Hani Mawardi

A Role of Oral Bacteria in Bisphosphonate-induced Osteonecrosis of the Jaw

No consensus has yet been reached to associate oral bacteria conclusively with the etio-pathogenesis of bisphosphonate-induced osteonecrosis of the jaw (BONJ). Therefore, the present study examined the effects of oral bacteria on the development of BONJ-like lesions in a mouse model. In the pamidronate (Pam)-treated mice, but not control non-drug-treated mice, tooth extraction followed by oral infection with Fusobacterium nucleatum caused BONJ-like lesions and delayed epithelial healing, both of which were completely suppressed by a broad-spectrum antibiotic cocktail. Furthermore, in both in vitro and in vivo experiments, the combination of Pam and Fusobacterium nucleatum caused the death of gingival fibroblasts (GFs) and down-regulated their production of keratinocyte growth factor (KGF), which induces epithelial cell growth and migration. Therefore, in periodontal tissues pre-exposed to bisphosphonate, bacterial infection at tooth extraction sites caused diminished KGF expression in GFs, leading to a delay in the epithelial wound-healing process that was mitigated by antibiotics.

Medical management update: Non-Hodgkin lymphoma

Lymphoma is a heterogeneous malignancy of the lymphatic system characterized by proliferation of lymphoid cells or their precursors. Non-Hodgkin lymphoma (NHL) is associated with significant morbidity and is the seventh leading cause of death in the United States. Manifestations of NHL as well as complications of the disease and its management are frequently encountered in the head and neck region and often require specific treatment and modifications in the provision of oral health care. The purpose of this article is to review current concepts of the pathophysiology, as well as medical and oral health care management of NHL.

Combined topical dexamethasone/tacrolimus therapy for management of oral chronic GVHD

Chronic GVHD (cGVHD) frequently affects the oral cavity. The purpose of this study was to estimate the efficacy of combined topical dexamethasone (DEX) and tacrolimus (TAC) solutions in the management of oral cGVHD. The records of 14 patients with oral cGVHD treated with combined topical DEX/TAC were reviewed retrospectively. Pre-to-post treatment changes in subjective and objective measures were evaluated at a median follow-up of 60 days. Serum TAC levels were examined. Marginal objective improvement was detected at follow-up. The median pre-to-post treatment differences were 0.5 (range, −1 to 1) for erythema score, and 0.5 (range, 0 to 2) for lichenoid score, (P=0.06, 0.07 and 0.02, respectively). Subjective improvement was noted in three of four measures at the follow-up visit. The median differences in pain, sensitivity and dryness scores were 1 (range −1 to 6), 1 (range −3 to 5) and 2.5 (range, −5 to 5), respectively (0–10 scale, P<0.05). Four patients (37%) showed increased serum TAC levels; however, all remained within therapeutic range. In conclusion, combined topical DEX/TAC therapy appears to be effective in reducing symptoms attributable to oral cGVHD. Our data has shown minimal evidence of systemic TAC absorption.

Additive effects of orexin B and vasoactive intestinal polypeptide on LL-37-mediated antimicrobial activities.

The present study examined the bactericidal effects of orexin B (ORXB) and vasoactive intestinal peptide (VIP) alone or combined with cationic antimicrobial peptides, such as LL-37, on Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans and Staphylococcus aureus. The bactericidal effect of ORXB or VIP alone was detected in low NaCl concentration, but attenuated in physiological NaCl concentration (150 mM). However, such attenuated bactericidal activities of ORXB and VIP in 150 mM NaCl were regained by adding LL-37. Therefore, our results indicate that VIP and ORXB appear to mediate bactericidal effects in concert with LL-37 in the physiological context of mucosal tissue.

