Indications for implant-supported rehabilitation of the posterior atrophic maxilla: A multidisciplinary consensus among experts in the field utilising the modified Delphi method.

PURPOSE: To establish consensus-driven guidelines that could support the clinical decision-making process for implant-supported rehabilitation of the posterior atrophic maxilla and ultimately improve long-term treatment outcomes and patient satisfaction. MATERIALS AND METHODS: A total of 33 participants were enrolled (18 active members of the Italian Academy of Osseointegration and 15 international experts). Based on the available evidence, the development group discussed and proposed an initial list of 20 statements, which were later evalu-ated by all participants. After the forms were completed, the responses were sent for blinded ana-lysis. In most cases, when a consensus was not reached, the statements were rephrased and sent to the participants for another round of evaluation. Three rounds were planned. RESULTS: After the first round of voting, participants came close to reaching a consensus on six statements, but no consensus was achieved for the other fourteen. Following this, nineteen statements were rephrased and sent to participants again for the second round of voting, after which a consensus was reached for six statements and almost reached for three statements, but no consensus was achieved for the other ten. All 13 statements upon which no consensus was reached were rephrased and included in the third round. After this round, a consensus was achieved for an additional nine statements and almost achieved for three statements, but no consensus was reached for the remaining statement. CONCLUSION: This Delphi consensus highlights the importance of accurate preoperative planning, taking into consideration the maxillomandibular relationship to meet the functional and aesthetic requirements of the final restoration. Emphasis is placed on the role played by the sinus bony walls and floor in providing essential elements for bone formation, and on evaluation of bucco-palatal sinus width for choosing between lateral and transcrestal sinus floor elevation. Tilted and trans-sinus implants are considered viable options, whereas caution is advised when placing pterygoid implants. Zygomatic implants are seen as a potential option in specific cases, such as for completely edentulous elderly or oncological patients, for whom conventional alternatives are unsuitable.

Mucosal cyst aspiration in conjunction with maxillary sinus elevation: A clinical cohort study.

INTRODUCTION: Patients with mucosal cysts in the maxillary sinus require special consideration in patients who require implant therapy for the restoration when undergoing implant therapy for the restoration of the posterior maxillary dentition. Treatment strategies for these clinical situations remain controversial in the literature. Thus, this study seeks to describe a safe and effective therapeutic strategy for sinus augmentation in patients with pre-existing maxillary antral cysts. METHODS: A total of 15 patients and 18 sinuses were consecutively enrolled in this cohort study and underwent maxillary antral cyst treatment by needle aspiration and simultaneous maxillary sinus augmentation (MSA). During surgical procedures, threeimplants (Zimmer Biomet, Indiana, USA) were positioned in 11 sinuses and two implants (Zimmer Biomet, Indiana, USA) were positioned in 5 sinuses. RESULTS: Overall implant success and survival rates were 100% and 97.8%, respectively at 1 year and 5-year follow-ups. Crestal bone resorption averaged 0.3 ± 0.2 mm 5-year post-loading, showing bone stability. Implant survival rate at 5-year follow-up expressed predictability of the technique comparable to historical data when MSA was performed alone. Crestal bone resorption averaged 0.3 ± 0.2 mm 5 years post-loading and shows bone stability utilizing mucosal cyst aspiration with concomitant MSA procedures. Quality of life evaluation at 1-week post-op showed similar results to published historical data. In 81% (13 sinuses), the CBCT examination at 5-year follow-up showed no cyst reformation, in 19% (3 sinuses) cyst reformation was visible, but smaller in size when compared to the pre-op CBCT evaluation, and all the patients were asymptomatic. CONCLUSIONS: Maxillary sinus mucosal cyst aspiration with concomitant MSA, may be a viable option to treat maxillary sinus cyst.

Hyperbaric oxygen therapy as an adjunct treatment of periodontitis, MRONJ, and ONJ: a systematic literature review.

