Improved bioimpedance spectroscopy tissue classification through data augmentation from generative adversarial networks.

Bioimpedance spectroscopy is a tissue classification technique with many clinical applications. Similarly to other data-driven methods, it requires large amounts of data to accurately distinguish similar classes of tissue. Classifiers trained on small datasets typically suffer from over-fitting and lack the ability to generalise to previously unseen data. However, a large in or ex vivo spectral database is difficult to attain. Data collection is usually limited to studies that occur infrequently, and publicly available data is often not available. A solution to this problem is to artificially increase the training dataset by creating modified, yet accurate, copies of the original dataset. The most common techniques in spectral classification are to add noise to copies of the original data, over-sample it, or randomly interpolate pairs of the original data. However, simply perturbing or interpolating the data does not guarantee that the new dataset captures the key features of the original data needed for accurate classification. This study proposes a novel way to augment bioimpedance spectral data. It uses generative adversarial networks (GAN)-a model in which two neural networks (NN) compete with each other: while one NN artificially manufactures data that could be mistaken for real data, the role of the second NN is to identify which data it receives has been artificially created. The first NN then interactively adapts its output until the second NN can no longer flag artificially created data. The result is a new dataset that truly represents the features of the original data. In this study, three GAN architectures are used, i.e., the vanilla GAN, the deep convolutional GAN, and the Wasserstein GAN. Then, the generated data is used to train five classification methods, and their results are compared to a baseline that only uses the original data. The results from a dataset of 13 different tissue classes show that the deep convolutional GAN is most statistically similar to the original data and improves classification accuracy by 15% when compared to the same model trained only on the original data. The Wasserstein-GAN architecture also provides significant improvements of up to 24% better accuracy.

Improved Configurations for 3D Acoustoelectric Tomography With a Minimal Number of Electrodes.

OBJECTIVE: Acoustoelectric tomography (AET) is a hybrid imaging technique combining ultrasound and electrical impedance tomography (EIT). It exploits the acoustoelectric effect (AAE): an US wave propagating through the medium induces a local change in conductivity, depending on the acoustoelectric properties of the medium. Typically, AET image reconstruction is limited to 2D and most cases employ a large number of surface electrodes. METHODS: This article investigates the detectability of contrasts in AET. We characterize the AEE signal as a function of the medium conductivity and electrode placement, using a novel 3D analytical model of the AET forward problem. The proposed model is compared to a finite element method simulation. RESULTS: In a cylindrical geometry with an inclusion contrast of 5 times the background and two pairs of electrodes, the maximum, minimum, and mean suppression of the AEE signal are 68.5%, 3.12%, and 49.0%, respectively, over a random scan of electrode positions. The proposed model is compared to a finite element method simulation and the minimum mesh sizes required successfully model the signal is estimated. CONCLUSION: We show that the coupling of AAE and EIT leads to a suppressed signal and the magnitude of the reduction is a function of geometry of the medium, contrast and electrode locations. SIGNIFICANCE: This model can aid in the reconstruction of AET images involving a minimum number of electrodes to determine the optimal electrode placement.

Influence of tumor cell-derived TGF-ß on macrophage phenotype and macrophage-mediated tumor cell invasion.

