The Forefront of Dentistry-Promising Tech-Innovations and New Treatments.

KNOWLEDGE TRANSFER STATEMENT: This article discusses innovations in technology and treatments that have enormous potential to revolutionize our dental care, including novel concepts in electronic health records, communication between dentists and patients, biologics around diagnosis and treatment, digital dentistry, and, finally, the real-time optimization of information technology. The early implementation and validation of these innovations can drive down their costs and provide better dental and medical services to all members of our society.

Translating Science into Improved Health for All.

Our world is at a turning point with biological and social pathogens wreaking havoc at the same time that science and technology are exploding with new discoveries. It is a pivotal time for the new report Oral Health in America: Advances and Challenges to be released and a pivotal time for our profession to take action and lead. The art, science, and practice of dentistry is very different from 20 y ago when the original Surgeon General's report was released. We are on the precipice of individualized health care where providers will collaborate to deliver diagnostics and therapeutics that are data driven and inclusive of the social determinants of health. To move forward with alacrity requires a strong scientific foundation, effective educational approaches, an understanding of the upstream determinants of health, and partnerships across the health professions and beyond. Oral health has never been more important, and now is the time for our profession to further develop, elevate, and translate the science into practice and policy to improve the nation's health.

Impact of COVID-19 on Life Experiences of Essential Workers Attending a Dental Testing Facility.

OBJECTIVES: 1) To compare the impact of COVID-19 on the life experiences of essential workers attending a COVID-19 antibody testing clinic at a dental school. 2) To compare responses of dental, non-dental health care, and non-health care essential workers. 3) To assess acceptability/satisfaction of testing done in a dental setting. METHOD: A total of 984 participants completed a self-administered online questionnaire. RESULTS: Over 90% were healthy (i.e., not in a high-risk health-related group for COVID-19), did not have COVID-19 symptoms within 30 d, and always/frequently engaged in preventive measures. Fifty-eight percent thought that they had a 0% to 25% chance of having immunity/antibodies to COVID-19. Non-dental health care workers thought that their chance was significantly higher (P < 0.05) than others. Over 70% were sometimes, frequently, or always worried about their friends and loved ones getting COVID-19 and of resulting financial problems. Dental workers were significantly less afraid than non-dental health care and non-health care providers. For all groups, more than half of the respondents stated that the pandemic had a negative (somewhat worse or worse) impact on daily life (59%), interactions with others (65%), stress levels (66%), and enjoyment of life (56%). There were significant differences among all 3 groups regarding the percentage of individuals with a negative impact on job security (dental, 47%; non-dental health care, 34%; non-health care, 31%). However, more than half of the respondents stated that the pandemic had a positive impact (same, somewhat better, or much better) on caring about one another, self-care, and exercise. Knowing the results of an antibody test would decrease the level of stress and anxiety in 67% of respondents. Over 80% found a COVID-19 test received in a dental setting acceptable, were "definitely" satisfied, and would "definitely" recommend it to a friend, family, or coworker. CONCLUSIONS: These findings support that dental workers are as vulnerable as other essential workers to threats and psychological impacts of COVID-19. They also support the acceptability and satisfaction of testing for a pandemic done in a dental setting. KNOWLEDGE TRANSFER STATEMENT: The results of this study highlight the impact that pandemics such as COVID-19 can have on life experiences of essential workers, including dentists. It also highlights a role that dentistry can play within the broader health care system, during and beyond the current pandemic, to help with surveillance efforts of community health. Testing may also help alleviate stress and anxiety associated with these pandemics.

Clodronate-Loaded Liposome Treatment Has Site-Specific Skeletal Effects.