OBJECTIVE: To review the available prospective literature on hyperbaric oxygen (HBO) therapy for periodontal conditions. MATERIALS AND METHODS: A comprehensive electronic and manual search was performed to identify clinical studies on adult patients who underwent hyperbaric oxygen therapy for periodontal treatments. A systematic literature search was conducted in PubMed, Cochrane, and Dentistry Oral Sciences Source databases. RESULTS: Fourteen articles were included in the final literature review, of which five were RCTs and 11 were prospective clinical studies. Four studies discussed HBO as an adjunct to nonsurgical treatment of periodontitis, eight reported on HBO and osteoradionecrosis, and one examined HBO in bisphosphonate-related necrosis of the jaws. CONCLUSIONS: HBO has shown superior efficacy compared to antibiotics as a prophylactic measure in preventing osteoradionecrosis (ORN) in patients with a history of high mandibular irradiation. Clinicians should consider referring such patients for HBO therapy before and after tooth extractions. However, for the surgical excision of existing ORN lesions, HBO therapy does not yield significant benefits but does not negatively impact outcomes either. Regarding the treatment of periodontitis patients, the variability among studies prevents definitive conclusions. HBO therapy as an adjunct to SRP in periodontitis treatment produces mixed results. CLINICAL RELEVANCE: This study's clinical relevance lies in its exploration of the potential benefits of HBO for periodontal conditions. Also, it provides clinicians with insights into when and how to integrate HBO therapy into their treatment approaches, particularly for patients with a history of irradiation and those undergoing complex dental procedures.

Design, Synthesis, and Structure-Activity Relationship Studies of Novel GPR88 Agonists (4-Substituted-phenyl)acetamides Based on the Reversed Amide Scaffold.

The development of synthetic agonists for the orphan receptor GPR88 has recently attracted significant interest, given the promise of GPR88 as a novel drug target for psychiatric and neurodegenerative disorders. Examination of structure-activity relationships of two known agonist scaffolds 2-PCCA and 2-AMPP, as well as the recently resolved cryo-EM structure of 2-PCCA-bound GPR88, led to the design of a new scaffold based on the "reversed amide" strategy of 2-AMPP. A series of novel (4-substituted-phenyl)acetamides were synthesized and assessed in cAMP accumulation assays as GPR88 agonists, which led to the discovery of several compounds with better or comparable potencies to 2-AMPP. Computational docking studies suggest that these novel GPR88 agonists bind to the same allosteric site of GPR88 that 2-PCCA occupies. Collectively, our findings provide structural insight and SAR requirement at the allosteric site of GPR88 and a new scaffold for further development of GPR88 allosteric agonists.

Periodontitis stage and grade modifies the benefit of regular supportive periodontal care in terms of need for retreatment and mean cumulative cost.

AIM: This study aimed to characterize the periodontal breakdown during supportive periodontal care (SPC) and to quantify the corresponding cost-effectiveness of periodontal therapy. MATERIALS AND METHODS: Data were obtained from charts of patients who received active periodontal therapy (APT) with a minimum follow-up of ≥10 years. Analysis was done to identify factors associated with the incidence of additional sub-gingival instrumentation (SGI) and/or surgery (SUR) during SPC and mean cumulative cost of recurrence was calculated. All relevant data were collected. RESULTS: In all, 442 patients were included. Over the follow-up period, 62% of Stage I and II patients and 72% of Stage III and IV patients required further treatment following the APT; 56.5% of SGI patients and 78.6% of SUR patients received a second intervention. SUR patients received more SUR during the follow-up period (p = .035). Stage III and IV patients received more SUR during SPC than Stage I and II patients (p = .001). Grade C patients received more SUR during the follow-up period (p < .05). During the 5-year period preceding retreatment, the mean SPC visits were lower for patients who did not require retreatment (p < .001). Risk factors such as regularity of maintenance, smoking and diabetes were related to a higher chance of receiving SUR during the follow-up period (p < .05). The mean cumulative costs indicated less recurrence cost for compliers in Stage III and IV or Grade B and C but not for those in Stage I and II or Grade A. CONCLUSIONS: The risk of relapse in the maintenance population may be correlated with higher stage and grade, patient compliance, modifiable risk factors and the nature of the treatment provided during APT. The total cost of treatment of recurrences was lower for compliers in Stage III/IV and Grade B/C compared with erratic compliers with the same severity and risk.

Vertical Ridge Augmentation Using Collagen Membrane and Tenting Screws in the Esthetic Zone: A Case Series.

Successful rehabilitation of severely atrophic, short-span edentulous ridges in esthetic regions can seldom be done without some form of vertical ridge augmentation (VRA). The best available evidence shows that guided bone regeneration procedures may present a very predictable option with reduced potential for complications compared to alternative options. The present case series presents a novel technique to achieve predictable VRA with a low complication rate using tenting screws and cross-linked resorbable membranes. A total of 10 patients (5 men, 5 women) with severe vertical defects in the esthetic zone participated in this study. Following a mean healing time of 9.3 months, the mean defect resolution was 80%, with a mean vertical bone gain of 6.2 ± 1.61 mm. Only one case presented with reduced defect resolution (50%); however, the bone gain for this case was 6 mm.

Immediate Implant Placement Using the Socket Shield Technique: Clinical, Radiographic, and Volumetric Results Using 3D Digital Techniques-A Case Series.