Soluble RANKL Cleaved from Activated Lymphocytes by TNF-α–Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis

Host immune responses play a key role in promoting bone resorption in periodontitis via receptor activator of NF-κB ligand (RANKL)–dependent osteoclastogenesis. Both membrane-bound RANKL (mRANKL) expressed on lymphocytes and soluble RANKL (sRANKL) are found in periodontal lesions. However, the underlying mechanism and cellular source of sRANKL release and its biological role in periodontitis are unclear. TNF-α–converting enzyme (TACE) is reported to cleave the following: 1) precursor TNF-α with release of mature, soluble TNF-α and 2) mRANKL with release of sRANKL. Both soluble TNF-α and sRANKL are found in the periodontitis lesion, leading to the hypothesis that TACE expressed on lymphocytes is engaged in RANKL shedding and that the resulting sRANKL induces osteoclastogenesis. In the current study, upon stimulating PBLs with mitogens in vitro, RANKL expression, sRANKL secretion, and TACE expression were all upregulated. Among the four putative mRANKL sheddases examined in neutralization assays, TACE was the only functional sheddase able to cleave mRANKL expressed on PBL. Moreover, PBL culture supernatant stimulated with mitogens in the presence of anti-TACE Ab or anti-RANKL Ab showed a marked reduction of osteoclastogenesis from osteoclast precursors, indicating that TACE-mediated sRANKL may possess sufficient osteoclastogenic activity. According to double-color confocal microscopy, B cells expressed a more pronounced level of RANKL and TACE expression than T cells or monocytes in periodontally diseased gingiva. Conditioned medium of patients’ gingival lymphocyte culture increased in vitro osteoclastogenic activity, which was suppressed by the addition of anti-TACE Ab and anti-RANKL Ab. Therefore, TACE-mediated cleavage of sRANKL from activated lymphocytes, especially B cells, can promote osteoclastogenesis in periodontitis.

The antimicrobial activity of the appetite peptide hormone ghrelin

The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of ghrelin, acylated ghrelin (AG) and desacylated ghrelin (DAG), demonstrated the same degree of bactericidal activity against Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), while bactericidal effects against Gram-positive Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were minimal or absent, respectively. To elucidate the bactericidal mechanism of AG and DAG against bacteria, we monitored the effect of the cationic peptides on the zeta potential of E. coli. Our results show that AG and DAG similarly quenched the negative surface charge of E. coli, suggesting that ghrelin-mediated bactericidal effects are influenced by charge-dependent binding and not by acyl modification. Like most cationic antimicrobial peptides (CAMPs), we also found that the antibacterial activity of AG was attenuated in physiological NaCl concentration (150mM). Nonetheless, these findings indicate that both AG and DAG can act as CAMPs against Gram-negative bacteria.

Comments on “Osteonecrosis of the jaws in intravenous bisphosphonate use: Proposal for a modification of the clinical classification”

We read with interest the letter by Bagan et al. and their modification to the staging criteria for bisphosphonate-associated osteonecrosis (BRON) proposed by Ruggiero et al. and the American Association of Oral and Maxillofacial Surgeons (AAOMS). We also have noted that patients may present with chronic sinus tracts without evidence of exposed bone at initial visit, who subsequently develop necrotic bone, either in the usual form with visible exposure of bone in the oral cavity or through bone biopsy; two such cases were recently reported. As such, we also believe that the staging system should reflect this and to this end, we recently submitted a manuscript addressing this issue with a proposal for adding Stage 0 to the current classification. All of our cases did not have exposed bone at initial visit, and all had documented necrotic bone at a subsequent visit. As is true with the current classification, all patients must have been exposed to bisphosphonates and not have had radiation to the head and neck. In addition, patients should have other findings that support an evolving BRON such as radiographic changes of sclerosis or sequestrum formation, or very deep localized periodontal defects. The addition to the classification is as follows: Stage 0sa: Patients do not have exposed bone but have sinus tracts or localized deep periodontal pockets and are asymptomatic. The subscript ‘‘sa” stands for ‘‘suspicious, asymptomatic”. These patients are treated with chlorhexidine rinse only with close follow-up. Stage 0ss: Patients do not have exposed bone but have sinus tracts or deep periodontal pockets and are symptomatic. The subscript ‘‘ss” stands for ‘‘suspicious, symptomatic”. These patients are treated with antibiotics and chlorhexidine rinse with close follow-up. Patients in Stage 0 require close follow-up, such as every 1–2 months to document progression of disease, subsequent bone exposure or possibly the development of other pathology since lesions are at this point, only suspicious and not diagnostic for BRON. The staging system may also be used for patients with pain in the jaw, radiographic evidence suspicious for BRON even in the absence of sinus tracts. Because the patients often have other signs (such as radiographic findings), we use Stage 0 to indicate our high level of suspicion that there is an evolving BRON, to reduce the chances of over-diagnosing simple odontogenic infections (of endodontic or periodontal origin that commonly present with sinus tracts or deep periodontal pockets) as BRON. In the classification by Bagan et al., it appears that the presence of exposed bone is not required for any of the stages presented. This may cause other lesions to be inadver-

