Is preexisting inflamed jaw marrow a "hidden" co-morbidity affecting outcomes of COVID-19 infections? - Clinical comparative study.

Introduction: Exceedingly high levels of the chemokine CCL5/RANTES have been found in fatty degenerated osteonecrotic alveolar bone cavities (FDOJ) and aseptic ischemic osteolysis of the jaw (AIOJ) from toothless regions. Because CCL5/RANTES seems to have a prominent role in creating the COVID-19 "cytokine storm", some researchers have used the monoclonal antibody Leronlimab to block the CCR5 on inflammatory cells.Objective: Is preexisting FDOJ/AIOJ jaw marrow pathology a "hidden" co-morbidity affecting some COVID-19 infections? To what extent does the chronic CCL5/RANTES expression from preexisting FDOJ/AIOJ areas contribute to the progression of the acute cytokine storm in COVID-19 patients?Methods: Authors report on reducing the COVID-19 "cytokine storm" by treating infected patients through targeting the chemokine receptor 5 (CCR5) with Leronlimab and interrupting the activation of CCR5 by high CCL5/RANTES signaling, thus dysregulating the inflammatory phase of the viremia. Surgical removal of FDOJ/AIOJ lesions with high CCL5/RANTES from patients with inflammatory diseases may be classified as a co-morbid disease.Results: Both multiplex analysis of 249 FDOJ/AIOJ bone tissue samples as well as serum levels of CCL5/RANTES displayed exceedingly high levels in both specimens.Discussion: By the results the authors hypothesize that chronic CCL5/RANTES induction from FDOJ/AIOJ areas may sensitize CCR5 throughout the immune system, thus, enabling it to amplify its response when confronted with the virus. As conventional intraoral radiography does little to assess the quality of the alveolar bone, ultrasonography units are available to help dentists locate the FDOJ/AIOJ lesions in an office setting.Conclusion: The authors propose a new approach to containment of the COVID-19 cytokine storm by a prophylactic focus for future viral-related pandemics, which may be early surgical clean-up of CCL5/RANTES expression sources in the FDOJ/AIOJ areas, thus diminishing a possible pre-sensitization of CCR5. A more complete dental examination includes trans-alveolar ultrasono-graphy (TAU) for hidden FDOJ/AIOJ lesions.

Relapsing and Immune-Responsive Paroxysmal Jaw Clonus With Blepharospasm and Sialorrhea Associated With D2R Autoantibodies.

OBJECTIVES: To extend the symptomatic spectrum of acute neurologic syndrome associated with dopamine-2 receptor (D2R) antibodies. METHODS: A 13-year-old adolescent boy was admitted to the Neurology Department with abnormal jaw movements. The initial evaluation included laboratory examinations of blood, chest radiography, brain MRI, EEG, and neuropsychologic tests. Serum and CSF samples were collected for immunologic studies. The clinical outcome of the patient was followed up for 18 months after the first hospitalization. RESULTS: Paroxysmal jaw clonus, blepharospasm, and sialorrhea were observed in the patient with a history of Tourette syndrome and obsessive-compulsive disease and with an acute neurologic syndrome associated with D2R antibodies. The symptoms responded to IV methylprednisolone (IVMP), relapsed twice during prednisone reduction, and, finally, improved after the combined treatment of IVMP and IV immunoglobulin. DISCUSSION: Recognizing paroxysmal jaw clonus (possibly with blepharospasm and sialorrhea) and considering the relationship between these episodes and D2R antibodies will be helpful in the early diagnosis and treatment of immune neurologic syndromes.

Determination of the molecular mechanism by which macrophages and γδ-T cells contribute to ZOL-induced ONJ.

OBJECTIVE: This study aims to explore the molecular mechanism of macrophages and γδ-T cells in the ZOL drug-induced osteonecrosis of jaws based on the IFN-γ involved osteoblast differentiation signaling pathway. RESULTS: The number and apoptotic rate of CD11b+Gr1hi cells and γδ-T cells in the ONJ group were significantly higher. The TNF-α, IL-1ß, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were significantly higher in the ONJ group. The expression of CTSK and FGFR3 was lower in the ONJ group, but was higher in the NF-κB and ERBB2IP group. CONCLUSION: The proliferation of macrophages and γδ-T cells promote the inflammation in ZOL-induced jaw necrosis. METHODS: A total of 20 patients with osteonecrosis of the jaw from January 2016 to March 2018 were collected and assigned into the observation group, while 20 healthy subjects were assigned into the control group. Furthermore, 40 SD rats were selected and assigned into observation group, while 10 non-treatment SD rats were selected and assigned as controls. The distribution and proportion of CD11b+Gr1hi cells and γδ-T cells in the necrotic tissues of the jaw were analyzed. Then, the TNF-α, IL-1ß, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were measured. Afterwards, the expression of CTSK, FGFR3, NF-κB and ERBB2IP in the necrotic tissues of the jaw in the animal models were analyzed.