Extraction-site alveolar remodeling is a major concern due to negative volumetric hard and soft tissue changes that inevitably limit rehabilitation options and diminish esthetic outcomes. Surgical techniques employed to minimize alveolar dimensional changes are not always predictable. Utilizing a socket shield with an immediate surgical implant procedure helps maintain a thin portion of the root in the vestibular area and thus minimizes bone resorption, especially at the coronal cortical aspect. This case series assesses the dimensional changes in peri-alveolar structures via superimposition of the preoperative and 6-month postoperative 3D digital quantification of soft tissue. Fifty patients with 50 sites fulfilled the inclusion criteria. Implant survival was 100%, with no incidence of complications. Tissue changes were as follows: -0.85 mm at the mesial papilla, -0.95 mm at the distal papilla, -0.7 mm at both the vertical and horizontal central margins, -0.21 mm at a distance 4 mm from the margin, and -0.64 mm at the palatal central margin. The buccal contour was clinically convex in all cases. The site with highest frequency of > 1 mm of dimensional loss was the distal papilla (42% of sites), and the site with the lowest frequency was the point 4 mm from the midfacial margin (0% of sites).

In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid.

Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (1), a Lophophora alkaloid, has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1. We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine-N-oxide. In mice, the two diastereomers of pellotine-O-glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT)1D, 5-HT6, and 5-HT7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT6 and 5-HT7, where it was found to be an agonist at the former (EC50 = 94 nM, Emax = 32%) and an inverse agonist at the latter (EC50 = 291 nM, Emax = -98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors.

Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity.

To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure-activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity. Compound 13a was the most potent cAMP-based D1R antagonist identified and was also found to antagonize ß-arrestin translocation in a TANGO assay. Affinity assessments at other dopamine receptors revealed that 13a is selective for D1R and unlike other naturally-occurring THPBs such as (S)-stepholidine, lacks D2R affinity. In preliminary biopharmaceutical assays, excellent BBB permeation was observed for 13a. Further pharmacological studies are warranted on (S)-stepholidine congeners to harvest their potential as a source of novel, druggable D1R-targeted agents.

IL-17: Balancing Protective Immunity and Pathogenesis.

The biological role of interleukin 17 (IL-17) has been explored during recent decades and identified as a pivotal player in coordinating innate and adaptive immune responses. Notably, IL-17 functions as a double-edged sword with both destructive and protective immunological roles. While substantial progress has implicated unrestrained IL-17 in a variety of infectious diseases or autoimmune conditions, IL-17 plays an important role in protecting the host against pathogens and maintaining physiological homeostasis. In this review, we describe canonical IL-17 signaling mechanisms promoting neutrophils recruitment, antimicrobial peptide production, and maintaining the epithelium barrier integrity, as well as some noncanonical mechanisms involving IL-17 that elicit protective immunity.

Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists.

Partial agonists of peripheral cannabinoid receptors (CBRs) have potential therapeutic applications in several medical conditions. However, (-)-trans-Δ9-tetrahydrocannabinol (THC), the principal active component of marijuana, which is a partial agonist of CB1 and CB2 penetrates the central nervous system (CNS) and produces adverse effects. Peripherally restricted partial agonists of CBRs, particularly of CB1, can be used to treat illnesses safely and effectively with a better therapeutic index. Here, we report on our efforts to synthesize pyrazole partial CBR agonists with peripheral selectivity, resulting in lead compound 40. This compound is a potent partial agonist of CB1 with âˆ¼ 5-fold higher plasma biodistribution over brain and represents an early lead for optimization.

How to avoid intraoperative and postoperative complications in maxillary sinus elevation.

Maxillary sinus floor elevation, via the lateral approach, is one of the most predictable bone augmentation procedures performed in implant dentistry. but both intra- and postoperative complications can occur, and some of them are severe. Our aim is as follows: To review the pertinent literature on the topic, especially assessing the risk factors related to complications. To give clinical recommendations to minimize intra- and postoperative complications with the ultimate scope of improving the standard of clinical care and patient safety.

Supplement Consumption and Periodontal Health: An Exploratory Survey Using the BigMouth Repository.

