Geranylgeraniol (GGOH), incorporated into a bone cement pellet promotes osteoclast function and healing in a model of medication-related osteonecrosis of the jaw.

Introduction: There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in in vitro and in a proven animal model of MRONJ. Methods: 3H labelled GGOH (2 mM) was incorporated into a Hydroset bone cement pellet and release from the cement was assessed over time. To assess the effect on bone cell function, the GGOH-loaded cement was placed in a porous filter above cultured osteoclasts treated with bisphosphonate and the effect on osteoclast survival and function were measured. In a pilot study the effect of GGOH on osteotomy microstructure was measured in a rat model of MRONJ using a split mouth design. Results: The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel. Conclusion: These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ.

Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP).

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.

Controversies in the Management of Oral and Maxillofacial Infections.

The management and treatment of odontogenic infection, and its frequent extension into the head and neck, remains an important section of oral and maxillofacial surgical practice. This area of maxillofacial expertise is widely recognized by the medical community and an essential component to the hospital referral system. Although the general principles of infection management have not changed, there have been modifications in the timing of treatment sequences and treatment techniques. These modifications are influenced by the development of diagnostic methods and advances in bacterial genetics and antibiotic usage. This article reviews treatment considerations and controversies surrounding this subject.

Facial dysmorphology and odontogenic tumor development associated with inborn errors of metabolism: a case report.

PURPOSE: Inborn errors of metabolism (IEMs) are genetic disorders that alter normal physiologic functioning. Deficiency of 3-methylcrotonyl-coenzyme A carboxylase is one such IEM that can lead to major episodes of metabolic dysfunction. Certain IEMs are associated with characteristic congenital dysmorphic facial features. This can be problematic, because these dysmorphisms can mask underlying tumor growth. Literature is lacking on a causal relation between IEM and odontogenic tumor development. MATERIALS AND METHODS: This case was explained in detail and a review of the literature was undertaken. PubMed was used to search for articles involving surgical management of odontogenic myxoma (OM) and associations between odontogenic tumors and IEM. RESULTS: It was determined that the development of odontogenic tumors, specifically OM, is associated with IEMs. These tumors can easily be overlooked as a common dysmorphic feature of an IEM. CONCLUSION: IEMs lead to major metabolic disturbances and, thus, can alter the cellular microenvironment. Hypothetically, these alterations can lead to the development of odontogenic tumors. With the diagnosis of IEM becoming more common owing to improved newborn screening, careful attention should be given to these patients because of the possibility that dysmorphologic facial features could be masking underlying tumor growth.

Orbital hemorrhage and compressive optic neuropathy in patients with midfacial fractures receiving low-molecular weight heparin therapy.

While the implementation of deep vein thrombosis (DVT) prophylaxis in the hospital setting is a major concern, the use of antithrombotic agents is fraught with a variety of hemorrhagic complications. Due to increasing reports of adverse reactions to unfractionated heparin (UFH), several manufacturers have initiated product recalls. As a result, the use of low-molecular weight heparins (LMWHs) such as enoxaparin has risen substantially. In this paper, 2 orbital hemorrhagic complications in patients receiving enoxaparin therapy will be presented. The incidence of DVT in the OMS patient, recent prophylactic strategies, and their effectiveness will be reviewed.

Ophthalmic injuries in patients with zygomaticomaxillary complex fractures requiring surgical repair.

