the growth and exchange of signals between the ectoderm, the endoderm, the mesoderm and Cephalic Neural Crest Cells (CNCCs). During embryonic development, these tissues change their shape and relative position rapidly and come transiently in contact with each other. Molecular signals exchanged in restricted regions of tissue interaction are crucial in providing positional identity to the mesenchymes which will form the different skeletal and muscular components of the head. Slight spatio-temporal modifications of these signalling maps can result in profound changes in craniofacial development and might have contributed to the evolution of facial diversity. Abnormal signalling patterns could also be at the origin of congenital craniofacial malformations. This review brings into perspective recent work on spatial and temporal aspects of facial morphogenesis with particular focus on the molecular mechanisms of jaw specification.

Block versus random amphiphilic copolymers as antibacterial agents.

We examined the antibacterial and hemolytic activities in a series of amphiphilic block and random copolymers of poly(vinyl ether) derivatives prepared by base-assisting living cationic polymerization. Block and random amphiphilic copolymers with similar monomer compositions showed the same level of activity against Escherichia coli . However, the block copolymers are much less hemolytic compared to the highly hemolytic random copolymers. These results indicate that the amphiphilic copolymer structure is a key determinant of activity. Furthermore, the block copolymers induced dye leakage from lipid vesicles consisting of E. coli -type lipids, but not mammalian lipids, while the random copolymers disrupted both types of vesicles. In addition, both copolymers displayed bactericidal and hemolytic activities at concentrations 1 or 2 orders of magnitude lower than their critical (intermolecular) aggregation concentrations (CACs), as determined by light scattering measurements. This suggests that polymer aggregation or macromolecular assembly is not a requisite for the antibacterial activity and selectivity against bacteria over human red blood cells (RBCs). We speculate that different single-chain conformations between the block and random copolymers play an important role in the antibacterial action and underlying antibacterial mechanisms.

An endothelin-1 switch specifies maxillomandibular identity.

Articulated jaws are highly conserved structures characteristic of gnathostome evolution. Epithelial-mesenchymal interactions within the first pharyngeal arch (PA1) instruct cephalic neural crest cells (CNCCs) to form the different skeletal elements of the jaws. The endothelin-1 (Edn1)/endothelin receptor type-A (Ednra)-->Dlx5/6-->Hand2 signaling pathway is necessary for lower jaw formation. Here, we show that the Edn1 signaling is sufficient for the conversion of the maxillary arch to mandibular identity. Constitutive activation of Ednra induced the transformation of upper jaw, maxillary, structures into lower jaw, mandibular, structures with duplicated Meckel's cartilage and dermatocranial jaws constituted by 4 dentary bones. Misexpression of Hand2 in the Ednra domain caused a similar transformation. Skeletal transformations are accompanied by neuromuscular remodeling. Ednra is expressed by most CNCCs, but its constitutive activation affects predominantly PA1. We conclude that after migration CNCCs are not all equivalent, suggesting that their specification occurs in sequential steps. Also, we show that, within PA1, CNCCs are competent to form both mandibular and maxillary structures and that an Edn1 switch is responsible for the choice of either morphogenetic program.

Transradial retrieval of unintentionally extracted stent deployed 8 months prior during percutaneous coronary intervention to the stent-jailed side branch.

We experienced a case in which a previously deployed stent was extracted during a percutaneous coronary intervention to the stent-jailed side branch by the transradial approach. The stent was dislodged in the radial artery, was fully expanded, and partially deformed, making it difficult to retrieve via the radial sheath. Using a handmade flared guiding catheter, the expanded deformed stent was successfully retrieved via a 6-Fr radial sheath.

[A case report of implantation in augmented bone by guided bone regeneration technique].

