Issues with the surgical treatment of antiresorptive agent-related osteonecrosis of the jaws.

Antiresorptive agent-related osteonecrosis of the jaw is a rare but significant complication in patients using antiresorptive agents such as bisphosphonates and denosumab. Although the disease is well recognized, and many studies have been performed on the management of this condition, the treatment of severe osteonecrosis is still a challenge. Most recent studies have shown an advantage of surgical treatment over conservative treatment for stage 2/3 patients, but there is no consensus on the appropriate surgical procedures for antiresorptive agent-related osteonecrosis of the jaw. Furthermore, patients with severe systemic conditions may not be appropriate for extensive surgical treatment, and the treatment protocol for such patients has not been established. In this review, issues regarding the current surgical treatment for antiresorptive agent-related osteonecrosis of the jaws are discussed, with an emphasis on the clinical aspects.

Comparing immunocompetent and immunodeficient mice as animal models for bone tissue engineering.

OBJECTIVES: To understand the differences and similarities between immunocompetent and immunodeficient mice as ectopic transplantation animal models for bone tissue engineering. MATERIALS AND METHODS: Osteogenic cells from mouse leg bones were cultured, seeded on ß-TCP granules, and transplanted onto the backs of either immunocompetent or immunodeficient nude mice. At 1, 2, 4, and 8 weeks postoperatively, samples were harvested and evaluated by hematoxylin-eosin staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemical staining and quantitative PCR. RESULTS: In immunocompetent mice, inflammatory cell infiltration was evident at 1 week postoperatively and relatively higher expression of TNF-α and IL-4 was observed. In immunodeficient mice, new bone area and the number of TRAP-positive cells were larger at 4 weeks than in immunocompetent mice. The volume of new bone area in immunodeficient mice was reduced by 8 weeks. CONCLUSIONS: Bone regeneration was feasible in immunocompetent mice. However, some differences were observed between immunocompetent and immunodeficient mice in the bone regeneration process possibly due to different cytokine expression, which should be considered when utilizing in vivo animal models.

Effects of intravenous administration of umbilical cord blood CD34(+) cells in a mouse model of neonatal stroke.

Neonatal stroke occurs in approximately 1/4000 live births and results in life-long neurological impairments: e.g., cerebral palsy. Currently, there is no evidence-based specific treatment for neonates with stroke. Several studies have reported the benefits of umbilical cord blood (UCB) cell treatment in rodent models of neonatal brain injury. However, all of the studies examined the effects of administering either the UCB mononuclear cell fraction or UCB-derived mesenchymal stem cells in neonatal rat models. The objective of this study was to examine the effects of human UCB CD34(+) cells (hematopoietic stem cell/endothelial progenitor cells) in a mouse model of neonatal stroke, which we recently developed. On postnatal day 12, immunocompromized (SCID) mice underwent permanent occlusion of the left middle cerebral artery (MCAO). Forty-eight hours after MCAO, human UCB CD34(+) cells (1×10(5)cells) were injected intravenously into the mice. The area in which cerebral blood flow (CBF) was maintained was temporarily larger in the cell-treated group than in the phosphate-buffered saline (PBS)-treated group at 24h after treatment. With cell treatment, the percent loss of ipsilateral hemispheric volume was significantly ameliorated (21.5±1.9%) compared with the PBS group (25.6±5.1%) when assessed at 7weeks after MCAO. The cell-treated group did not exhibit significant differences from the PBS group in either rotarod (238±46s in the sham-surgery group, 175±49s in the PBS group, 203±54s in the cell-treated group) or open-field tests. The intravenous administration of human UCB CD34(+) cells modestly reduced histological ischemic brain damage after neonatal stroke in mice, with a transient augmentation of CBF in the peri-infarct area.

Integration of proteomics into systems biology of cancer.

Deciphering the complexity and heterogeneity of cancer, benefits from integration of proteomic level data into systems biology efforts. The opportunities available as a result of advances in proteomic technologies, the successes to date, and the challenges involved in integrating diverse datasets are addressed in this review.

Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.