PURPOSE: Injuries to the middle third of the face commonly destroy the integrity of the orbital skeleton, and are frequently complicated by injury to the eye, ranging between 2.7% and 90.6% in reported series. This article is a retrospecitve, descriptive case study assessing the spectrum and incidence of ophthalmic involvement in patients presenting with zygomaticomaxillary complex (ZMC) fractures. PATIENTS AND METHODS: Ninety-six patients with ZMC fractures who were surgically treated in 1 academic institution between 1996 and 2006 were assessed pre- and postoperatively by the same oculoplastic surgeon and were included in the study. All patients had a thorough ophthalmologic examination that included assessment of visual acuity, pupillary reactivity, anterior and posterior segment examination, and extraocular motility. In cases of optic neuropathy, automated perimetry was also performed. The variables reviewed included patients' age, gender, mechanism of injury, visual acuity, pupillary reactivity, extraocular motility, presence or absence of diplopia, ocular and orbital findings, and intraorbital hypoesthesia. RESULTS: Gender distribution of the patients was 88% male, with a mean age of 36 years. The most common etiology of trauma was assult (56%), followed by falls (21%). Most patients (66.6%) sustained minor ocular injuries such as subconjuctival hemorrhage, iris sphincter tear, and corneal abrasion. Subconjunctival hemorrhage was the most common minor injury, accounting for 55% of the cases. Major injuries such as ruptured globe and retinal hemorrhage occurred in 10% of the patients. Orbital findings such as restriction of extraocular movement occurred in 15% of cases. Symptomatic diplopia was noted in 16% of the patients and traumatic optic neuropathy occurred in 6%. Diplopia significantly improved in the first 3 postoperative months, dropping from a preoperative incidence of 16% to 2%. CONCLUSION: Comminuted ZMC fractures had been reported to be associated with a signficantly higher incidence of visual sequelae than other forms of midfacial injury. A 10% incidence of major or blinding injuries and a 6% incidence of traumatic optic neuropathy are significant, and warrants a prompt ophthalmologic examination of all patients with ZMC fractures as quickly as possible, and always preoperatively in injuries necessitating surgical repair.

The pattern of combined maxillofacial and cervical spine fractures.

PURPOSE: Prompt recognition of cervical fractures in patients with facial fractures is of prime importance, as failure to diagnose such injuries carries a significant risk of causing neurologic abnormalities, long-term disabilities, and even death. The aim of this retrospective case study is to describe the different patterns of combinations of maxillofacial and cervical spine (C-spine) injuries to provide guidance in diagnosis and care of patients with combined injuries. PATIENTS AND METHODS: The trauma directory of 1 academic institution was searched for records of 701 patients admitted with cervical spine fractures between January 2000 and June 2006. Patients who did not sustain a facial fracture in addition to their C-spine fracture were excluded. The search was narrowed to 44 patients (6.26%) who presented with combined C-spine and facial fractures. Descriptive statistics were performed in which the frequencies of the variables were presented and then exploration of the interaction between the different variables was carried out. RESULTS: A 6.28% incidence rate of combined C-spine and maxillofacial fractures is noted in this study. The most common cause of trauma was motor vehicle accidents (45.5%), followed by falls (36.4%). In regards to the types of maxillofacial fractures, 27.3% of the cases presented with isolated orbital fractures and 13.6% with isolated mandibular fractures. A total of 68.2% of the combined C-spine and facial fracture cases involved orbital fractures of some form. The most frequent level of C-spine fracture was isolated C2 fractures (31.8%) followed by isolated C4 and C6 fractures (6.8% each). When the mechanism of trauma were compared to the types of C-spine and maxillofacial fractures, falls were found to be the most frequent mechanism causing both isolated orbital and C2 fractures. CONCLUSION: The rule of presuming that all patients with maxillofacial fractures have an unstable C-spine injury should stand. This should be emphasized in patients with orbital fractures and we plead for a higher index of suspicion for C-spine injuries in such patients.

Evaluating a dental practice for purchase or associateship.

Private dental practice can be achieved through either outright ownership or an associateship in conjunction with senior dentists; the decision depends on personal and professional objectives and goals. Once a decision is made, the time and effort required to identify an appropriate practice, negotiate the terms of purchase or associateship, and transition to the new practice can be daunting. This article reviews the process and provides an overview of the general steps involved in the evaluation of a dental practice for purchase or associateship. With appropriate knowledge and preparation, due diligence, and ethical and sensitive behavior, transitioning to private practice can be successful and lead to professional and personal fulfillment.