Ineffective oral wound healing is detrimental to patients' oral health-related quality of life. Delineating the cellular mechanisms involved in optimal healing will elicit better approaches to treating patients with compromised healing. Osteal macrophages have recently emerged as important positive regulators of bone turnover. The contributions of macrophages to long bone healing have been studied, but their role in oral osseous wound healing following tooth extraction is less clear. Clodronate-loaded liposomes were used as a tool to deplete macrophages in C57BL/6J mice and assess oral osseous bone fill after extraction. In addition to macrophage ablation, osteoclast ablation occurred. Interestingly, depletion of macrophages and osteoclasts via clodronate treatment had differential effects based on skeletal location. In the nonwounded tibiae, clodronate treatment significantly increased CD68+ cells and decreased F4/80+ cells in the marrow, which correlated with increased trabecular bone volume fraction after 7 and 14 d. Serum formation and resorptive markers P1NP and TRAcP 5b were decreased as were tibial TRAP+ osteoclasts. In healing extraction sockets, clodronate treatment increased extraction socket trabecular bone thickness at 14 d, which correlated with decreased TRAP+ osteoclasts and F4/80+ macrophages. Conversely, nonwounded maxillary interseptal bone was unaffected by clodronate treatment. Furthermore, the increase in extraction socket bone fill with clodronate was less than the large increase in trabecular bone observed in a nonwounded long bone. These data suggest a temporal and spatial specificity in the roles of macrophages and osteoclasts in normal turnover and healing.

Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis.

Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80+CD206+) were identified in PCa bone resident tumors in mice. Induced M2-like macrophages in vitro were more proficient at phagocytosis (efferocytosis) of apoptotic tumor cells than M1-like macrophages. Moreover, soluble factors released from efferocytic versus nonefferocytic macrophages increased PC-3 prostate cancer cell numbers in vitro. Trabectedin exposure reduced M2-like (F4/80+CD206+) macrophages in vivo. Trabectedin administration after PC-3 cell intracardiac inoculation reduced skeletal metastatic tumor growth. Preventative pretreatment with trabectedin 7 days prior to PC-3 cell injection resulted in reduced M2-like macrophages in the marrow and reduced skeletal tumor size. Together, these findings suggest that M2-like monocytes and macrophages promote PCa skeletal metastasis and that trabectedin represents a candidate therapeutic target.

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.

The skeletal impact of the chemotherapeutic agent etoposide.

Effects of the chemotherapeutic agent etoposide on the skeleton were determined in mice. Numbers of bone marrow cells were reduced and myeloid cells were increased. Bone volume was significantly decreased with signs of inhibition of bone formation. Etoposide after pre-treatment with zoledronic acid still reduced bone but overall bone volume was higher than with etoposide alone. INTRODUCTION: Chemotherapeutics target rapidly dividing tumor cells yet also impact hematopoietic and immune cells in an off target manner. A wide array of therapies have negative side effects on the skeleton rendering patients osteopenic and prone to fracture. This study focused on the pro-apoptotic chemotherapeutic agent etoposide and its short- and long-term treatment effects in the bone marrow and skeleton. METHODS: Six- to 16-week-old mice were treated with etoposide (20-25 mg/kg) or vehicle control in short-term (daily for 5-9 days) or long-term (3×/week for 17 days or 6 weeks) regimens. Bone marrow cell populations and their phagocytic/efferocytic functions were analyzed by flow cytometry. Blood cell populations were assessed by CBC analysis. Bone volume and area compartments and osteoclast numbers were measured by microCT, histomorphometry, and TRAP staining. Biomarkers of bone formation (P1NP) and resorption (TRAcP5b) were assayed from serum. Gene expression in bone marrow was assessed using qPCR. RESULTS: Flow cytometric analysis of the bone marrow revealed short-term etoposide reduced overall cell numbers and B220+ cells, with increased marrow apoptotic (AnnexinV+PI-) cells, mesenchymal stem-like cells, and CD68+, CD45+, and CD11b+ monocyte/myeloid cells (as a percent of the total marrow). After 6 weeks, the CD68+, Gr1+, CD11b+, and CD45+ cell populations were still relatively increased in etoposide-treated bone marrow. Skeletal phenotyping revealed etoposide decreased bone volume, trabecular thickness, and cortical bone volume. Gene expression in the marrow for the leptin receptor and CXCL12 were reduced with short-term etoposide, and an increased ratio of RANKL/OPG mRNA was observed. In whole bone, Runx2 and osteocalcin gene expressions were reduced, and in serum, P1NP was significantly reduced with etoposide. Treatment with the antiresorptive agent zoledronic acid prior to etoposide increased bone volume and improved the etoposide-induced decrease in skeletal parameters. CONCLUSIONS: These data suggest that etoposide induces apoptosis in the bone marrow and significantly reduces parameters of bone formation with rapid reduction in bone volume. Pre-treatment with an antiresorptive agent results in a preservation of bone mass. Preventive approaches to preserving the skeleton should be considered in human clinical studies.

