Computer-assisted bone augmentation, implant planning and placement: An in vitro investigation.

AIM: To assess in vitro the workflow for alveolar ridge augmentation with customised 3D printed block grafts and simultaneous computer-assisted implant planning and placement. METHODS: Twenty resin mandible models with an edentulous area and horizontal ridge defect in the region 34-36 were scanned with cone beam computed tomography (CBCT). A block graft for horizontal ridge augmentation in the region 34-36 and an implant in the position 35 were digitally planned. Twenty block grafts were 3D printed out of resin and one template for guided implant placement were stereolithographically produced. The resin block grafts were positioned onto the ridge defects and stabilised with two fixation screws each. Subsequently, one implant was inserted in the position 35 through the corresponding template for guided implant placement. Optical scans of the study models together with the fixated block graft were performed prior to and after implant placement. The scans taken after block grafting were superimposed with the virtual block grafting plan through a best-fit algorithm, and the linear deviation between the planned and the achieved block positions was calculated. The precision of the block fixation was obtained by superimposing the 20 scans taken after grafting and calculating the deviation between the corresponding resin blocks. The superimposition between the scans taken after and prior to implant placement was performed to measure a possible displacement in the block position induced by guided implant placement. The (98-2%)/2 percentile value was determined as a parameter for surface deviation. RESULTS: The mean deviation in the position of the block graft compared to the virtual plan amounted to 0.79 ± 0.13 mm. The mean deviation between the positions of the 20 block grafts measured 0.47 ± 0.2 mm, indicating a clinically acceptable precision. Guided implant placement induced a mean shift of 0.16 ± 0.06 mm in the position of the block graft. CONCLUSIONS: Within the limitations of this in vitro study, it can be concluded that customised block grafts fabricated through CBCT, computer-assisted design and 3D printing allow alveolar ridge augmentation with clinically acceptable predictability and reproducibility. Computer-assisted implant planning and placement can be performed simultaneously with computer-assisted block grafting leading to clinically non-relevant dislocation of block grafts.

Influence of pedestal diameter on mode instabilities in Yb/Ce/Al-doped fibers.

In this paper we present numerical and experimental results revealing that the mode instability threshold of highly Yb-doped, Ce/Al co-doped pedestal fibers is affected by the size of the index-increased pedestal structure surrounding the core. An alternative preparation technology for the realization of large mode area fibers with very large Al-doped silica pedestals is introduced. Three different pedestal fiber design iterations characterized by low photodarkening were manufactured and tested in counter-pumped amplifier setups. Up to 1.9 kW continuous-wave output power of near-diffraction-limited beam quality (M2 = 1.26) was achieved with an 18/200/420 µm fiber of very low NA = 0.042, limited only by the occurrence of mode instabilities.

Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice.

BACKGROUND: Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and nonalcoholic fatty liver disease but estrogen has undesirable side effects, which negate its beneficial effects in premenopausal and postmenopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. Estrogen receptor α (ERα) is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: (1) inducing gene transcription by direct binding to specific DNA sequences, (2) inducing tethered transcription with other DNA-binding factors, and (3) stimulating nongenomic action through membrane-associated ERα. However, it is still unclear which mechanisms mediate ERα-dependent protection against hepatic steatosis. METHODS: To understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA-binding domain mutant mouse (KIKO) and liver-specific ERα knockout mouse (LERKO) fed high-fat diets (HFD). The KIKO mouse disrupts the direct DNA-binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum alanine aminotransferase (ALT) levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis. RESULTS: Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed wild-type (WT) controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls that correlated with increased serum testosterone levels. CONCLUSIONS: ERα-mediated direct transcription in non-hepatic tissues is essential for estrogen-mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.

[News in osteogenesis imperfecta: from research to clinical management]. / Nouveautés dans l'ostéogenèse imparfaite: de la recherche à la prise en charge multidisciplinaire.