In oral squamous cell carcinoma (OSCC), macrophages are the most abundant immune cell type in the tumor microenvironment (TME). Macrophage infiltration is inversely proportional to prognosis and disease survival, particularly when these tumor-associated macrophages (TAM) assume an M2-like phenotype. This phenotype is determined by cues from the microenvironment, especially tumor cell-secreted molecules, and is associated with increased production of extracellular-matrix-degrading enzymes, angiogenic molecules and immunosuppressing cytokines. This study investigates, in vitro and in vivo, the relative contribution of OSCC cell-secreted transforming growth factor beta (TGF-ß) on the phenotype of macrophages and on macrophage-facilitated tumor invasion. TCGA database shows a positive correlation between high expression of TGFB1 and macrophage infiltrate in Head and neck squamous cell carcinoma (HNSCC). THP-1 derived-macrophages were exposed to the secretome of two OSCC cell lines using two strategies to block the effects of neoplastic cell-secreted TGF-ß: pre-treatment with a TGF-ß receptor type I kinase inhibitor (LY364947) and antibody-mediated depletion. RT-qPCR, ELISA and flow cytometry determined macrophage phenotype after exposure to conditioned medium (CM) from H-314 (TGF-ßhigh) or SCC-9 (TGF-ßlow) cell lines. The influence of TGF-ß on macrophage-mediated tumor cell invasion (myogel and CAM assays) and chemotaxis (Boyden chamber) was assessed using co-cultures of macrophages and OSCC cells in which macrophages were pre-conditioned with the secretome of OSCC cells in the presence and absence of LY364947. Blocking the effects of TGF-ß skewed macrophages to the M1 end of the phenotype by differential effects depending on the strategy for inhibiting the influence of TGF-ß and on the neoplastic cell secretome. In vitro and in vivo invasion of H-314 cell line was reduced by inhibiting TGFBR1 signaling in macrophages, whereas SCC-9 cell invasion was not affected. SCC-9/macrophage reciprocal chemotaxis were enhanced by inhibiting TGFBR1 signaling in macrophages, whereas only macrophage chemotaxis to H314 products was inhibited by inhibiting TGFBR1. In summary, blocking the effects of OSCC cell-secreted TGF-ß in macrophages attenuates M2-like phenotypical traits of macrophages and can impact invasion and chemotaxis of tumor cells differentially.

Galanin mediates tumor-induced immunosuppression in head and neck squamous cell carcinoma.

PURPOSE: Galanin receptor 2 (GALR2) plays a significant role in the progression of head and neck squamous cell carcinomas (HNSCC). Since there is virtually no information on immunomodulation mediated by its ligand in the tumor microenvironment, we assessed the effects of galanin on peripheral blood mononuclear cells (PBMCs). METHODS: After verification of GALR2 expression and it activity in PBMCs we evaluated the effect of galanin and conditioned media from HNSCC cell lines silenced for galanin or antibody-depleted, on proliferation, apoptosis, cytokine expression and activation/differentiation of immune cells. RESULTS: We found that galanin alone and as a component of the HNSCC secretome decreased HNSCC cell proliferation and expression of pro-inflammatory cytokines (IFNγ, IL-12, IL-17A, IL-1α, IL-6 and TNF-α), whilst increasing apoptosis and expression of pro-tumoral cytokines/growth factors (IL-10, IL-4, PDGF and GM-CSF). T cell activation (using CD69 as activation marker) and anti-tumoral phenotypes in CD4+ T cells (Th1 and Th17) were found to be suppressed. In vivo, tumor growth was found to be increased in the presence of galanin-stimulated PBMCs. Data from The Cancer Genome Atlas (TCGA) revealed that high expression of galanin was associated with a reduced overall survival of patients with HNSCC. CONCLUSION: Our data indicate that galanin secreted by HNSCC cells exhibits immune-suppressive and pro-tumoral effects.

Development of a tissue discrimination electrode embedded surgical needle using vibro-tactile feedback derived from electric impedance spectroscopy.

Some tumours may not be detected by ultrasound during biopsy, but recent evidence has shown that different tissues can be discerned by electric impedance. This paper explores the application of vibrotactile feedback in an electrode embedded needle to help classify tissue during fine-needle aspiration biopsy from bioimpedance measurements. The process uses electric impedance spectroscopy from 10 Hz to 349 kHz to fit the double-dispersion Cole model through the Newton-Raphson algorithm. A Naive Bayes classifier is then used on the equivalent circuit parameters to estimate the tissue at the needle tip. The method is validated through a series of experiments and user trials. The results show that the vibrotactile feedback is able to help the operator in determining the tissue the needle is in, suggesting that this may prove to be a useful supplement to the standard procedure used today. Graphical Abstract This paper explores the application of vibrotactile feedback for an electrode embedded needle to help classify tissue from electric impedance measurements. The data is fit to an equivalent circuit using Newton- Raphon's method. A Naive Bayes classifier is trained and later used in an experiment to estimate the tissue at the needle tip and provide an assigned vibrotacticle feedback to the user.