Role of dendritic cell-mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw.

Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood. Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol in impairment of differentiation and function of migratory and tissue-resident DCs, promoting disruption of T-cell activation in vitro. Results demonstrated a Zol induced impairment in DC functions and an increased bacterial load in the oral cavity. DC-deficient mice were predisposed to osteonecrosis following dental extraction. Zol treatment of DCs in vitro caused an impairment in immune functions including differentiation, maturation, migration, antigen presentation, and T-cell activation. We conclude that the mechanism of Zol-induced osteonecrosis of the jaw involves disruption of DC immune functions required to clear bacterial infection and activate T cell effector response.

Comparación de inmunoexpresión de receptores CD68 en células gigantes y mononucleadas en lesiones central y periférica de células gigantes de los maxilares / A comparison of immunoexpression of CD68 receptors in giant cell and mononuclear cells of central and peripheral giant cell lesions of the jaws

Introducción: La lesión central (LCCG) y periférica (LPCG) de células gigantes de los maxilares, son lesiones reactivas con comportamiento clínico diferente. Objetivo: Comparar la inmunoexpresión de CD68 en células gigantes (CGm) mononucleares (CMn) en lesiones central y periférica de los maxilares. Material y métodos: Se evaluaron 35 casos de LCCG y 24 de LPCG en bloques de parafi na que podían ser procesadas para la expresión del anticuerpo CD68. La inmunoexpresión se valoró en el citoplasma de ambas poblaciones celulares, obteniendo proporciones; la inmunoexpresión se categorizó en intensa, moderada, leve. Las proporciones se compararon con χ2, siendo signifi cativo p ≤ 0.05. Resultados: Para las CGm de LCCG, CD68 se expresó en una proporción de 96 versus 84.2% LPCG (p < 0.005). La proporción de la tinción de la expresión intensa y moderada fue más frecuente en las LCCG (p = 0.032). Las proporciones entre las CMn 59.3% LCCG versus 18.6% en la LPCG (p < 0.001). Hubo diferencia en intensidad de CD68, en las CMn de LCCG fue mayor (p = 0.002). Conclusiones: La alta expresión de CD68 en las CGM y CMn en la lesión central y periférica confi rma su fenotipo de macrófago. Las diferencias entre las proporciones y la tinción a CD68 refl eja mayor actividad fagocítica posiblemente relacionada con el comportamiento clínico (AU)

Introduction: Central (CGCL) and Peripheral (PGCL) giant cell lesions of jaws are reactive lesions displaying diff erent behavior patterns. Objective: To compare CD68 immunoexpression between CGCL and PCGL in giant multinucleated and mononuclear cells. Material and methods: 35 CGCL and 24 PGCL were retrieved from paraffi n-embedded biopsy, as well as the feasibility to analyze CD68 immunoexpression. The immunoexpression was analyzed in cytoplasm both cell populations cellular, for and staining intensity was categorized as intense, moderate or faint. Proportions were compared by χ2, making a p ≤ 0.05 value signifi cate. Results: In 96% of CGCL's in GMCs displayed CD68, as compared to 84.2% in PGCL, (p < 0.005). The proportion of stained cells, intense to moderate staining was more frequent in CGCL (p = 0.032). The proportion CD68 was expressed in 59.3% or CGCL mononuclear cells, as compared to 18.6% in PGCL, (p < 0.001). There was diff erence in staining CD68 intensity between mononuclear cells in CGCL, (p = 0.002). Conclusions: The high CD68 expression frequency in GMCs and mononuclear cells in central and peripheral GCL confi rm a macrophage phenotype; a more intense staining in CGML and GMCs suggests a more active phagocytic activity, and possibility underline the diff erent clinical behavior (AU)

Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw.

PURPOSE OF REVIEW: Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ. RECENT FINDINGS: The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.

Follow-up of patients with systemic immunological diseases undergoing fatty-degenerative osteolysis of the jawbone surgery and treated with RANTES 27CH.