Osteogenesis imperfecta (OI) is a rare genetic disease. Today we are able to propose an adapted and efficient management to the patients with this rare disorder (and their families) thanks to a strong collaboration of clinicians and researchers. Recent knowledge regarding the genetics of OI permits an accurate diagnosis of the specific type of OI and its own molecular mechanism, a genetic counseling for family planning and prenatal diagnosis, and in addition more targeted therapeutic options. A specific support with re-education for patients with OI is necessary and efficient. To optimize patient care, a multidisciplinary consultation is proposed at the CHUV, moreover a web site is available for patients, families and therapists: www.infomaladiesrares.ch

High-sensitivity dispersive Mach-Zehnder interferometer based on a dissimilar-doping dual-core fiber for sensing applications.

A dual-core fiber in which one of the cores is doped with germanium and the other with phosphorus is used as an in-line Mach-Zehnder dispersive interferometer. By ensuring an equal length but with different dispersion dependencies in the interferometer arms (the two cores), high-sensitivity strain and temperature sensing are achieved. Opposite sensitivities for high and low wavelength peaks were also demonstrated when strain and temperature was applied. To our knowledge this is the first time that such behavior is demonstrated using this type of in-line interferometer based on a dual-core fiber. A sensitivity of (0.102±0.002) nm/µÎµ, between 0 and 800 µÎµ and (-4.2±0.2) nm/°C between 47°C and 62°C is demonstrated.

Preinterventional Third-Molar Assessment Using Robust Machine Learning.

Machine learning (ML) models, especially deep neural networks, are increasingly being used for the analysis of medical images and as a supporting tool for clinical decision-making. In this study, we propose an artificial intelligence system to facilitate dental decision-making for the removal of mandibular third molars (M3M) based on 2-dimensional orthopantograms and the risk assessment of such a procedure. A total of 4,516 panoramic radiographic images collected at the Center of Dental Medicine at the University of Zurich, Switzerland, were used for training the ML model. After image preparation and preprocessing, a spatially dependent U-Net was employed to detect and retrieve the region of the M3M and inferior alveolar nerve (IAN). Image patches identified to contain a M3M were automatically processed by a deep neural network for the classification of M3M superimposition over the IAN (task 1) and M3M root development (task 2). A control evaluation set of 120 images, collected from a different data source than the training data and labeled by 5 dental practitioners, was leveraged to reliably evaluate model performance. By 10-fold cross-validation, we achieved accuracy values of 0.94 and 0.93 for the M3M-IAN superimposition task and the M3M root development task, respectively, and accuracies of 0.9 and 0.87 when evaluated on the control data set, using a ResNet-101 trained in a semisupervised fashion. Matthew's correlation coefficient values of 0.82 and 0.75 for task 1 and task 2, evaluated on the control data set, indicate robust generalization of our model. Depending on the different label combinations of task 1 and task 2, we propose a diagnostic table that suggests whether additional imaging via 3-dimensional cone beam tomography is advisable. Ultimately, computer-aided decision-making tools benefit clinical practice by enabling efficient and risk-reduced decision-making and by supporting less experienced practitioners before the surgical removal of the M3M.

Novel prediction models for hyperketonemia using bovine milk Fourier-transform infrared spectroscopy.

Metabolic diseases driven by negative energy balance in dairy cattle contribute to reduced milk production, increased disease incidence, culling, and death. Cow side tests for negative energy balance markers are available but are labor-intensive. Milk sample analysis using Fourier transform infrared spectroscopy (FTIR) allows for sampling numerous cows simultaneously. FTIR prediction models have moderate accuracy for hyperketonemia diagnosis (beta-hydroxybutyrate (BHB) ≥ 1.2 mmol/L). Most research using FTIR has focused on homogenous datasets and conventional prediction models, including partial least squares, linear discriminant analysis, and ElasticNet. Our objective was to evaluate more diverse modeling options, such as deep learning, gradient boosting machine models, and model ensembles for hyperketonemia classification. We compiled a sizable, heterogeneous dataset including milk FTIR and concurrent blood samples. Blood samples were tested for blood BHB, and wavenumber data was obtained from milk FTIR analysis. Using this dataset, we trained conventional prediction models and other options listed above. We demonstrate prediction model performance is similar for convolutional neural networks and ensemble models to simpler algorithm options. Results obtained from this study indicate that deep learning and model ensembles are potential algorithm options for predicting hyperketonemia in dairy cattle. Additionally, our results indicate hyperketonemia prediction models can be developed using heterogeneous datasets.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity.

Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.

Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases.

BACKGROUND: Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD. OBJECT: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group. METHODS AND RESULTS: We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases. CONCLUSION: Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.

First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

Academic freedom and the classified information system.

Executive Order 12356, signed by President Reagan on 2 April 1982, prescribes a system for classifying information on the basis of national security concerns. The order gives unprecedented authority to government officials to intrude at will in controlling academic research that depends on federal support. As such, it poses a serious threat to academic freedom and hence to scientific advances and the national security.

Holt-Oram syndrome associated with anomalies of the feet.

Holt-Oram syndrome (HOS) (OMIM 142900) is characterized by upper-extremity malformations involving the radial, thenar, or carpal bones and a personal and/or family history of congenital heart defects (CHDs). It is inherited in an autosomal dominant manner. The TBX5 gene located on chromosome 12 (12q24.1) is the only gene currently known to be associated with HOS and is associated with variable phenotypes. We report on the clinical and molecular characterization of a HOS family with three affected individuals and a novel mutation (Lys88ter). We discuss genotype-phenotype correlations, the presence of foot anomalies in one affected individual, and the role of atypical features in HOS differential diagnosis.

Two-dimensional high-precision fiber waveguide arrays for coherent light propagation.

Fiber waveguide arrays can be applied as a very useful tool for the investigation of effects in discrete optics. The observation of coherent propagation in such discrete waveguide arrays requires, however, high structural precision and great material homogeneity. The fabrication of such a fiber array with close tolerances compared to conventional fiber technology is discussed. Linear propagation effects are modeled for an ideal fiber waveguide array and are compared with experimental results. The good agreement of these results with each other indicates the applicability of such fiber waveguide arrays in studying linear and non-linear properties in discrete optics.

Simultaneous administration of vardenafil and alcohol does not result in a pharmacodynamic or pharmacokinetic interaction in healthy male subjects.

OBJECTIVES: To investigate the pharmacodynamic effects of the combined administration of vardenafil and ethanol on blood pressure and heart rate and to study the mutual pharmacokinetic interaction, safety and tolerability of the combination. METHODS: 12 healthy male subjects aged 18 - 45 years received 3 different single-dose treatments in a randomized, double-blind, placebo-controlled crossover design: 20 mg vardenafil plus 0.5 g/kg ethanol, vardenafil plus placebo and ethanol plus placebo. Heart rate (HR) as well as systolic (SBP) and diastolic blood pressure (DBP) were measured in supine position after 15 min of rest at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15 and 24 h post dosing using a validated oscillometric sphygmomanometer. Vardenafil, vardenafil metabolite M-1 and ethanol pharmacokinetics were assessed. RESULTS: There were no statistically significant differences between treatments in DBP and SBP. Significantly higher increases in HR were seen when the combination vardenafil/ethanol and ethanol/placebo treatment, respectively, was compared with vardenafil/placebo treatment. The difference between the 2 treatments including ethanol, however, was not significant. All hemodynamic changes were not clinically relevant. The pharmacokinetics of vardenafil and ethanol were not changed in the treatment "vardenafil + ethanol" compared to the respective treatment with vardenafil and ethanol alone. The most frequently reported adverse events were vasodilation and nasal congestion, well-known side effects of PDE-5 inhibitors such as vardenafil. CONCLUSION: Concomitant administration of vardenafil and alcohol was well-tolerated. No clinically relevant pharmacodynamic or pharmacokinetic interactions were detected.

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity and spontaneous cytotoxicity in normals and cancer patients as assayed by human erythrocyte lysis.

