The efficacy of bone reconstructive therapies in the management of peri-implantitis. A systematic review and meta-analysis.

AIM: To evaluate the efficacy of bone reconstructive procedures for the reduction of probing pocket depth (PPD), bleeding on probing (BOP), and suppuration in peri-implantitis-related bone defects at ≥12-month follow-up. MATERIALS AND METHODS: Three databases were searched for randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared bone reconstructive therapies to access flap surgery (AFS) (Focused Question-FQ 1), and RCTs, CCTs, and prospective case series that assessed the efficacy of reconstructive therapies (FQ 2). Meta-analysis was performed for FQ1 when more than three studies were identified, while for FQ2 a network was drawn based on RCTs with common treatment arms. RESULTS: Seven RCTs were identified for FQ1 while five RCTs and six prospective case series for FQ2. There was no significant difference in PPD change between AFS and reconstructive surgery (-0.387; p = .325) at 12 months. Furthermore, no clear differences in terms of PPD and BOP changes resulted from the different reconstructive therapies included in the network. Only a small percentage of treated cases with any modality achieved peri-implantitis resolution, as defined by different composite outcomes. CONCLUSIONS: Reconstructive surgery does not offer significant improvements in peri-implant clinical parameters as compared to AFS at 12 months. It was not possible to establish a hierarchy of efficacy among the different biomaterials employed for reconstructive surgery.

Regulation of gingival fibroblast phenotype by periodontal ligament cells in vitro.

OBJECTIVES: Stem cell transplantation has shown modest effects on periodontal tissue regeneration, and it is still unclear how regenerative effects utilizing this modality are mediated. A greater understanding of the basic interactions between implanted and host cells is needed to improve future strategies. The aims of this study were to investigate the effects of periodontal ligament (PDL) cells on expression of periodontal markers and alkaline phosphatase (ALP) activity of gingival fibroblasts (GF). MATERIALS AND METHODS: Primary human PDL cells were co-cultured with primary GF cultures either by direct co-culture with subsequent FACS sorting or indirect co-culture using transwell cultures and PDL cell conditioned medium. Expression of periodontal markers, asporin, nestin, and periostin, was assessed by qPCR and immunofluorescence staining. Alkaline phosphatase (ALP) expression was assessed by qPCR, histochemical staining, and activity assessed by para-nitrophenol enzymatic assay. Single cultures of PDL cells and GF were used as controls. The role of Wnt signaling on ALP activity was assessed via Dkk1-mediated inhibition. RESULTS: PDL cells significantly upregulated expression of PDL markers in GF with both direct and indirect co-culture methods when compared to controls (6.05 vs. 0.73 and 59.48 vs. 17.55 fold change of asporin expression). PDL/GF cell co-cultures significantly increased ALP activity in GF when compared with single GF cultures. Similar results were obtained when using conditioned medium isolated from PDL cell cultures. Dkk1 caused dose-dependent reduction in ALP activity of GF cultured in PDL cell conditioned medium. CONCLUSIONS: PDL cells stimulate expression of periodontal markers and osteogenic capacity of gingival fibroblasts via paracrine signaling which can be partially inhibited with addition of the Wnt antagonist, Dkk1.Further studies are required to identify specific secreted factors responsible for this activity.

Toward individualized prediction of seizure recurrence: Hippocampal neuroimaging features in a cohort of patients from a first seizure clinic.

PURPOSE: We performed an exploratory analysis of electroencephalography (EEG) and neuroimaging data from a cohort of 51 patients with first seizure (FS) and new-onset epilepsy (NOE) to identify variables, or combinations of variables, that might discriminate between clinical trajectories over a one-year period and yield potential biomarkers of epileptogenesis. METHODS: Patients underwent EEG, hippocampal and whole brain structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) within six weeks of the index seizure, and repeat neuroimaging one year later. We classified patients with FS as having had a single seizure (FS-SS) or having converted to epilepsy (FS-CON) after one year and performed logistic regression to identify combinations of variables that might discriminate between FS-SS and FS-CON, and between FS-SS and the combined group FS-CON + NOE. We performed paired t-tests to assess changes in quantitative variables over time. RESULTS: Several combinations of variables derived from hippocampal structural MRI, DTI, and MRS provided excellent discrimination between FS-SS and FS-CON in our sample, with areas under the receiver operating curve (AUROC) ranging from 0.924 to 1. They also provided excellent discrimination between FS-SS and the combined group FS-CON + NOE in our sample, with AUROC ranging from 0.902 to 1. After one year, hippocampal fractional anisotropy (FA) increased bilaterally, hippocampal radial diffusivity (RD) decreased on the side with the larger initial measurement, and whole brain axial diffusivity (AD) increased in patients with FS-SS; hippocampal volume decreased on the side with the larger initial measurement, hippocampal FA increased bilaterally, hippocampal RD decreased bilaterally and whole brain AD, FA and mean diffusivity increased in the combined group FS-CON + NOE (corrected threshold for significance, q = 0.017). CONCLUSION: We propose a prospective, multicenter study to develop and test models for the prediction of seizure recurrence in patients after a first seizure, based on hippocampal neuroimaging. Further longitudinal neuroimaging studies in patients with a first seizure and new-onset epilepsy may provide clues to the microstructural changes occurring at the earliest stages of epilepsy and yield biomarkers of epileptogenesis.