PATIENT: A 53-year-old female with root fracture of the second premolar in the right mandible underwent implant therapy. After extraction, the GBR (guided bone regeneration) technique was applied to the bone defect in June 2000. At 6 months after GBR, implants were placed in the augmented bone. The final prosthesis was restored in July 2001. DISCUSSION: The bone around the implants was evaluated by using X-ray CT images, before and after GBR, and three years after final restoration. The three images showed the same bone conditions around the implants. CONCLUSION: It is important to evaluate bone condition around implants using X-ray CT. Bone defects can be augmented by the GBR technique, and the bone condition around the implants was stable after function.

Load evaluation of the da Vinci surgical system for transoral robotic surgery.

Transoral robotic surgery, performed with the da Vinci surgical system (da Vinci), is a surgical approach for benign and malignant lesions of the oral cavity and laryngopharynx. It provides several unique advantages, which include a 3-dimensional magnified view and ability to see and work around curves or angles. However, the current da Vinci surgical system does not provide haptic feedback. This is problematic because the potential risks specific to the transoral use of the da Vinci include tooth injury, mucosal laceration, ocular injury and mandibular fracture. To assess the potential for intraoperative injuries, we measured the load of the endoscope and the instrument of the da Vinci Si surgical system. We pressed the endoscope and instrument of the da Vinci Si against Load cell six times each and measured the dynamic load and the time-to-maximum load. We also struck the da Vinci Si endoscope and instrument against the Load cell six times each and measured the impact load. The maximum dynamic load was 7.27 ± 1.31 kg for the endoscope and 1.90 ± 0.72 for the instrument. The corresponding time-to-maximum loads were 1.72 ± 0.22 and 1.29 ± 0.34 s, but the impact loads were significantly lower than the dynamic load. It remains possible that a major load is exerted on adjacent structures by continuous contact with the endoscope and instrument of da Vinci Si. However, there is a minor delay in reaching the maximum load. Careful monitoring by an on-site assistant may, therefore, help prevent contiguous injury.

Mechanical evaluation of newly developed mouthpiece using polyethylene terephthalate glycol for transoral robotic surgery.

Transoral robotic surgery (TORS), performed with the da Vinci surgical system (da Vinci), has been classified as a surgical approach for benign and malignant lesions of the oral cavity and laryngopharynx. It provides several unique advantages, which include a three-dimensional magnified view, ability to see and work around curves or angles, and the availability of two or three robotic arms. At present, however, the da Vinci surgical system does not provide haptic feedback. The potential risks specific to the transoral use of the da Vinci include tooth injury, mucosal laceration, ocular injury, and mandibular fracture. To prevent such intra-operative tooth injuries, we created a mouthpiece made of polyethylene terephthalate glycol (PETG) individually shaped for the patient's teeth. We compared the safety and efficacy of the PETG mouthpiece with those of a conventional mouthpiece made of ethylene-vinyl acetate (EVA). To determine the difference in tooth injury resulting from the two types of mouthpiece, we constructed an experimental system to measure load and strain. We measured the dynamic load and the strain from the rod to the tooth using the PETG and EVA mouthpiece. The rod was pressed against the tooth model outfitted with two types of mouthpiece and the dynamic load was measured with a load cell and the strain with a strain gage. The maximum dynamic load was 1.29 ± 0.03 kgf for the PETG mouthpiece and 2.24 ± 0.05 kgf for the EVA mouthpiece. The load against the tooth was thus less for the EVA mouthpiece. The strain was -166.84 ± 3.94 and 48.24 ± 7.77 µÎµ, respectively, while the load direction was parallel to that of the tooth axis for the PETG mouthpiece and perpendicular to the tooth axis for the EVA mouthpiece. The PETG mouthpiece reduced the tooth load compared with the EVA mouthpiece and the load direction was in parallel to the tooth axis. The PETG mouthpiece thus enhances tooth safety for TORS.

Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan.

The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.

Inflammatory tumor in pancreatic tail induced by endoscopic ablation with cyanoacrylate glue for gastric varices.