Characterization and management of exfoliative cheilitis: a single-center experience

Exfoliative cheilitis (EC) is a rare inflammatory condition affecting the vermilion of the lips and characterized by production of a thick keratin scale. Given the limited available data, the approach to optimal management of EC remains unclear. The objective of this retrospective study was to characterize the clinical features, management, and outcomes of a series of patients with EC. Fifteen patients with a median age of 59 years and a female-to-male ratio of 2:1 were diagnosed with EC from 2000 to 2010. Parafunctional lip licking (53%) and a history of psychiatric disorders (40%) were common. Ten patients (66%) returned for follow-up, with an overall response rate (partial or complete) of 80% at a median of 2 months, most frequently associated with the use of topical calcineurin inhibitors or moisturizing agents. Management of EC with topical calcineurin inhibitors and moisturizing agents is associated with clinical improvement, but prospective trials are needed.

Osteonecrosis of the jaw associated with ziv-aflibercept

Medication-related osteonecrosis of the jaw (MRONJ) has been associated with medications that include bisphosphonates (BPs), denosumab, bevacizumab and sunitinib. Ziv-aflibercept is a recombinant human vascular endothelial growth factor (VEGF) receptor which has been used to treat patients with various advanced solid tumors. We report three patients without a history of the use of medications known to cause MRONJ presenting with jaw osteonecrosis typical for MRONJ following therapy with ziv-aflibercept. All patients had metastatic gastrointestinal cancer treated with ziv-aflibercept and were evaluated for MRONJ because of exposed bone in the oral cavity. None of the patients had received antiresorptive therapies or any other medication known to cause MRONJ, and none had received radiation therapy to the jaws. Patients were aged 43, 51, 63 and all were males. Patients received 7, 16 and 23 cycles of ziv-aflibercept treatment and developed necrotic bone. All three patients presented with mandibular involvement, with two reporting pain. Patients were managed with anti-microbial mouth rinse, antibiotics and non-surgical sequestrectomy and followed up for 1.5, 2, and 2 months; two patients became asymptomatic while one patient continued to have pain. These three reported patients with a history of ziv-aflibercept therapy and no reported use of other medications known to cause MRONJ developed exposed necrotic bone of the jaw. We believe that ziv-aflibercept is another medication that can potentially cause MRONJ probably through its anti-VEGF activity, similar to bevacizumab and sunitinib.

Current understanding of the relationship between periodontal and systemic diseases

Periodontal disease (PD) is among the most common infectious diseases affecting humans. While the burden of periodontal disease on oral health has been extensively investigated, a possible specific relationship between the disease and systemic health is a relatively new area of interest. More recently it has been suggested that PD has an etiological role in the development of atherosclerotic cardiovascular disease, diabetes mellitus, and preterm low-birth weight, among others. In this review, we critically evaluate the current knowledge on the relation between PD and systemic diseases overall, and specifically with cardiovascular diseases. The best available evidence today suggests that the infection and inflammatory reaction associated with PD may contribute toward systemic disease. It is critical that dentists and physicians are well informed of the potential general health impact of periodontal disease so that they are in a position to knowledgeably counsel patients.