Comparison of PED and FRED flow diverters for posterior circulation aneurysms: a propensity score matched cohort study.

BACKGROUND: Flow diversion is a common endovascular treatment for cerebral aneurysms, but studies comparing different types of flow diverters are scarce. OBJECTIVE: To perform a propensity score matched cohort study comparing the Pipeline Embolization Device (PED) and Flow Redirection Intraluminal Device (FRED) for posterior circulation aneurysms. METHODS: Consecutive aneurysms of the posterior circulation treated at 25 neurovascular centers with either PED or FRED were collected. Propensity score matching was used to control for age, duration of follow-up imaging, adjunctive coiling, and aneurysm location, size, and morphology; previously ruptured aneurysms were excluded. The two devices were compared for the following outcomes: procedural complications, aneurysm occlusion, and functional outcome. RESULTS: A total of 375 aneurysms of the posterior circulation were treated in 369 patients. The PED was used in 285 (77.2%) and FRED in 84 (22.8%) procedures. Aneurysms treated with the PED were more commonly fusiform and larger than those treated with FRED. To account for these important differences, propensity score matching was performed resulting in 33 PED and FRED unruptured aneurysm pairs. No differences were found in occlusion status and neurologic thromboembolic or hemorrhagic complications between the two devices. The proportion of patients with favorable functional outcome was higher with FRED (100% vs 87.9%, p=0.04). CONCLUSION: Comparative analysis of PED and FRED for the treatment of unruptured posterior circulation aneurysms did not identify significant differences in aneurysm occlusion or neurologic complications. Variations in functional outcomes warrant additional investigations.

Development of an in vitro model of the dentogingival junction using 3D organotypic constructs.

OBJECTIVES: The overall aim was to propose a plausible model of the dentogingival junction (DGJ) to deepen our understanding of the extrinsic influences responsible for the development of the junctional epithelial phenotype. The specific objective was to test the hypothesis that epithelial migration and proliferation would be inhibited by periodontal ligament (PDL) fibroblasts in an in vitro model of the DGJ consisting of 3D organotypic cultures. BACKGROUND: Previously, we showed that 3D organotypic cultures containing human gingival fibroblasts (HGF) supported the development of a multi-layered epithelium, while constructs containing human periodontal ligament fibroblasts (HPDLF) resulted in epithelial atrophy (Lu EMC, Hobbs C, Dyer CJ, Ghuman M, Hughes FJ. J Perio Res., 2020). However, changes in epithelial phenotype have not been studied within an in vitro model of the DGJ. METHODS: The in vitro model of the DGJ comprised of a donor HGF construct (H400 epithelium overlying HGF-collagen matrix) supported by a dimensionally larger recipient collagen bed enriched with HPDLF. Samples were harvested, fixed and processed for immunohistochemistry. The changes in epithelial migration and proliferation following contact with HPDLF were assessed by measuring the horizontal extension of the epithelial outgrowth on the recipient collagen matrix. RESULTS: Within our in vitro model of the DGJ, epithelial migration and proliferation were inhibited following contact with the recipient HPDLF. By contrast, the control set-up showed a relative increase in epithelial growth, where the epithelium came into contact with the recipient HGF. Overall, there were limited changes in the molecular expression of keratin markers. CONCLUSION: This study has proposed a plausible in vitro model of the DGJ to illustrate the role of different fibroblasts in the regulation of dentogingival epithelia. Furthermore, it suggests that the anatomical positional stability of the JE and its apparent resistance to apical migration could be associated with its interaction with the PDL.