Polymorphisms in Genes of Lipid Metabolism Are Associated with Type 2 Diabetes Mellitus and Periodontitis, as Comorbidities, and with the Subjects' Periodontal, Glycemic, and Lipid Profiles.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and periodontitis (P) commonly occur as comorbidities, but the commonalities in the genetic makeup of affected individuals is largely unknown. Since dyslipidemia is a frequent condition in these individuals, we investigate the association of genomic variations in genes involved in lipid metabolism with periodontal, glycemic, lipid profiles, and the association with periodontitis and T2DM (as comorbidities). METHODS: Based on clinical periodontal examination and biochemical evaluation, 893 subjects were divided into T2DM+P (T2DM subjects also affected by periodontitis, n = 205), periodontitis (n = 345), and healthy (n = 343). Fourteen single-nucleotide polymorphisms (SNPs) were investigated: LDLR gene (rs5925 and rs688), APOB (rs676210, rs1042031, and rs693), ABCC8 (rs6544718 and 6544713), LPL (rs28524, rs3735964, and rs1370225), HNF1A (rs2650000), APOE (rs429358 and rs7412), and HNF4A (rs1800961). Multiple linear and logistic regressions (adjusted for covariates) were made for all populations and stratified by sex and smoking habits. RESULTS: Individuals carrying APOB-rs1042031-CT (mainly women and never smokers) had a lower risk of developing periodontitis and T2DM (T2DM+P); altogether, this genotype was related with healthier glycemic, lipid, and periodontal parameters. Significant disease-phenotype associations with gene-sex interaction were also found for carriers of APOB-rs1676210-AG, HNF4A-rs1800961-CT, ABCC8-rs6544718-CT, LPL-rs13702-CC, and LPL-rs285-CT. CONCLUSIONS: Polymorphisms in lipid metabolism genes are associated with susceptibility to T2DM-periodontitis comorbidities, demonstrating gene-sex interaction. The APOB-rs1042031 was the most relevant gene marker related to glucose and lipid metabolism profiles, as well as with obesity and periodontitis.

Electrical Impedance Tomography for Robot-Aided Internal Radiation Therapy.

High dose rate brachytherapy (HDR) is an internal based radiation treatment for prostate cancer. The treatment can deliver radiation to the site of dominant tumor growth within the prostate. Imaging methods to delineate the dominant tumor are imperative to ensure the maximum success of HDR. This paper investigates the feasibility of using electrical impedance tomography (EIT) as the main imaging modality during robot-aided internal radiation therapy. A procedure utilizing brachytherapy needles in order to perform EIT for the purpose of robot-aided prostate cancer imaging is proposed. It is known that cancerous tissue exhibits different conductivity than healthy tissue. Using this information, it is hypothesized that a conductivity map of the tissue can be used to locate and delineate cancerous nodules via EIT. Multiple experiments were conducted using eight brachytherapy needle electrodes. Observations indicate that the imaging procedure is able to observe differences in tissue conductivity in a setting that approximates transperineal HDR and confirm that brachytherapy needles can be used as electrodes for this purpose. The needles can access the tissue at a specific depth that traditional EIT surface electrodes cannot. The results indicate the feasibility of using brachytherapy needles for EIT for the purpose internal radiation therapy.

Sonographic Diagnosis of COVID-19: A Review of Image Processing for Lung Ultrasound.

The sustained increase in new cases of COVID-19 across the world and potential for subsequent outbreaks call for new tools to assist health professionals with early diagnosis and patient monitoring. Growing evidence around the world is showing that lung ultrasound examination can detect manifestations of COVID-19 infection. Ultrasound imaging has several characteristics that make it ideally suited for routine use: small hand-held systems can be contained inside a protective sheath, making it easier to disinfect than X-ray or computed tomography equipment; lung ultrasound allows triage of patients in long term care homes, tents or other areas outside of the hospital where other imaging modalities are not available; and it can determine lung involvement during the early phases of the disease and monitor affected patients at bedside on a daily basis. However, some challenges still remain with routine use of lung ultrasound. Namely, current examination practices and image interpretation are quite challenging, especially for unspecialized personnel. This paper reviews how lung ultrasound (LUS) imaging can be used for COVID-19 diagnosis and explores different image processing methods that have the potential to detect manifestations of COVID-19 in LUS images. Then, the paper reviews how general lung ultrasound examinations are performed before addressing how COVID-19 manifests itself in the images. This will provide the basis to study contemporary methods for both segmentation and classification of lung ultrasound images. The paper concludes with a discussion regarding practical considerations of lung ultrasound image processing use and draws parallels between different methods to allow researchers to decide which particular method may be best considering their needs. With the deficit of trained sonographers who are working to diagnose the thousands of people afflicted by COVID-19, a partially or totally automated lung ultrasound detection and diagnosis tool would be a major asset to fight the pandemic at the front lines.