Regulated-on-activation, normal T cell expressed and secreted (also called RANTES, CCL5 or R/C) is a chemotactic cytokine that plays a key role in recruiting immune cells to inflammatory sites. R/C is involved in the pathogenesis of many systemic immune-mediated diseases (SIDs) and is upregulated in fatty-degenerative osteolysis jawbone (FDOJ) cavitations. Surgical cleaning of degenerative areas reduces the source of chronic R/C but might not be sufficient to re-establish the altered immunological patterns. The aim of the present study was to collect clinical data from patients suffering from sids who underwent dental surgery of FDOJ areas (n=46), by measuring R/C serum levels at the first visit (V0) prior to surgery, and at the second visit (V1). The majority of patients (n=41) were treated one month with ultra-low dose RANTES (27CH), a medicine used in micro-immunotherapy, while five patients were not. Mean and standard deviation of R/C serum levels at V0 in treated and untreated patients were respectively 48.5±25.8ng/ml and 42.48±22.22ng/ ml. Untreated patients had a tendency towards higher R/C levels at V1 (68.36±30.7ng/ml; p=0.062), while an opposite tendency was observed in treated patients (40.9±20.3ng/ml; p=0.129). Investigators observed that a cut-off set at 40ng/ml at V0 seemed to be predictive of the efficacy of the dental surgery/treatment (p=0.0013, n=26) and that gender could influence R/C levels and patient's responsiveness. The Authors, being aware that this is a preliminary follow-up, wanted to lay the basis for forthcoming studies, in which a larger cohort of patients and well-defined inclusion/exclusion criteria will be established.

Immunoprecipitation high performance liquid chromatographic analysis of healing process in chronic suppurative osteomyelitis of the jaw.

PURPOSE: Chronic suppurative osteomyelitis (CSO) of the jaw is one of the most difficult infectious diseases to manage, because it causes progressive bony destruction and is associated with bacterial inhabitation of the sequestra. A combination of antibiotic therapy and surgical debridement is often used to treat CSO. Nevertheless, various systemic conditions can lead to life-threatening complications. METHODS: The present study aimed to explore the wound healing progress in 16 cases of CSO through protein expression analysis of postoperative exudates (POE) that were collected 6 h, 1 day, and 2 days after saucerization and/or decortication. A bony lesion was removed during surgery and then examined pathologically, and the CSO POE was examined by immunoprecipitation thus high performance chromatography (IP-HPLC). The POE at 6 h was used as a comparative control. RESULTS: Histologically the CSO lesion showed a necrotic granulomatous lesion heavily infiltrated with polymorphonuclear leukocytes, macrophages, and plasma cells, admixed with multiple sequestra inhabited by bacterial colonies. The IP-HPLC analysis displayed a slight increase in innate immunity-related proteins, i.e., NFkB, TNFα, IL-1, IL-6, IL-28, and LL-37, but a gradual decrease of bacteria-related inflammatory proteins, i.e., IL-8, IL-12, CD31, CD68, and lysozyme. The angiogenesis-related proteins, i.e., VEGF-A and VEGF-C, were slightly decreased but TGF-ß1 and bFGF were markedly increased on day 2. The osteogenesis-related proteins, i.e., OPG and ALP, were slightly increased, while the osteoclastogenesis-related protein, RANKL was slightly decreased compared to the control. CONCLUSION: These findings indicate that the infected CSO undergoes a rapid wound healing process with active osteogenesis and a gradual decrease in bacteria-related inflammation, predicting a favorable prognosis after surgery. Moreover, IP-HPLC can be useful in monitoring the POE and wound healing processes during the postoperative period.

Immunoexpression of NF-ĸB and their inhibitory subunits IĸBα and IĸBß in giant cell lesions of the jaws: implications for their clinical behavior.