Oral management in a patient with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disorder of connective tissue. FOP results in debilitating heterotopic ossification of the axial and appendicular skeleton. Permanent ankylosis of the temporomandibular joint (TMJ) is a common late finding, but is usually preceded by specific inciting trauma. Extreme care must be exercised when carrying out routine dental care to prevent soft tissue trauma. Oral health care for patients with FOP is usually complex. There are additional considerations when oral surgical procedures, such as extractions, are needed. Maintaining a balance between oral health and disease progression in these patients is challenging, as they frequently present with advanced oral disease. Fiber optic-assisted placement of the nasoendotracheal tube is the standard of care. Intramuscular injections including mandibular blocks must be avoided. Permanent fusion of the TMJ leads to malnutrition, inanition, and aspiration of food. In patients with complete TMJ ankylosis, dental extractions can be safely and effectively performed while accessing teeth from the buccal aspect. This approach has successfully resulted in decreased morbidity in these patients as well as others with limited oral opening.

Trigeminal nerve injuries after mandibular implant placement--practical knowledge for clinicians.

Endosseous mandibular implant placement can result in injuries to the peripheral branches of the trigeminal nerve even with the most careful preoperative planning and intraoperative technique. In the past, many patients have been discouraged from seeking repair for such injuries because of the unreliability of the techniques for correcting the injury. It is now possible to perform microneurosurgical repair of such injuries. If the repair is done in a timely fashion, sensation can be improved or restored and painful nerve dysesthesia can be relieved. This article reviews the different types of nerve injuries, their symptoms and diagnosis, and provides information for clinicians to manage their implant patients with neurosensory disturbance.

Molecular interactions of human immunodeficiency virus type 1 with primary human oral keratinocytes.

Infection of the oral mucosa of human immunodeficiency virus type 1 (HIV-1)-infected individuals remains an under-evaluated and somewhat enigmatic process. Nonetheless, it is of profound importance in the ongoing AIDS pandemic, based on its potential as a site of person-to-person transmission of the virus as well as a location of HIV-1 pathogenesis and potential reservoir of disease in the setting of virally suppressive highly active antiretroviral therapy. We utilized molecular and virological techniques to analyze HIV-1 infection of primary human mucosal cells and also evaluated the proapoptotic potential of selected HIV-1 proteins in primary isolated human oral keratinocytes. Primary isolated human oral keratinocytes were plated on 0.4 microM polyethylenetetraphthalate cell culture inserts to form an in vitro oral mucosal layer. The strength of this layer in forming a barrier was determined by measuring trans-epithelial electrical current passage across the monolayer. The oral keratinocyte monolayers had trans-epithelial electrical resistance of approximately 176 to 208 omega. For viral infectivity assays, the macrophage-tropic (R5) HIV-1 strains, YU-2 and ADA, and T-cell-line-tropic (X4), NL4-3 virions, incubated with or without deoxynucleoside triphosphates (dNTPs) and/or the polyamines spermine and spermidine, were used to infect oral keratinocytes. Of importance, polyamines and dNTPs have been shown to enhance natural endogenous reverse transcription (NERT), a step essential for early lentiviral infection, and are abundantly present in human semen. The infectivities of HIV-1 strains YU-2, ADA, and NL4-3 for these primary keratinocytes were dramatically increased by the addition of physiological concentrations of dNTPs, spermine, and spermidine. Binding and viral internalization assay studies showed no differences in these oral mucosal cells, with or without NERT-altering agents. It was also observed that the recombinant, cell-free HIV-1 proteins Nef, Tat, and gp120 (R5) induced apoptosis in primary oral keratinocytes compared with the results seen with nontreated cells or cells treated with glutathione S-transferase protein as a control under similar conditions. Microarray analyses suggested that HIV-1 gp120 and Tat induce apoptosis in primary human oral keratinocytes via the Fas/FasL apoptotic pathway, whereas induction of apoptosis by Nef occurs through both Fas/FasL and mitochondrial apoptotic pathways. Thus, these findings suggest molecular mechanisms by which semen in particular, as well as other bodily fluids such as cervicovaginal secretions, could increase oral transmission of HIV-1 via increasing infectivity in confluent and low-replicating oral keratinocytes. As well, the induction of apoptosis in human oral keratinocytes with relevant HIV-1-specific proteins suggests another potential complementary mechanism by which the oral mucosa barrier may be disrupted during HIV-1 infection in vivo.