Smoking reduces cathelicidin LL-37 and human neutrophil peptide 1-3 levels in the gingival crevicular fluid of patients with periodontitis.

BACKGROUND: Antimicrobial peptides are components of innate immune response that have a key role on susceptibility and resistance of the oral cavity to diseases. This study aimed to investigate the influence of smoking on cathelicidin LL-37 and human neutrophil peptides 1 through 3 (HNP 1-3) levels in the gingival crevicular fluid (GCF) of patients with periodontitis. The relationship between levels of these peptides with the periodontal status and selected inflammatory mediators levels in smokers and non-smokers was also evaluated. METHODS: Forty patients with periodontitis, 20 smokers and 20 non-smokers were recruited. After a full periodontal clinical assessment, GCF samples were collected from healthy (n = 5) and diseased (n = 5) sites of each patient. Peptides and inflammatory mediators in the GCF were quantitated by sandwich ELISAs and Multiplex assay, respectively. RESULTS: Diseased sites had significantly (P <0.05) higher levels of LL-37 and lower levels of HNP 1-3 than healthy sites in both smokers and non-smokers. Diseased sites of smokers presented significantly lower levels of LL-37 and HNP 1-3 when compared with diseased sites of non-smokers. Concentration of LL-37 was directly correlated with the presence of proinflammatory mediators matrix metalloproteinase (MMP)-8 and interleukin (IL)-1ß and inversely correlated with concentration of IL-10. HNP 1-3 concentration was positively correlated with IL-10 and negatively correlated with concentrations of MMP-8 and IL-1ß. CONCLUSIONS: Smoking was associated with reduced levels of LL-37 and HNP 1-3 in GCF of patients with periodontitis. LL-37 had a distinct expression pattern from HNP 1-3: LL-37 was upregulated in diseased sites, and HNP 1-3 was increased in periodontally healthy sites.1.

Validation in a Brazilian population of gene markers of periodontitis previously investigated by GWAS and bioinformatic studies.

BACKGROUND: Bioinformatic tools and genome-wide association studies (GWAS) have led to comprehensive identification of single nucleotide polymorphisms (SNPs) associated with periodontitis in diverse populations. Here we aimed to detect and validate the association of seven SNPs as genetic markers of susceptibility to periodontitis in a Brazilian population. METHODS: This case-control study assessed complete periodontal parameters of 714 subjects with periodontal status classified as healthy/mild periodontitis (n = 356) and moderate/severe periodontitis (n = 358). Genotyping for rs187238, rs352140, rs1360573, rs2521634, rs3811046, rs3826782, and rs7762544 SNPs were evaluated. Genetic-phenotype associations, and sex or smoking effects of SNPs on periodontitis were tested using multiple logistic regressions adjusted for covariates. RESULTS: The rs2521634-AA (close to NPY gene) presented increased risk for severe periodontitis (OR = 2.34; 95% CI = 1.19-4.59). The rs3811046-GG (IL37 gene) demonstrated increased risk for moderate periodontitis (OR = 2.58; 95% CI = 1.28-5.18). Higher risk for moderate periodontitis was found in male with rs7762544-AG close to NCR2 gene. The rs352140-TT in the TLR9 gene proved to be associated with lower risk to severe periodontitis in men. The rs2521634-AA was associated with higher percentage of interproximal probing pocket depth (P = .004). CONCLUSIONS: This is the first evidence of validation in a Brazilian population of genetic markers of periodontitis previously investigated by GWAS and bioinformatics studies. SNPs in the NPY, IL37, and NCR2 genes were associated with susceptibility to moderate or severe periodontitis; whereas the TLR9 marker was associated with lower chance to develop severe periodontitis. Those SNPs had sex- and smoking-habit-specific effects on periodontitis; reinforcing the genetic profile predisposing to periodontitis.

Nine Degree-of-Freedom Kinematic Modeling of the Upper-Limb Complex for Constrained Workspace Evaluation.