BACKGROUND: The unpredictable behavior of giant cell lesions (GCLs) of the jaws parallels its controversial histogenesis. This study evaluated a possible association between the immunohistochemical expression of NF-ĸB, the inhibitory subunits IĸBα/IĸBß, and clinicopathological variables with the behavior of central and peripheral GCLs of the jaws. MATERIALS AND METHODS: Paraffin-embedded samples of GCLs of the jaws (n = 68) were prepared for histological/immunohistochemical assessment. Demographic and clinicopathological parameters were assessed to determine the behavior of the lesions. A staining-intensity-distribution (SID) score was used to assess the immunomarkers reactivity. The association between significant candidate immunohistochemical predictor variables regarding clinical behavior was analyzed individually and adjusted for confounding using a binary logistic regression model. RESULTS: While univariate analysis revealed a positive association of NF-ĸB SID score, NF-ĸB nuclear expression, IĸBα SID score, and NF-ĸB to inhibitors average ratio with the aggressive status of GCLs, after bivariate logistic regression analysis, only NF-ĸB nuclear expression, IĸBα SID score, and NF-ĸB to inhibitors average ratio remained as robust predictors of aggressiveness. Confounding and interaction effects regarding clinicopathological candidate predictor variables were also noted. CONCLUSION: It looks that clinical behavior of GCLs of the jaws may be strong/independently linked to the increased nuclear expression of NF-ĸB, higher NF-ĸB to inhibitors average ratio, and decreased IĸBα SID score. Notwithstanding, there are simultaneously synergistic and opposing interactive effects with respect to age stratum, growth rate, multinucleated giant cells count, and mononuclear stromal cells density in the susceptible host that may increase the tissue destruction observed in aggressive GCLs.

[Cytokines level in patients with drug-induced jaw necrosis].

The study included 15 patients with purulent inflammatory diseases of maxillofacial area and 25 patients with facial bone necrosis induced by synthetic drugs. Pro- and anti-inflammatory cytokines levels in saliva and wound fluid were analyzed in two groups. The results proved cytokines to play important role in jaw necrosis induced by drugs containing red phosphorus.

[Complex approach to assessment of condition severity in patients with pyoinflammatory odontogenous diseases].

Dynamics of mean value indices and mean dispersion doesn't exclude the feedback (Mayanskiy D.N., 2008) in process of study the disease according to cooperative processes using system leukocyte-monocyte-lymphocyte (L+M+LM). The authors investigated a dynamic balance between these cell substratums and collagen formation. Acute inflammatory processes in tissues of maxillofacial area accompanied by leukemoid response of peripheral blood in the form of leukocytosis (10 x 10(9)-15 x 10(9)/l and more). The authors completely agree with the opinion of M.M. Solov'yov (2012) and N.K. Artyushenko (2008) that mechanism of this reaction is associated with both the leukocyte redistribution in the inflammation zone and with changes of hematopoietic rostock which aimed to balance the affected compensatory mechanisms of nonspecific resistance.

Effects of antiresorptive agents on osteomyelitis: novel insights into the pathogenesis of osteonecrosis of the jaw.

The effects of antiresorptive agents (e.g., alendronate [Aln], osteoprotegerin [OPG]) on bone infection are unknown. Thus, their effects on implant-associated osteomyelitis (OM) were investigated in mice using PBS (placebo), gentamycin, and etanercept (TNFR:Fc) controls. None of the drugs affected humoral immunity, angiogenesis, or chronic infection. However, the significant (P < 0.05 vs. PBS) inhibition of cortical osteolysis and decreased draining lymph node size in Aln- and OPG-treated mice was associated with a significant (P < 0.05) increase in the incidence of high-grade infections during the establishment of OM. In contrast, the high-grade infections in TNFR:Fc-treated mice were associated with immunosuppression, as evidenced by the absence of granulomas and presence of Gram(+) biofilm in the bone marrow. Collectively, these findings indicate that although antiresorptive agents do not exacerbate chronic OM, they can increase the bacterial load during early infection by decreasing lymphatic drainage and preventing the removal of necrotic bone that harbors the bacteria.

The immunoprofile of odontogenic keratocyst (keratocystic odontogenic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts.

BACKGROUND: The aggressive biological behavior of odontogenic keratocysts (OKCs), unlike that of other odontogenic cysts, has argued for its recent re-classification as a neoplasm, 'keratocystic odontogenic tumor'. Identification of mutations in the PTCH gene in some of the OKCs that were expected to produce truncated proteins, resulting in loss of control of the cell cycle, provided additional support for OKCs having a neoplastic nature. METHODS: We investigated the immunohistochemical expression of the sonic hedgehog (SHH) signaling pathway-related proteins, PTCH, smoothened (SMO) and GLI-1, and of the SHH-induced bcl-2 oncoprotein in a series of primary OKC (pOKC), recurrent OKC (rOKC) and nevoid basal cell carcinoma syndrome-associated OKCs (NBCCS-OKCs), and compared them to solid ameloblastomas (SAMs), unicystic ameloblastomas (UAMs), 'orthokeratinized' OKCs (oOKCs), dentigerous cysts (DCs) and radicular cysts (RCs). RESULTS: All studied lesions expressed the SHH pathway-related proteins in a similar pattern. The expression of bcl-2 in OKCs (pOKCs and NBCCS-OKCs) and SAMs was significantly higher than in oOKCs, DCs and RCs (P < 0.001). CONCLUSIONS: The present results of the immunoprofile of OKCs (that includes the expression of the SHH-related proteins and the SHH-induced bcl-2 oncoprotein) further support the notion of OKC having a neoplastic nature. As OKCs vary considerably in their biologic behavior, it is suggested that the quality and quantity of interactions between the SHH and other cell cycle regulatory pathways are likely to work synergistically to define the individual phenotype and corresponding biological behavior of this lesion.

Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis.

BACKGROUND: Recent reports have identified an association between osteonecrosis of the jaw or facial bones and treatment with nitrogen-containing intravenous bisphosphonates. We investigated this association by use of data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare claims. METHODS: We identified 16,073 cancer patients who were diagnosed between January 1, 1986, and December 31, 2002, and were treated intravenously with the bisphosphonates pamidronate and/or zoledronic acid between January 1, 1995, and December 31, 2003. We matched 28,698 bisphosphonate nonusers, at a 2:1 ratio, to 14,349 bisphosphonate users on month and year of the first bisphosphonate administration received by users, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipemia, pancreatitis, or chemotherapy with L-asparaginase), bone metastasis, and SEER program geographic region. Patients were followed until the study's end on December 31, 2003; loss of coverage from Medicare Parts A and B; or one of the following outcomes: a diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first. RESULTS: Use of intravenous bisphosphonates was associated with an increased risk of jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% confidence interval [CI] = 1.86 to 5.32) and an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw (HR = 11.48, 95% CI = 6.49 to 20.33), compared with nonuse. The absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using intravenous bisphosphonates and 0.30 events per 100 patients not using such drugs. The risk of each outcome increased as cumulative dose increased (e.g., for 4-8 infusions, HR for operations on the jaw and facial bones = 3.63, 95% CI = 0.77 to 17.08; for more than 21 infusions, HR = 9.18, 95% CI = 1.74 to 48.53). CONCLUSION: Users of intravenous bisphosphonates had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones. The increased risk may reflect an increased risk for osteonecrosis of the jaw.

Effects of positive pressure in odontogenic keratocysts.

Intracystic fluid pressure is thought to be involved in odontogenic cyst growth. In this study, we investigated the effects of positive pressure on the expression of interleukin-1alpha (IL-1alpha), matrix metalloproteinases (MMPs), and prostaglandin E2 (PGE2) in odontogenic keratocysts to determine whether this pressure stimulates inflammatory cytokine production and signaling of osteoclastogenic events. Positive pressure enhanced the expression of IL-1alpha mRNA and protein in odontogenic keratocyst epithelial cells, and increased the secretion of MMP-1, MMP-2, MMP-3, and PGE2 in a co-culture of odontogenic keratocyst fibroblasts and the epithelial cells. The pressure-induced secretions were inhibited by an interleukin-1 receptor antagonist. Recombinant human interleukin-1alpha (rhIL-1alpha) increased the secretion of MMP-1, MMP-2, MMP-3, and PGE2 in the fibroblasts. Furthermore, in the fibroblasts, rhIL-1alpha enhanced the expression of macrophage colony-stimulating factor (M-CSF) mRNA, and rhIL-1alpha-induced PGE2 increased the expression of nuclear factor kappaB ligand (RANKL) mRNA. Thus, positive pressure may play a crucial role in odontogenic keratocyst growth via stimulating the expression of IL-1alpha in epithelial cells.

[Velopharyngeal palsy: a case report].