Increasing evidences show that immune response affects the reparative mechanisms in injured brain. Recently, we have demonstrated that CD4(+)T cells serve as negative modulators in neurogenesis after stroke, but the mechanistic detail remains unclear. Glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), a multifaceted regulator of immunity belonging to the TNF receptor superfamily, is expressed on activated CD4(+)T cells. Herein, we show, by using a murine model of cortical infarction, that GITR triggering on CD4(+)T cells increases poststroke inflammation and decreases the number of neural stem/progenitor cells induced by ischemia (iNSPCs). CD4(+)GITR(+)T cells were preferentially accumulated at the postischemic cortex, and mice treated with GITR-stimulating antibody augmented poststroke inflammatory responses with enhanced apoptosis of iNSPCs. In contrast, blocking the GITR-GITR ligand (GITRL) interaction by GITR-Fc fusion protein abrogated inflammation and suppressed apoptosis of iNSPCs. Moreover, GITR-stimulated T cells caused apoptosis of the iNSPCs, and administration of GITR-stimulated T cells to poststroke severe combined immunodeficient mice significantly reduced iNSPC number compared with that of non-stimulated T cells. These observations indicate that among the CD4(+)T cells, GITR(+)CD4(+)T cells are major deteriorating modulators of poststroke neurogenesis. This suggests that blockade of the GITR-GITRL interaction may be a novel immune-based therapy in stroke.

Radiographic findings and prognosis of simple bone cysts of the jaws.

OBJECTIVE: The aim was to evaluate the possibility of radiographic prediction of the prognosis of simple bone cysts (SBCs) of the jaws. METHODS: The relationship between the radiographic findings and treatment outcome (healing or recurrence) was investigated in 31 cases treated in the authors' hospital and 108 published cases. RESULTS: In 17 of our 31 cases, the lesions had radiographic findings of a preserved lamina dura adjacent to the lesion, with a smooth margin, and no or smooth bone expansion, and all of them healed after surgery. In the other 14 cases, there was resorption of the lamina dura, a scalloped margin, nodular bone expansion, root resorption, a sclerotic mass or multiple cavities, and nine cases of recurrence. Although there was incomplete information in the published case studies, similar results were noted. CONCLUSIONS: It was concluded that there was a relationship between the radiographic features of the lesions and prognosis. Radiographic examination should be used not only for discovering and diagnosing the lesions, but also for predicting possible prognosis.

Triage screening for osteoporosis in dental clinics using panoramic radiographs.

Many patients with osteoporosis go undiagnosed because typically no symptoms are present before a fracture. Triage screening to refer patients to appropriate medical professionals for further investigation would be useful to address the increase in the incidence of osteoporotic fractures. Dental clinics may offer a new triage screening pathway because dentists frequently take radiographs of bones in the course of dental treatment. A major premise for such triage screening in dental clinics is that dentists can readily use a screening tool in their dental practice. For example, cortical width and shape of the mandible detected on panoramic radiographs may be appropriate indices for triaging individuals with osteoporosis. To date, several investigators have demonstrated significant associations between cortical indices on panoramic radiographs and bone mineral density of the skeleton generally, such as the spine and femur, biochemical markers of bone turnover and risk of osteoporotic fractures. Further, in two recent Japanese clinical trials, approximately 95% of women who were identified by trained dentists in their clinics using cortical shape findings did have osteopenia or osteoporosis. These findings support the possibility that dental clinics may offer a new triage platform to identify individuals with otherwise undetected osteoporosis.

Detection of post-menopausal women with low bone mineral density and elevated biochemical markers of bone turnover by panoramic radiographs.

OBJECTIVES: The detection of an eroded mandibular cortex on panoramic radiographs and questionnaire-based screening tools show similar diagnostic efficacies for identifying osteoporosis in post-menopausal women. We evaluated whether both tools also have similar diagnostic performances in identifying women with osteoporosis and elevated biochemical markers of bone turnover who have a high risk of fracture. METHODS: Urinary N-telopeptide cross-links of type I collagen (NTx) (corrected for creatinine) and serum levels of total non-bone-specific alkaline phosphatase (ALP) were measured in 99 post-menopausal women aged 44-70 years (mean +/- standard deviation (SD), 54.6 +/- 5.2 years) who underwent bone mineral density (BMD) assessment and panoramic radiography. BMD was measured at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. The Female Osteoporosis Self-assessment Tool for Asia (FOSTA), which is based on age and weight, was used as the questionnaire-based screening tool. Osteoporosis was defined as a BMD T-score of -2.5 or less at either the lumbar spine or the femoral neck. RESULTS: Urinary NTx and serum ALP were significantly associated with cortical erosion, but not with the FOSTA. The areas under the receiver operating characteristics (ROC) curve for identifying participants with osteoporosis were 0.784 for FOSTA and 0.827 for the detection of cortical erosion, and for identifying participants with osteoporosis and elevated urinary NTx they were 0.700 for FOSTA and 0.807 for the detection of cortical erosion. CONCLUSIONS: Our results suggest that panoramic radiography is superior to questionnaire-based screening for identifying women who are at high risk of fracture.

Bone marrow stromal cell therapy improves femoral bone mineral density and mechanical strength in ovariectomized rats.