The design of rehabilitation devices for patients experiencing musculoskeletal disorders (MSDs) requires a great deal of attention. This article aims to develop a comprehensive model of the upper-limb complex to guide the design of robotic rehabilitation devices that prioritize patient safety, while targeting effective rehabilitative treatment. A 9 degree-of-freedom kinematic model of the upper-limb complex is derived to assess the workspace of a constrained arm as an evaluation method of such devices. Through a novel differential inverse kinematic method accounting for constraints on all joints1820, the model determines the workspaces in which a patient is able to perform rehabilitative tasks and those regions where the patient needs assistance due to joint range limitations resulting from an MSD. Constraints are imposed on each joint by mapping the joint angles to saturation functions, whose joint-space derivative near the physical limitation angles approaches zero. The model Jacobian is reevaluated based on the nonlinearly mapped joint angles, providing a means of compensating for redundancy while guaranteeing feasible inverse kinematic solutions. The method is validated in three scenarios with different constraints on the elbow and palm orientations. By measuring the lengths of arm segments and the range of motion for each joint, the total workspace of a patient experiencing an upper-limb MSD can be compared to a preinjured state. This method determines the locations in which a rehabilitation device must provide assistance to facilitate movement within reachable space that is limited by any joint restrictions resulting from MSDs.

Local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing in periodontitis: Randomized, placebo-controlled, double-blind split-mouth clinical trial.

OBJECTIVE: Assess a single local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing (SRP) in nonsurgical periodontal treatment (NPT). MATERIALS AND METHODS: Twenty healthy subjects with periodontitis received SRP+PLGA/PLA nanoparticles loaded with 50 µg of curcumin (N-Curc) or SRP+empty nanoparticles. Probing pocket depth (PPD), clinical attachment level (CAL), and bleeding on probing (BOP) were monitored at baseline, 30, 90, and 180 days. IL-1α, IL-6, TNFα, and IL-10 in the gingival crevicular fluid (GCF) were assessed by ELISA, and counts of 40 bacterial species were determined by DNA hybridization at baseline, 3, 7, and 15 days post-therapy. RESULTS: PPD, CAL, and BOP were similarly and significantly improved in both experimental groups. There was no difference in GCF cytokine levels between experimental groups, although IL-6 was decreased at 3 days only in the N-Curc group. NPT reduced counts of red complex bacterial species in both groups. Veillonella Parvula counts increased significantly only in N-Curc group at 7 days, whereas Aggregatibacter actinomycetemcomitans counts increased significantly only in the control group from day 3 to day 15. CONCLUSION: We conclude that a single local administration of nanoencapsulated curcumin in periodontally diseased sites had no additive benefits to NPT. CLINICAL RELEVANCE: Our results showed that a single local application of curcumin-loaded nanoparticles associated with nonsurgical periodontal therapy did not improve clinical outcomes. Hence, our findings do not support the use of curcumin as an adjunct to nonsurgical periodontal therapy.

Silencing matrix metalloproteinase-13 (Mmp-13) reduces inflammatory bone resorption associated with LPS-induced periodontal disease in vivo.

OBJECTIVES: The aim of this study was to evaluate the effect of specific inhibition of MMP-13 on inflammation and inflammatory bone resorption in a murine model of lipopolysaccharide (LPS)-induced periodontitis. MATERIALS AND METHODS: Periodontitis was induced in mice by micro-injections of LPS into the gingival tissues adjacent to the palatal surfaces of maxillary molars twice a week for 15 days. Matrix metalloproteinase-13 (Mmp-13) shRNA or a specific biochemical inhibitor were also injected into the same sites in alternating days with the LPS injections. Efficacy of shRNA-mediated silencing of Mmp-13 was verified by quantitative real-time polymerase chain reaction (qPCR) and immunoblot. Bone resorption was assessed by microcomputed tomography (uCT). Histological sections stained with hematoxylin/eosin (H/E) were used in the stereometric analysis of the inflammatory infiltrate. Gingival tissues were used to evaluate expression of Mmp-13, Il-6, Tnf-α, Ptgs2, and Rankl (qPCR). Protein levels of TGF-ß and IL-10 in the tissues were determined by enzyme-linked immunosorbent assays (ELISA) or by MMP-13 and p38 immunoblot. RESULTS: Silencing Mmp-13 expression reduced bone resorption significantly. Expression of Mmp-13, Il-6, and Tnf-α, as well as the protein levels of IL-6 and TNF-α, was reduced in the animals treated with adenovirus-delivered shRNA; however, these effects were not associated with modulation of p38 MAPK signaling. Interestingly, inhibition Mmp-13 did not affect the severity of inflammatory infiltrate. CONCLUSIONS: Site-specific inhibition of MMP-13 reduced bone resorption and production of inflammatory mediators associated with periodontal disease. CLINICAL RELEVANCE: The results suggest that site-specific inhibition of MMP-13 may be an interesting strategy to modulate inflammation and reduce bone resorption in osteolytic inflammatory diseases.