Here we present a case of velopharyngeal palsy. An 18-year-old man had hyperemia in his left conjunctivum. One or two weeks later he experienced nasal speech and difficulty in swallowing. General physical examination was normal. The only abnormal neurological finding was palato-pharyngeal paralysis on the right side. MRI of the head and neck had no abnormalities. Acute and convalescent sera showed no rise in viral antibody titer. CSF examination was normal except for the increased IgG% and IgG.albumin index. Treatment consisted of glycerol and steroid, and his symptom improved within two or three weeks. We think immunological mechanism is important because CSF examination showed increased IgG% and IgG.albumin index in our case. Acquired and isolated velopharyngeal palsy is uncommon. Only 26 cases have been reported so far. This is the first case in Japan. The disease has some characteristics. This occurs in childhood and adolescence. Onset is sudden, consisting in rhinolalia and dysphagia. On examination there is asymmetry of the pharynx and deviation of the uvula contralateral to the affected side. There is no other neurological abnormalities. Complete spontaneous recovery is usual. In some cases viral infection is the cause, but in most cases the cause is unknown. In contrast, the disease with both acquired velopharyngeal palsy and vocal cord palsy is relatively common. This occurs in the middle aged or elderly people. In addition to dysphagia and hoarse voice, this disease often accompanies neurological abnormalities such as other cranial nerve palsy and meningitis, fever, and pain in the pharyngeal region. In most cases viral infection is the cause.

Comparison of proliferating cell nuclear antigen expression in odontogenic keratocyst and ameloblastoma: an immunohistochemical study.

Proliferating cell nuclear antigen (PCNA) is a nuclear protein synthesized in the late G1 and S phase of the cell cycle, and immunohistochemical detection of the protein represents a useful marker for the proliferating fraction of cells in tissue specimens. PCNA expression was studied in odontogenic keratocysts (n = 15) and ameloblastomas (n = 46) using an avidin-biotin-peroxidase complex method on routinely processed paraffin sections. The percentage of PCNA-positive cells determined by point counting was significantly lower in the ameloblastomas (mean 9.4%, standard deviation (SD) 11.0) than in odontogenic keratocysts (mean 29.9%, SD 24.0). In ameloblastomas, the mean percentage of PCNA-positive cells was lowest in the acanthomatous pattern and highest in plexiform pattern. The mean percentage of PCNA-positive cells in plexiform pattern was non-significantly higher than that in follicular pattern. The mean percentage of PCNA-positive cells in plexiform and follicular patterns was significantly higher than that in cystic and acanthomatous patterns. The frequency of PCNA-positive cells was significantly higher in the peripheral cells of follicular and plexiform patterns than in the central cells of both patterns (p < 0.01). Therefore, peripheral cells were regarded as reserve cell of central cells. The mean percentage of PCNA-positive cells in the epithelial lining of odontogenic keratocyst was not significantly different from those in the peripheral cells of follicular and plexiform patterns of ameloblastoma. In contrast, the odontogenic keratocyst exhibited a mean percentage of PCNA-positive cells which was statistically higher than that in other histological elements of ameloblastomas. The present study suggests that odontogenic keratocyst is regarded as benign odontogenic tumour.

The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis.

We studied 55 patients (50 women, 5 men) with severe facial pain and biopsy-proven neuralgia-inducing cavitational osteonecrosis (NICO) of the alveolar bone of the jaws. Our aim was to assess the pathophysiologic contributions to NICO of anticardiolipin antibodies (aCLA), thrombophilia (increased tendency to intravascular thrombi), and hypofibrinolysis (reduced ability to lyse thrombi). Of the 55 patients, 43 (78%) had one or more tests positive for thrombophilia or hypofibrinolysis (or both), and only 12 (22%) were normal. Eighteen of 55 (33%) patients had high aCLA (> 2 SD above mean value for control subjects); immunoglobulin G (IgG) (p = 0.01) and immunoglobulin A (IgA)(p = 0.001) levels were higher in patients than in controls. The distribution of elevated aCLA immunoglobulin classes among patients was as follows: IgG alone, 5 (9%); IgA alone, 7 (13%); and IgM alone, 3 (5%). Three patients (5%) had high levels of both IgG and IgA aCLA. Other defects of the thrombotic or fibrinolytic systems in the 55 patients included high lipoprotein(a) in 36% (vs 20% in control subjects (p = 0.03)), low stimulated tissue plasminogen activator activity (tPA-Fx) in 22% (vs 7% in control subjects (p = 0.08)), high plasminogen activator inhibitor activity (PAI-Fx) in 18% (vs 8% in control subjects (p = 0.03)), resistance to activated protein C in 16% (vs 0% in control subjects (p = 0.007)), low antigenic protein C in 4+ (vs 0% in control subjects (p > 0.2)), and low antigenic protein S in 4% (vs 0% in control subjects (p > 0.2)). Anticardiolipin antibodies and other defects of the thrombotic and fibrinolytic systems appear to be common, potentially reversible pathogenetic risk factors associated with osteonecrosis of the jaw.