BACKGROUND: Dietary supplements have been investigated for their impact on the periodontal apparatus (alveolar bone, mucosa, periodontal ligament, and cementum) and their hypothetical protective role against periodontitis. There remains a gap in the field in this area. Thus, the present study aims to examine the correlation between populations who report taking different dietary supplements and their relative periodontal health. METHODS: The BigMouth dental data repository derived from the dental Electronic Health Records (EHRs) of the University of Michigan school of dentistry was used to extract data relating to all patients who fulfilled the eligibility criteria. The prevalence of periodontitis compared to periodontal health as related to supplement consumption was assessed. RESULTS: A total of 118,426 individuals (55,459 males and 62,967 females) with self-reported consumption of the dietary supplements of interest were identified in the University of Michigan database via the BigMouth repository. Associations with the following vitamins were investigated, Vitamin B, Vitamin C, Vitamin D, Vitamin E, Multivitamins, Fish oil, Calcium, Omega 3, Saw palmetto, Zinc, Sildenafil, Flax seed, Folic acid, Garlic pills, Ginger pills, Ginko, Ginseng, Glucosamine, Iron, and Magnesium. Out of these supplements, only multivitamins and iron were found to significantly favor periodontal health, while folic acid and vitamin E significantly favored periodontitis. CONCLUSIONS: This study found a minimal association between the consumption of dietary supplements with periodontal health.

Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation.

GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists.

HER2 as a potential therapeutic target on quiescent prostate cancer cells.

Quiescent prostate cancer (PCa) cells are common in tumors but are often resistant to chemotherapy. Quiescent PCa cells are also enriched for a stem-like tumor initiating population, and can lead to recurrence after dormancy. Unfortunately, quiescent PCa cells are difficult to identify and / or target with treatment in part because the relevant markers are intracellular and regulated by protein stability. We addressed this problem by utilizing PCa cells expressing fluorescent markers for CDKN1B (p27) and CDT1, which can separate viable PCa cells into G0, G1, or combined S/G2/M populations. We used FACS to collect G1 and G0 PC3 PCa cells, isolated membrane proteins, and analyzed protein abundance in G0 vs G1 cells by gas chromatography mass spectrometry. Enrichment analysis identified nucleocytoplasmic transport as the most significantly different pathway. To identify cell surface proteins potentially identifying quiescent PCa cells for future patient samples or for antibody based therapeutic research, we focused on differentially abundant plasma membrane proteins, and identified ERBB2 (HER2) as a cell surface protein enriched on G0 PCa cells. High HER2 on the cell membrane is associated with quiescence in PCa cells and likely induced by the bone microenvironment. Using a drug conjugated anti-HER2 antibody (trastuzumab emtansine) in a mouse PCa xenograft model delayed metastatic tumor growth, suggesting approaches that target HER2-high cells may be beneficial in treating PCa. We propose that HER2 is deserving of further study in PCa as a target on quiescent cells to prevent recurrence, decrease chemotherapy resistance, or eradicate minimal residual disease.

Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor.

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [3H]RTI-33, derived from a synthetic agonist RTI-13951-33. [3H]RTI-33 has a specific activity of 83.4 Ci/mmol and showed one-site, saturable binding (KD of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells. A competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.

Using the BigMouth repository for periodontal medicine: Breaking the chains?

BACKGROUND: To achieve the ultimate therapeutic reality of disease prevention, we must first conduct a thorough review of periodontal and peri-implant diseases concomitant with their mechanistic, predisposing, and precipitating factors to address the present oral/systemic needs of our patients. METHODS: An innovative dental research patient data repository (RPDR) named BigMouth was successfully launched in August 2012 with data on more than 4.5 million patients seen in 11 dental schools (members of the Consortium of Oral Health Research and Informatics, COHRI). RESULTS: Level 1 data access allots researchers with count data that may be used to formulate and test initial hypotheses based on preliminary data trends. Level 2 access gives more detailed, patient-level information with full periodontal charts. Of note, radiographic data were not accessible at the time of writing this manuscript. CONCLUSION: As we support the use of these innovative "big data" tools for exploratory use, we bring to the forefront the purposeful intention to (1) not overproject unsubstantiated relationships and (2) simultaneously pursue grounding of the mechanistic underpinnings of found associations.

The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects.

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics.

Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist.

Human trace amine-associated receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potent hTAAR1 antagonists remains elusive. Herein, we report the results of structure-activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44, 34). RTI-7470-44 exhibited an IC50 of 8.4 nM in an in vitro cAMP functional assay, a Ki of 0.3 nM in a radioligand binding assay, and showed species selectivity for hTAAR1 over the rat and mouse orthologues. RTI-7470-44 displayed good blood-brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. Finally, RTI-7470-44 increased the spontaneous firing rate of mouse VTA dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. Collectively, this work provides a promising hTAAR1 antagonist probe that can be used to study TAAR1 pharmacology and the potential therapeutic role in hypodopaminergic diseases such as PD.