Perillyl alcohol has antibacterial effects and reduces ROS production in macrophages.

Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis. Among the monoterpenes with significant biological properties, there is the perillyl alcohol (POH), which can be found in several essential oils and has shown immunomodulatory properties in recent studies, which may be interesting in the treatment of non-neoplastic inflammatory disorders. Objective To determine the antibacterial and immune modulatory activities of the POH. Methodology The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the POH for two significant Gram-negative periodontal pathogens were determined by macrodilution and subculture, respectively. Cell proliferation and cytotoxicity in RAW 264.7 macrophages were determined by Trypan Blue and mitochondrial enzymatic activity assay. The modulation of reactive oxygen species (ROS) was analyzed by flow cytometry and expression of TNF and arginase-1 by real-time PCR. Results The POH was effective against P. gingivalis (ATCC 33277) and F. nucleatum (ATCC 25586) with MIC= MBC=1600 µM. No cytotoxicity up to 100 µM was observed on macrophages. The cell proliferation was inhibited from 48 hours at 100 µM (p<0.05) and 250 µM (p<0.01). The POH increased ROS production at both 10 µM and 100 µM (p<0.05) in unstimulated cells. The PMA-induced ROS production was not affected by POH, whereas 100 µM significantly reduced lipopolysaccharide-induced (LPS-induced) ROS. The expression of TNF was not affected by POH in unstimulated cells or in cells polarized to M1 phenotype, whereas both concentrations of POH reduced (p<0.05) the expression of arginase-1 in M2-polarized macrophages. Conclusion The POH has antibacterial activity against periodontal pathogens and reduced proliferation of murine macrophages without significant cytotoxicity at concentrations up to 100 µM. In addition, the POH reduced the LPS-induced ROS and the expression of arginase-1 in M2-polarized macrophages.

Design and Control of a 3 Degree-of-Freedom Parallel Passive Haptic Device.

Teleoperated robotic surgery and surgical simulation provide surgeons with tools that can improve the health outcomes of their patients. The limiting factor in many of these systems, however, is the lack of a haptic system that can render high impedance without compromising transparency or stability. To address this issue, we constructed a 3-Degree-of-Freedom haptic device using brakes as actuators. A novel controller is also proposed to increase the range of forces the device can generate and eliminate stiction. The device uses a modified Delta kinematic structure making it light and rigid. Since brakes are intrinsically stable, the device safely generates a wide range of impedance making it well suited for many surgical applications. The novel controller attempts to minimize the sum of forces acting perpendicular to the virtual surface eliminating un-smooth force output and stiction characteristic to passive devices, while increasing the range of displayable forces. The controller was validated using six testing scenarios where it rendered contact with frictionless surfaces. When using the controller, the device rendered the desired surface without stiction. Since the controller successfully rendered complex geometry, it can also work in other applications, such as robotic surgery and surgical simulation.

Impact of Kinematic Structure on the Force Displayability of Planar Passive Haptic Devices.

Haptic devices containing passive actuators, such as controllable brakes or dampers, are an attractive alternative to their motor-driven counterparts due to intrinsic stability and improved impedance bandwidth. Passive actuators cannot generate energy and, therefore, the output force can only oppose the applied velocity. In the same way the kinematic structure of traditional manipulators is designed to maximize dexterity and manipulability, one must consider adapting the device topology to optimize force displayability when designing passive actuators. This article introduces a set of metrics to evaluate and compare the performance of 2-degree-of-freedom (DOF) serial and parallel passive haptic devices. These metrics consider the impact of the kinematic structure on the force displayability according to the directions of the device velocity and desired force. Applying these metrics to nine manipulators revealed that: 1.) serial manipulators can generate passive forces in all directions equally regardless of the link length ratio; 2.) the base link length of five-bar parallel manipulators strongly influences passive force displayability; 3.) five-bar parallel manipulators with the base link length of zero can generate the widest range of passive forces when all links have the same length. The novel performance metrics presented in this paper can aid in the design of 2-DOF passive haptic devices.