BACKGROUND: This study aimed to determine the influence of bone marrow stromal cells (BMSC) on the degree and sustainability of ovariectomy-induced bone loss. METHODS: Allogenic BMSC were injected into either the left or right femur of 15 ovariectomized rats (OVX). Saline was injected into the contralateral femur as a vehicle control. Five rats were killed at 8 weeks and 5 rats at 24 weeks. The other five OVX rats received serial injections 4 weeks after the first injection and were killed 24 weeks after the first injection. To confirm osteoporotic model, five rats received sham operation. Bone mineral density (BMD) was measured using dual-energy X-ray absorptometry. Mechanical properties were evaluated by three-point bending. RESULTS: The OVX rats showed significantly lower BMD compared with that of the sham operated rats. BMD at the femoral mid-shaft was significantly greater in the BMSC-injected bones compared with the control bones. At week 8, ultimate load and stiffness were also improved in the BMSC-injected bones compared with controls. At 24 weeks, the stiffness of control and BMSC-injected bones was statistically indistinguishable. The additional injection aided preservation of both BMD and mechanical properties. DISCUSSION: The present study suggests that bone strength may be improved by direct BMSC injection.

Observer performance in diagnosing osteoporosis by dental panoramic radiographs: results from the osteoporosis screening project in dentistry (OSPD).

Mandibular cortical erosion detected on dental panoramic radiographs (DPRs) may be useful for identifying women with osteoporosis, but little is known about the variation in diagnostic efficacy of observers worldwide. The purpose of this study was to measure the accuracy in identifying women at risk for osteoporosis in a worldwide group of observers using DPRs. We constructed a website that included background information about osteoporosis screening and instructions regarding the interpretation of mandibular cortical erosion. DPRs of 100 Japanese postmenopausal women aged 50 years or older who had completed skeletal bone mineral measurements by dual energy X-ray absorptiometry were digitized at 300 dpi. These were displayed on the website and used for the evaluation of diagnostic efficacy. Sixty observers aged 25 to 66 years recruited from 16 countries participated in this study. These observers classified cortical erosion into one of three groups (none, mild to moderate, and severe) on the website via the Internet, twice with an approximately 2-week interval. The diagnostic efficacy of the Osteoporosis Self-Assessment Tool (OST), a simple clinical decision rule based on age and weight, was also calculated and compared with that of cortical erosion. The overall mean sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the 60 observers in identifying women with osteoporosis by cortical erosion on DPRs were 82.5, 46.2, 46.7, and 84.0%, respectively. Those same values by the OST index were 82.9, 43.1, 43.9, and 82.4%, respectively. The intra-observer agreement in classifying cortical erosion on DPRs was sufficient (weighted kappa values>0.6) in 36 (60%) observers. This was significantly increased in observers who specialized in oral radiology (P<0.05). In the 36 observers with sufficient intra-observer agreement, the overall mean sensitivity, specificity, PPV, and NPV in identifying women with osteoporosis by any cortical erosion were 83.5, 48.7, 48.3, and 85.7%, respectively. The mean PPV and NPV were significantly higher in the 36 observers with sufficient intra-observer agreement than in the 24 observers with insufficient intra-observer agreement. Our results reconfirm the efficacy of cortical erosion findings in identifying postmenopausal women at risk for osteoporosis, among observers with sufficient intra-observer agreement. Information gathered from radiographic examination is at least as useful as that gathered from the OST index.

Reactive oxygen scavenging activity of matured whiskey and its active polyphenols.

The quality of whiskey is known to improve remarkably by its storage over many years. This process is commonly termed "maturing." In this process, polyphenols derived from lignin and tannin of the barrel have an important role in not only forming the matured flavor and taste but also contributing to the advance of clustering ethanol and water in whiskey. It is also likely that polyphenols generally possess reactive oxygen (RO) scavenging activity. The present study evaluated the RO scavenging activity (free-radical scavenging activity, H(2)O(2) reduction activity under peroxidase coculture, and H(2)O(2)scavenging activity) of 24 single malt whiskeys with a maturation age of 10 to 30 y produced in Japanese, Scotch (Islay), or Scotch (Speyside and Highland) regions. Single malt whiskey not only showed RO scavenging activity but there was also a positive correlation between this activity and the maturation age of whiskey exceeding the difference resulting from the manufacturing region. A nonvolatile fraction derived from the barrel was responsible for RO scavenging activity. In particular, the contents of ellagic and gallic acids and lyoniresinol, the main polyphenolic compounds in whiskey, increased with maturation age. For the free-radical scavenging activity per molecule, each compound was 1.68 to 3.14 times that of trolox (a water-soluble vitamin E). The activities of ellagic acid, gallic acid, and lyoniresinol in the whiskey (Yamazaki 18) were equivalent to that of 80.3, 31.2, and 11.1 ppm trolox, respectively. Accordingly, the total activity of these 3 compounds accounted for about 20% of the activity of the whiskey (630.7 ppm trolox).