A 65-year-old Japanese man was hospitalized with back pain in April 1998. At age 63 years, endoscopic ablation with cyanoacrylate glue had been performed for bleeding gastric varices. At the time of the present admission, a low-density mass (about 23 mm in diameter) was seen in the tail of the pancreas, and splenic vein occlusion and collateral veins were revealed on computed tomography. A hypoechoic tumor (about 22 mm in diameter) and splenic vein occlusion were clearly visualized on the pancreas tail via endoscopic ultrasonography. Venous phase of the splenic arteriogram revealed a completely occluded splenic vein in the hilus of the spleen. Thus, the patient was diagnosed with pancreatic cancer (stage I: T2N0M0). A surgical resection of the pancreatic tumor was performed, and a pancreatic tail resection with part of stomach around the pancreas tail, and splenectomy, were selected for this patient, in June 1998. Histopathological examination of the resected tumor revealed capsuled abscess formation with foreign body reaction between the stomach and the pancreas tail, and necrosis was present in the pancreas around the abscess. There were some deposits of cyanoacrylate glue in the tumor. The mass was considered to be an inflammatory tumor. In summary, this case of inflammatory pancreas tumor is a novel complication after endoscopic obliterative therapy with cyanoacrylate glue.

[A statistical survey of the fabrication of single restorations (in 2002)].

A statistical survey based on laboratory records was carried out to determine the state of fabrication of restorations at the dental hospital of Tokyo Medical and Dental University during the six month period from April 1 to September 30, 2002. A comparison was also done with a previous survey that had been carried out in 1986 and 1997 to detect the possible change and alternations in the near future. From the findings of this survey, the following conclusions can be drawn. 1. A total of 7,864 restorations were fabricated during the six months in 2002, and of these, 6,740 restorations (85.7%) were covered by health insurance, and 1,124 (14.3%) were not. 2. Compared with the previous data in 1986 and 1997, decreased numbers of inlays and cast post & cores were the distinctive features that affected the decrease of total numbers. 3. The rate of restorations that were not covered by health insurance slightly increased to 14.3%, compared with 12.3% in 1997.

[Statistical analysis of the fabrication of fixed and removable partial dentures (in 2002)].

A statistical survey based on laboratory records was performed on the number of fixed partial dentures and removable partial dentures fabricated at the dental hospital of Tokyo Medical and Dental University from April 1 to September 30, 2002. A comparison was also performed with a previous survey that had been carried out in 1997 to detect any change and possible alternations in the near future. From the findings of this statistical survey, the conclusions were as follows: 1. A total of 2,656 fixed and removable partial dentures were fabricated during the six-month period in 2002. 2. The 3-unit fixed partial denture was most common (64.0%), and the number of fixed partial dentures decreased as the number of units increased. 3. For a single missing tooth, a fixed partial denture was more popular (80.8%) than a removable partial denture. 4. For two missing teeth, there was little difference between the number of fixed and removable partial dentures. In the anterior region, fixed partial denture was more common, while in contrast, in the posterior region, removable partial denture was more common.

Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms.

Endothelin-1 (Edn1), originally identified as a vasoconstrictor peptide, is involved in the development of cranial/cardiac neural crest-derived tissues and organs. In craniofacial development, Edn1 binds to Endothelin type-A receptor (Ednra) to induce homeobox genes Dlx5/Dlx6 and determines the mandibular identity in the first pharyngeal arch. However, it remains unsolved whether this pathway is also critical for pharyngeal arch artery development to form thoracic arteries. Here, we show that the Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism. Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning, which include persistent first and second pharyngeal arteries, resulting in additional branches from common carotid arteries. Neural crest cell labeling with Wnt1-Cre transgene and immunostaining for smooth muscle cell markers revealed that neural crest cells abnormally differentiate into smooth muscle cells at the first and second pharyngeal arteries of Ednra knock-out embryos. By contrast, Dlx5/Dlx6 knockout little affect the development of pharyngeal arch arteries and coronary arteries, the latter of which is also contributed by neural crest cells through an Edn-dependent mechanism. These findings indicate that the Edn1/Ednra signaling regulates neural crest differentiation to ensure the proper patterning of pharyngeal arch arteries, which is independent of the regional identification of the pharyngeal arches along the dorsoventral axis mediated by Dlx5/Dlx6.

Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients.

BACKGROUND/AIMS: Anemia is commonly observed as a side effect in a treatment with protease inhibitors combined with peginterferon alpha and ribavirin for hepatitis C virus infection. This study assessed the safety, tolerability, viral kinetics, and selection of variants in telaprevir monotherapy for 24 weeks, and outcomes of the off-study treatment with peginterferon alpha-2b and ribavirin among Japanese female patients at a median age of 54 years who were difficult to treat with the standard therapy (peginterferon alpha-2b and ribavirin) alone in Japan. METHODS: Four treatment-naïve patients with chronic hepatitis C virus subtype 1b infection received telaprevir (750 mg every 8 h) alone for 24 weeks. All patients then started the off-study treatment with peginterferon alpha-2b and ribavirin. Safety, tolerability, hepatitis C virus RNA levels, and emergence of telaprevir-resistant variants were monitored. RESULTS: During the 24 weeks of telaprevir monotherapy, there was no discontinuation due to adverse events, but 2 patients stopped the intake at weeks 6 and 15 because of viral breakthrough. Emergence of telaprevir-resistant variants was observed in 3 patients who showed viral breakthrough. These variants were eliminated by the off-study treatment, and sustained virological response was achieved in all patients. CONCLUSIONS: Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin.

DNA detection on a power-free microchip with laminar flow-assisted dendritic amplification.

In this paper, we describe DNA detection experiments using our two original technologies, power-free microchip and laminar flow-assisted dendritic amplification (LFDA), which were previously applied to immunoassays. A microchip was fabricated by combining a poly(dimethylsiloxane) (PDMS) part having microchannel patterns and a glass plate modified with probe DNA. We carried out two kinds of experiments: the detection of 21-base biotinylated target DNA and the detection of single-nucleotide polymorphism (SNP) in 56-base unlabeled target DNA by sandwich hybridization with biotinylated probe DNA. For both of the experiments, the necessary solutions were injected into microchannels not by an external power source, but by air dissolution into the PDMS part. After a hybridization reaction, the LFDA was started by injecting FITC-labeled streptavidin and biotinylated anti-streptavidin antibody onto the reaction site. With a detection time of 20 min, the limit of detection (LOD) for the biotinylated target was 2.2 pM, and the LOD for the SNP was 10-30 pM, depending on the SNP type.

Flower micelle of amphiphilic random copolymers in aqueous media.

The structure of the flower micelle formed by an amphiphilic random copolymer, sodium (2-acrylamido)-2-methylpropanesulfonate and N-dodecylmethacrylamide p(AMPS/C12), in 0.05 M aqueous NaCl was investigated by fully atomistic molecular dynamics simulation as well as by light scattering, and the results were compared with the flower micelle model of the minimum loop size, recently proposed by Kawata et al. [Macromolecules 2007, 40, 1174-1180]. After a sufficiently long simulation time, simulated p(AMPS/C12) chain with the degree of polymerization of 200 and C12 content of 50 mol % formed a unicore micelle, of which radius of gyration was much smaller than the AMPS homopolymer with the same degree of polymerization. The simulated micellar structure was analyzed in terms of density distribution functions for dodecyl groups, the main chain, and sulfonate groups as functions of the radial distance r from the center of mass of dodecyl groups. Only dodecyl groups exist at r less, similar 1.5 nm, and the main chain and sulfonate groups distribute in the range of r between 1.5 and 3.5 nm, but there were dodecyl groups coexisting with the main chain and sulfonate groups beyond r = 1.5 nm. All these structural features, as well as hydrodynamic radius data for p(AMPS/C12) with C12 contents higher than ca. 20 mol % obtained by light scattering, agreed with the predictions of the flower micelle model of the minimum loop size.