The monocyte-macrophage system has long been recognized as a necessary accessory to the immune response. Recently, however, monocyte-macrophages have been shown to be important effectors of cell-mediated cellular cytotoxicity (both antibody dependent and antibody independent). In this study, monocyte-mediated cellular cytotoxicity of both types was assessed on 51Cr-labeled human erythrocytes (type B+) using autologous and standardized AB serum, and monocytes from 57 normal controls, 16 women with benign breast disease, and 175 patients with cancers of the breast (44 patients), colorectum (46 patients), head and neck (33 patients), lung (13 patients), and melanoma (39 patients). Although results were variable, many of the patients had depressed antibody-dependent cellular cytotoxicity suggesting decreased ability of their monocyte-macrophage to lyse the sensitized erythrocytes. Enhanced antibody-dependent cellular cytotoxicity was observed in patients with localized colorectal cancer, but this effect was reversed in patients with advanced disease. Serum factors did not significantly affect responses in most cases. The clinical relevance of this assay remains to be determined.

A human homologue of the Drosophila tumour suppressor gene l(2)gl maps to 17p11.2-12 and codes for a cytoskeletal protein that associates with nonmuscle myosin II heavy chain.

Inactivation of the tumour suppressor gene lethal(2) giant larvae (D-lgl) of Drosophila leads to malignant transformation of the presumptive adult optic centers in the larval brain and tumours of the imaginal discs. These malignancies result from the disorganization of a cytoskeletal network in which the D-LGL protein participates. Here we describe the isolation of a cDNA encoding the human homologue to the D-lgl gene designated as hugl. The hugl cDNA detects a locus spanning at least 25 kilobases (kb) in human chromosome band 17p11.2-12, which is centromeric to the p53 gene and recognizes a 4.5 kb RNA transcript. The hugl gene is expressed in brain, kidney and muscle but is barely seen in heart and placenta. Sequence analysis of the hugl cDNA demonstrates a long open reading frame, which has the potential to encode a protein of 1057 amino acids with a predicted molecular weight of 115 kDaltons (kD). To further substantiate and identify the HUGL protein, we have prepared polyclonal rabbit antibodies against synthetic peptides corresponding to the amino and carboxyl termini of the conceptual translation product of the hugl gene. The affinity-purified anti-HUGL antibodies recognize a single protein with an apparent molecular weight of approximately 115 kD. Similar to the Drosophila protein, HUGL is part of a cytoskeletal network and, is associated with nonmuscle myosin II heavy chain and a kinase that specifically phosphorylates HUGL at serine residues.

Proton nuclear magnetic resonance study of the solution distal histidine orientation in monomeric Chironomus thummi thummi cyanomet hemoglobins. Dynamic stability of the heme pocket as monitored by labile proton exchange.

The 1H nuclear magnetic resonance spectral characteristics of the cyano-Met form of Chironomus thummi thummi monomeric hemoglobins I, III and IV in 1H2O solvent are reported. A set of four exchangeable hyperfine-shifted resonances is found for each of the two heme-insertion isomers in the hyperfine-shifted region downfield of ten parts per million. An analysis of relaxation, exchange rates and nuclear Overhauser effects leads to assignments for all these resonances to histidine F8 and the side-chains of histidine E7 and arginine FG3. It is evident that in aqueous solution, the side-chain from histidine E7 does not occupy two orientations, as found for the solid state, rather the histidine E7 side-chain adopts a conformation similar to that of sperm whale myoglobin or hemoglobin A, oriented into the heme pocket and in contact with the bound ligand. Evidence is presented to show that the allosteric transition in the Chironomus thummi thummi hemoglobins arises from the "trans effect". An analysis of the exchange with bulk solvent of the assigned histidine E7 labile proton confirms that the group is completely buried within the heme pocket in a manner similar to that found for sperm whale cyano-Met myoglobin, and that the transient exposure to solvent is no more likely than in mammalian myoglobins with the "normal" distal histidine orientation. Finally, a comparison of solvent access to the heme pocket of the three monomeric C. thummi thummi hemoglobins, as measured from proton exchange rates of heme pocket protons, is made and correlated to binding studies with the diffusible small molecules such as O2.