Differential regulation of epithelial growth by gingival and periodontal fibroblasts in vitro.

OBJECTIVES: To investigate the underlying molecular mechanisms by which gingival and periodontal ligament (PDL) fibroblasts regulate epithelial phenotype. BACKGROUND: Fibroblast populations regulate the epithelial phenotype through epithelial-mesenchymal interactions (EMI). Previous studies have proposed that maintenance of the junctional epithelium (JE) is dependent on the differential effects from gingival and PDL tissues. However, these cell populations are undefined and the signalling mechanisms which may regulate JE are unknown. METHODS: Immunohistochemical analyses were performed on formalin-fixed paraffin-embedded sections of dentogingival tissues to identify phenotypic differences in fibroblast populations. The effect of distinct fibroblasts on epithelial phenotype was studied via 3D organotypic cultures, consisting of an H400 epithelium supported by human gingival fibroblasts (HGF) or human periodontal ligament fibroblasts (HPDLF), embedded in collagen gel. To investigate the involvement of Wnt signalling in EMI, the Wnt antagonist rhDKK1 was added to HGF constructs. The gene expression of Wnt antagonists and agonists was tested via RNA extraction and qPCR. Specific gene silencing using RNA interference was performed on HPDLF/HGF constructs. RESULTS: Gingival fibroblasts were characterized by Sca1 expression, and PDL fibroblasts, characterized by Periostin and Asporin expression. Through the construction of 3D organotypic cultures, we showed that HGF supported epithelial multilayering, whilst HPDLF failed to support epithelial cell growth. Furthermore, HGF constructs treated with rhDKK1 resulted in a profound reduction in epithelial thickness. We identified SFRP4 to be highly specifically expressed in HPDLF, at both the mRNA and protein levels. A knockdown of SFRP4 in HPDLF constructs led to an increase in epithelial growth. CONCLUSION: The study demonstrates the presence of phenotypically distinct fibroblast populations within dentogingival tissues and that these specific populations have different influences on the epithelium. Our data suggest that a downregulation of Wnt signalling within PDL may be important in maintaining the integrity and anatomical position of the JE.

Experience With the Pipeline Embolization Device for Posterior Circulations Aneurysms: A Multicenter Cohort Study.

BACKGROUND: The Pipeline Embolization Device (PED; Medtronic) has been used off-label for the treatment of challenging posterior circulation aneurysms. Data on this modality are primarily limited to small retrospective single-center series. OBJECTIVE: To assess safety and efficacy of this treatment by establishing an international, multicenter collaboration. METHODS: Consecutive posterior circulation aneurysms treated with the PED from 2012 to 2019 across 11 neurovascular centers were retrospectively reviewed. Baseline demographics, aneurysm and treatment characteristics, complications, occlusion status, and functional outcome were assessed. RESULTS: There were 149 posterior circulation aneurysms treated with PED in 146 patients. A total of 24 (16.4%) patients presented with subarachnoid hemorrhage. Most aneurysms were dissecting/blister (36.2%) in morphology, followed by saccular (35.6%) and fusiform (28.2%). The most common locations were the vertebral (51.7%) and basilar arteries (22.8%). Complete or near-complete occlusion (>90%) was achieved in 90.9% of aneurysms at a median follow-up of 12 mo. Dissecting/blister aneurysms were most likely to occlude (P = .06). Symptomatic neurologic complications occurred in 9.4% of aneurysms, associated with larger size, ruptured presentation, presentations with brain stem compression, cranial nerve palsy, or stroke. Favorable functional outcome (modified Rankin Score 0-2) was achieved in 86.2% of patients. There were 6 fatalities of which 4 occurred in aneurysmal subarachnoid hemorrhage patients. CONCLUSION: This multicenter study shows that PED for the treatment of posterior circulation is preferentially used for the treatment of fusiform and dissecting/blister aneurysm morphologies. Despite the challenges presented by these less-common morphologies, flow diversion may be performed with a neurologic complication rate of about 10% and favorable long-term aneurysm occlusion rates.

Non-Surgical Periodontal Therapy - Evidence and Opinion.

Effective non-surgical periodontal therapy is fundamental to achieve and maintain periodontal health, particularly in individuals who are susceptible to periodontitis. This article aims to highlight current evidence and published guidance, together with personal insights and suggestions from the author's clinical experience to help with management of patients utilising this common treatment modality.