Visualization of intracerebral arteries by synchrotron radiation microangiography.

BACKGROUND AND PURPOSE: Small cerebral vessels are a major site for vascular pathology leading to cerebral infarction and hemorrhage. However, such small cerebral vessels are difficult to visualize by using conventional methods. The goal of our study was the development of methodology allowing visualization of small cerebral arteries in rodents, suitable for experimental models. MATERIALS AND METHODS: Using barium sulfate as a contrast material, we obtained microangiographic images of physiologic and pathologic changes consequent to cerebral infarction in mouse brain by monochromatic synchrotron radiation (SR). To achieve high-resolution and high-contrast images, we used a new x-ray camera with a pixel size of 4.5 microm, and we set the energy level at 37.5 keV, just above the K absorption of barium. RESULTS: Small intracerebral arteries ( approximately 30 microm in diameter) were clearly visualized, as well as the cortical branches (50-70 microm in diameter) at the brain surface. The limit of detection appeared to be vessels approximately 10 microm in diameter. Compared with the noninfarcted side, the number of intracerebral arteries was dramatically decreased in the middle cerebral artery area affected by stroke. CONCLUSIONS: These results indicate the potential of SR for evaluating pathologic changes in small cerebral arteries and for monitoring the impact of pro- and antiangiogenic therapeutic strategies.

A comparative study of simple bone cysts of the jaw and extracranial bones.

OBJECTIVES: To improve the interpretation of simple bone cyst (SBC) lesions of the jaw. METHODS: A comparative study of SBC lesions of the jaw and extracranial bones was performed through a literature survey. RESULTS: In extracranial SBC, the cavities were always filled with fluid, and a high recurrence rate was shown through extensive research. Aneurysmal bone cyst (ABC) was included in the differential diagnosis owing to some clinicopathologic similarities. Fluid, gas and blood were found in the cavity in jawbone SBC, and recurrence was believed to be rare. Differential diagnosis was rarely discussed in the literature. CONCLUSIONS: Based on reports, the cavity did not normally contain gas because no air-fluid level was observed on panoramic radiographs and no density/intensity area indicating gas was seen on CT or MRI. A blood-filled cavity should be examined carefully, and the possibility of an ABC should be considered. The recurrence rate needs to be re-estimated because an extensive survey has not been performed to clarify the treatment outcomes of jawbone SBC.

Metastatic retinoblastoma of the maxilla and mandible.

Metastatic retinoblastoma of the jaws is very rare. We present a 4-year-old boy with metastatic retinoblastoma that involved both the maxilla and mandible simultaneously. Enhanced CT indicated bone-destructive masses with partially non-enhanced area and enhanced margin in the right maxilla and left mandible. MRI showed well-delineated masses that were isointense on T(1) weighted images and hyperintense on T(2) weighted images. Four weeks after chemotherapy and bone marrow transplantation, the size of lesions remarkably decreased. The patient died 19 months later with extensive tumour metastases despite additional chemotherapy. In this case, the dental crypt of a permanent tooth was considered the potential target through which retinoblastoma metastasized to the jaws.

Recommendation of modified classification for odontogenic carcinomas.

Primary squamous cell carcinoma (SCC) derived from odontogenic epithelium is diagnosed as primary intraosseous carcinoma (PIOC). The term "intraosseous" means the bone marrow spaces. Odontogenic cells, however, exist not only in the bone marrow space but also in the periodontal space and the subepithelial soft tissue space. In our survey for 36 SCC lesions of odontogenic origin, many lesions involved two or all of the three spaces. There was only one lesion which involved the bone marrow space alone. In some cases, the extent of the early lesions was restricted around the tooth or at a part of the alveolar crest. The possibility of a SCC of odontogenic origin arising in the periodontal and the subepithelial soft tissue spaces was suggested. We proposed the term "Odontogenic SCC" to replace "PIOC".

Effect of supplemental pre-operative fluid on postoperative nausea and vomiting.

In a prospective, double-blind, randomised controlled trial, we studied the effects of pre-operative fluid load on post-operative nausea and vomiting. Eighty patients attending for laparoscopic cholecystectomy or gynaecological surgery were randomly allocated to receive 2 ml.kg-1 (conservative) or 15 ml.kg-1 (supplemental) Hartmann's solution intravenously, shortly before induction of anaesthesia. During the operation, fluid management was identical in both groups. During the first post-operative 24 h, post-operative nausea and vomiting occurred in 29 patients (73%) in the conservative fluid group and nine patients (23%) in the supplemental fluid group (p = 0.01). Supplemental pre-operative fluid is an inexpensive and safe therapy for reducing post-operative nausea and vomiting.

RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease.

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.