NLRC4 inflammasome has a protective role on inflammatory bone resorption in a murine model of periodontal disease.

There is virtually no information on the role of NLRC4 inflammasome on bone resorption and inflammation associated with periodontitis. Bacterial-associated experimental periodontitis was induced in wild-type (WT) and Nlrc4-KO C57BL/6 mice. 3 µL of a 1 × 109 UFC/mL PBS suspension of heat-killed Gram-negative bacteria were injected (3x/week for 4 weeks) directly into the gingival tissues of WT and Nlrc4-KO mice (n = 6/genotype). Control animals were injected bilaterally (3x/week for 4 weeks) in the same sites with the same volume of the PBS vehicle. Alveolar bone resorption was quantified by µCT. Inflammatory infiltrate in the gingival tissues was assessed qualitatively in H&E-stained slides and by the detection of a pan-leukocyte marker (CD45) and a neutrophil marker (Ly6G) using immunofluorescence. Modulation of Rankl, Mmp-13, Tnf-a, Il-6 and Il-10 expression in the gingival tissues was determined by RT-qPCR. Osteoclastogenesis was assessed in vivo by biochemical staining for TRAP. The relevance of NLRC4 for RANKL-induced osteoclastic differentiation and activity was investigated in vitro using bone marrow-derived macrophages from WT and Nlrc4-KO mice. Bone resorption was significantly greater in Nlrc4-KO mice; however there were no differences between WT and Nlrc4-KO mice on osteoclast numbers and on the inflammatory infiltrate. In vitro, osteoclast activity was significantly enhanced in Nlrc4-deficient macrophages; whereas RANKL-induced differentiation was not affected. Expression of the selected candidate genes was also similarly increased by the induction of experimental periodontal disease, except for the expression of Tnf-alpha and Il-10, which was already significantly higher in the gingival tissues of Nlrc4-KO mice. We conclude that NLRC4 inflammasome has a protective role on inflammatory bone resorption in this experimental model. Furthermore, the bone-sparing effect may be related with the modulation of osteoclast activity.

Severe magnesium deficiency compromises systemic bone mineral density and aggravates inflammatory bone resorption.

We sought to evaluate the effects of magnesium (Mg) intake deficiency on bone metabolism in rats with induced periodontal disease (PD). Holtzman rats were randomly divided into two groups: Control - animals fed a standard diet and test - animals fed a diet with 90% Mg deficiency. After 60 days on the diets, all animals received ligature on the lower left first molars to induce PD. Animals were euthanized after 30 days following ligature placement. Blood and urine were collected for determination of serum concentrations of Mg, calcium, osteocalcin (OCN), alkaline phosphatase and parathyroid hormone (PTH) by enzyme-linked immunosorbent assay, and the urinary concentration of deoxypyridinoline (DPD). Systemic bone mineral density (BMD), bone volume and architectural bone parameters were evaluated by micro-CT in L4 lumbar vertebrae and mandible. Tartrate-resistant acid phosphatase staining and immunohistochemical (IHC) analysis of inducible nitric oxide synthase (iNOS), Runt-related transcription factor 2 (RUNX2), CD86, CD80, proliferating cell nuclear antigen, vascular endothelial growth factor, OCN and osteopontin were investigated. Reverse-transcription polymerase chain reaction was employed to assess mRNA expression of receptor-activator of nuclear factor-kB ligand, osteoprotegerin (OPG) and interleukin (IL)-6. Mg deficiency was associated with higher concentrations of PTH and DPD, and significant decrease on both systemic and mandibular BMD, as well as greater severity of alveolar and trabecular bone loss. Significant increase in osteoclasts was observed in the test group with PD. IHC analysis showed significant increase in the expression of iNOS and decreased expression of OCN and RUNX2. Increased IL-6 mRNA and decreased OPG mRNA expressions were evidenced in the test group with PD. Mg deficiency caused systemic effects indicative of altered bone metabolism in the vertebrae and affected both immune and stromal cells, aggravating inflammatory bone resorption in the ligature-induced model of periodontitis.

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions.

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.