Gingival fibroblasts prevent BMP-mediated osteoblastic differentiation.

OBJECTIVES: The inhibitory action of the superficial gingival connective tissues may limit the regenerative potential of alveolar bone in periodontal therapy or dental implant applications. The aims of this study were to investigate the hypothesis that gingival fibroblasts (GF) can inhibit bone morphogenetic protein (BMP)-induced osteoblastic differentiation, to determine their expression of BMP inhibitors, and finally to determine whether reduction of these inhibitors can relieve suppression of osteoblastic differentiation. METHODS: Gingival fibroblasts were co-cultured either directly or indirectly with calvarial osteoblasts to assess alkaline phosphatase inhibitory activity, a marker of osteoblastic differentiation. To test total BMP-inhibitory activity of rat GF, conditioned media (GFCM) were collected from cultures. ROS 17/2.8 osteoblastic cells were stimulated with BMP2, together with GFCM. Inhibitor expression was tested using RT-qPCR, Western blotting and in situ hybridization. Removal of inhibitors was carried out using immunoprecipitation beads. RESULTS: Co-culture experiments showed GF-secreted factors that inhibit BMP-stimulated ALP activity. 10 ng/ml BMP2 increased alkaline phosphatase expression in ROS cells by 41%. GFCM blocked BMP activity which was equivalent to the activity of 100 ng/ml Noggin, a well-described BMP inhibitor. Cultured gingival fibroblasts constitutively expressed BMP antagonist genes from the same subfamily, Grem1, Grem2 and Nbl1 and the Wnt inhibitor Sfrp1. Gremlin1 (6.7 × reference gene expression) had highest levels of basal expression. ISH analysis showed Gremlin1 expression was restricted to the inner half of the gingival lamina propria and the PDL. Removal of Gremlin1 protein from GFCM eliminated the inhibitory effect of GFCM on ALP activity in ROS cells. Subsequent addition of recombinant Gremlin1 restored the inhibitory activity. CONCLUSIONS: Factors secreted by gingival fibroblasts inhibit BMP-induced bone formation and a range of BMP inhibitors are constitutively expressed in gingival connective tissues. These inhibitors, particularly Gremlin1, may limit coronal alveolar bone regenerative potential during oral and periodontal surgery.

Site-specific differences in osteoblast phenotype, mechanical loading response and estrogen receptor-related gene expression.

The osteoporosis-resistant nature of skull bones implies inherent differences exist between their cellular responses and those of other osteoporosis-susceptible skeletal sites. Phenotypic differences in calvarial and femoral osteoblastic responses to induction of osteogenesis, mechanical loading, estrogen, growth factor and cytokine stimulation were investigated. Primary rat calvarial and femoral adult male osteoblasts were cultured and osteoblastic mineralisation and maturation determined using Alizarin Red staining and expression of osteogenic marker genes assessed. Expression of known mechanically-responsive genes was compared between sites following loading of scaffold-seeded cells in a bioreactor. Cell proliferation and differentiation following growth factor and estrogen stimulation were also compared. Finally expression of estrogen receptors and associated genes during osteogenic differentiation were investigated. Calvarial osteoblasts exhibited delayed maturation (45d. vs 21d.) and produced less mineralised matrix than femoral osteoblasts when osteogenically induced. PDGF-BB and FGF2 both caused a selective increase in proliferation and decrease in osteoblastic differentiation of femoral osteoblasts. Mechanical stimulation resulted in the induction of the expression of Ccl2 and Anx2a selectively in femoral osteoblasts, but remained unchanged in calvarial cells. Estrogen receptor beta expression was selectively upregulated 2-fold in calvarial osteoblasts. Most interestingly, the estrogen responsive transcriptional repressor RERG was constitutively expressed at 1000-fold greater levels in calvarial compared with femoral osteoblasts. RERG expression in calvarial osteoblasts was down regulated during osteogenic induction whereas upregulation occurred in femoral osteoblasts. Bone cells of the skull are inherently different to those of the femur, and respond differentially to a range of stimuli. These site-specific differences may have important relevance in the development of strategies to tackle metabolic bone disorders.

Sprouty 2, an Early Response Gene Regulator of FosB and Mesenchymal Stem Cell Proliferation During Mechanical Loading and Osteogenic Differentiation.