Targeted delivery of chemotherapeutic agents using improved radiosensitive liquid core microcapsules and assessment of their antitumor effect.

PURPOSE: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. METHODS AND MATERIALS: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 microg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl(2) solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy (60)Co gamma-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. RESULTS: Microcapsules that had been polymerized using a 4.34% CaCl(2) solution supplemented with 5.0 x 10(-3)% (10(-3)% meant or 10%(-3)) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. CONCLUSION: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

Recombinase-mediated cassette exchange reveals the selective use of Gq/G11-dependent and -independent endothelin 1/endothelin type A receptor signaling in pharyngeal arch development.

The endothelin (Edn) system comprises three ligands (Edn1, Edn2 and Edn3) and their G-protein-coupled type A (Ednra) and type B (Ednrb) receptors. During embryogenesis, the Edn1/Ednra signaling is thought to regulate the dorsoventral axis patterning of pharyngeal arches via Dlx5/Dlx6 upregulation. To further clarify the underlying mechanism, we have established mice in which gene cassettes can be efficiently knocked-in into the Ednra locus using recombinase-mediated cassette exchange (RMCE) based on the Cre-lox system. The first homologous recombination introducing mutant lox-flanked Neo resulted in homeotic transformation of the lower jaw to an upper jaw, as expected. Subsequent RMCE-mediated knock-in of lacZ targeted its expression to the cranial/cardiac neural crest derivatives as well as in mesoderm-derived head mesenchyme. Knock-in of Ednra cDNA resulted in a complete rescue of craniofacial defects of Ednra-null mutants. By contrast, Ednrb cDNA could not rescue them except for the most distal pharyngeal structures. At early stages, the expression of Dlx5, Dlx6 and their downstream genes was downregulated and apoptotic cells distributed distally in the mandible of Ednrb-knock-in embryos. These results, together with similarity in craniofacial defects between Ednrb-knock-in mice and neural-crest-specific Galpha(q)/Galpha(11)-deficient mice, indicate that the dorsoventral axis patterning of pharyngeal arches is regulated by the Ednra-selective, G(q)/G(11)-dependent signaling, while the formation of the distal pharyngeal region is under the control of a G(q)/G(11)-independent signaling, which can be substituted by Ednrb. This RMCE-mediated knock-in system can serve as a useful tool for studies on gene functions in craniofacial development.

Molecular dynamics of retinoic acid-induced craniofacial malformations: implications for the origin of gnathostome jaws.

BACKGROUND: Intake of retinoic acid (RA) or of its precursor, vitamin A, during early pregnancy is associated with increased incidence of craniofacial lesions. The origin of these teratogenic effects remains enigmatic as in cranial neural crest cells (CNCCs), which largely contribute to craniofacial structures, the RA-transduction pathway is not active. Recent results suggest that RA could act on the endoderm of the first pharyngeal arch (1stPA), through a RARbeta-dependent mechanism. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that RA provokes dramatically different craniofacial malformations when administered at slightly different developmental times within a narrow temporal interval corresponding to the colonization of the 1(st) PA by CNCCs. We provide evidence showing that RA acts on the signalling epithelium of the 1(st) PA, gradually reducing the expression of endothelin-1 and Fgf8. These two molecular signals are instrumental in activating Dlx genes in incoming CNCCs, thereby triggering the morphogenetic programs, which specify different jaw elements. CONCLUSIONS/SIGNIFICANCE: The anatomical series induced by RA-treatments at different developmental times parallels, at least in some instances, the supposed origin of modern jaws (e.g., the fate of the incus). Our results might provide a conceptual framework for the rise of jaw morphotypes characteristic of gnathostomes.