Sprouty 2 (Spry2), an inhibitor of MAP kinase signaling was previously shown by our group to be induced during mechanical loading of mesenchymal stem cells (MSCs). Here, we studied the implication of Spry2 activation during mechanical loading and chemically induced MSC differentiation. Spry 2 expression showed an immediate early response during mechanical loading and chemical induction of osteogenic differentiation and followed the same pattern as osteogenic associated gene FosB and was necessary for the induction of FosB, as Spry 2 knock down also abrogated the upregulation of FosB expression. Spry 2 knock down was, also associated with an early response of the osteogenic genes Runx-2 and ALP. Neither the knock-down of Spry 2 nor the subsequent reduction in FosB had any effect on mid-late osteogenesis or mineralization but was associated with a significant increase in proliferation of MSC. These effects were possibly governed by negative regulation of MEK/Erk signaling as Spry 2 knock down resulted in an increase in phosphorylation of Erk1/2. In summary, our results shows the involvement of Spry2 in regulation of FosB and Runx2 genes, MAPK signaling and proliferation of MSC. Taken together these results suggest a possible role for Spry2 in regulation of MSC functions in response to mechanical loading and osteogenic differentiation. J. Cell. Biochem. 118: 2606-2614, 2017. © 2017 Wiley Periodicals, Inc.

DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1α and mTOR signalling.

Stem cell fate decisions to remain quiescent, self-renew or differentiate are largely governed by the interplay between extracellular signals from the niche and the cell intrinsic signal cascades and transcriptional programs. Here we demonstrate that DNA Damage Inducible Transcript 4 (DDIT4) acts as a link between HIF1α and mTOR signalling and regulation of adult stem cell fate. Global gene expression analysis of mesenchymal stem cells (MSC) derived from single clones and live RNA cell sorting showed a direct correlation between DDIT4 and differentiation potentials of MSC. Loss and gain of function analysis demonstrated that DDIT4 activity is directly linked to regulation of mTOR signalling, expression of pluripotency genes and differentiation. Further we demonstrated that DDIT4 exert these effects down-stream to HIF1α. Our findings provide an insight in regulation of adult stem cells homeostasis by two major pathways with opposing functions to coordinate between states of self-renewal and differentiation.

Evaluation of anterior third of superior sagittal sinus in normal population: Identifying the subgroup with dominant drainage.

BACKGROUND/OBJECT: The ligation and transection of anterior third of superior sagittal sinus (AT-SSS) is an important step to approach anterior skull base lesions. Some clinical studies have shown frontal lobe venous infarct following such surgical procedures questioning the safety of its ligation. We have studied the variations in venous drainage patterns to AT-SSS in the normal population using postcontrast magnetic resonance venogram (MRV). A novel scoring system to recognize the subgroup with dominant venous drainage from frontal lobes has been described. MATERIALS AND METHODS: In this study, 60 three-dimensional contrast-enhanced (CE) MRVs were obtained from those cases being evaluated for a headache not harboring any intracranial mass lesion. The AT-SSS with all its draining veins was studied in detail. Morphology of individual veins such as length, caliber, tributaries, and angulation with AT-SSS was studied, and a numerical value of 0 or 1 was assigned for each of the above parameters. Summing up these scores derived from the individual cortical veins quantified the drainage of AT-SSS. RESULTS: There are 3-4 veins on either side draining to AT-SSS. Barely, 3% of the veins had > 3 tributaries. Only 6.6% of veins had a caliber >3 mm, and 16.5% drained at acute angles to AT-SSS. About 26% of the veins did cross at least half of the lateral frontal lobe. We found in 26 individuals the AT-SSS score was 0-2, in 22 it was 3-5 and, in only in 12 (20%) the score was 6 or more (dominant drainage). CONCLUSION: There are anatomical variations in venous drainage of frontal lobes into AT-SSS. Those with dominant drainage are likely to develop venous congestion and complications if sacrificed. It is possible to identify these individuals on the basis of venous drainage pattern as shown in CE-MRV.

Bronchial artery embolization in chronic pulmonary thromboembolism: A therapeutic dilemma.

Bronchial artery embolization is the treatment of choice for the management of life-threatening massive hemoptysis. Chronic pulmonary thromboembolism (PTE) is one of the rare causes of hemoptysis. Management of hemoptysis in chronic PTE is a point of debate. In this article, we have reported one case of hemoptysis in chronic PTE managed successfully with bronchial artery embolization.