PTH and Vitamin D Repress DMP1 in Cementoblasts.

A complex feedback mechanism between parathyroid hormone (PTH), 1,25(OH)2D3 (1,25D), and fibroblast growth factor 23 (FGF-23) maintains mineral homeostasis, in part by regulating calcium and phosphate absorption/reabsorption. Previously, we showed that 1,25D regulates mineral homeostasis by repressing dentin matrix protein 1 (DMP1) via the vitamin D receptor pathway. Similar to 1,25D, PTH may modulate DMP1, but the underlying mechanism remains unknown. Immortalized murine cementoblasts (OCCM.30), similar to osteoblasts and known to express DMP1, were treated with PTH (1-34). Real-time quantitative polymerase chain reaction (PCR) and Western blot revealed that PTH decreased DMP1 gene transcription (85%) and protein expression (30%), respectively. PTH mediated the downregulation of DMP1 via the cAMP/protein kinase A (PKA) pathway. Immunohistochemistry confirmed the decreased localization of DMP1 in vivo in cellular cementum and alveolar bone of mice treated with a single dose (50 µg/kg) of PTH (1-34). RNA-seq was employed to further identify patterns of gene expression shared by PTH and 1,25D in regulating DMP1, as well as other factors involved in mineral homeostasis. PTH and 1,25D mutually upregulated 36 genes and mutually downregulated 27 genes by ≥2-fold expression (P ≤ 0.05). Many identified genes were linked with the regulation of bone/tooth homeostasis, cell growth and differentiation, calcium signaling, and DMP1 transcription. Validation of RNA-seq results via PCR array confirmed a similar gene expression pattern in response to PTH and 1,25D treatment. Collectively, these results suggest that PTH and 1,25D share complementary effects in maintaining mineral homeostasis by mutual regulation of genes/proteins associated with calcium and phosphate metabolism while also exerting distinct roles on factors modulating mineral metabolism. Furthermore, PTH may modulate phosphate homeostasis by downregulating DMP1 expression via the cAMP/PKA pathway. Targeting genes/proteins mutually governed by PTH and 1,25D may be a viable approach for designing new therapies for preserving mineralized tissue health.

Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of ß-catenin activation of the DKK1 promoter in prostate cancer.

Prostate cancer (PCa)bone metastases are unique in that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by PCa cells and intermittent PTHrP exposure has bone anabolic effects, suggesting that PTHrP could contribute to the excess bone mineralization. Wnts are bone-productive factors produced by PCa cells, and the Wnt inhibitor Dickkopfs-1 (DKK1) has been shown to promote PCa progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as PCa progresses, led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in PCa cells and, hence, allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a transcription factor (TCF) response element site. Furthermore, chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that PTHrP mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of ß-catenin, which binds the most proximal DKK1 promoter, the TCF response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of PCa.

Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing.

SUMMARY: Administration of intermittent parathyroid hormone (PTH) promoted healing of tibial osseous defects and tooth extraction wounds and prevented the development of necrotic lesions in rats on a combined bisphosphonate and steroid regimen. INTRODUCTION: Osteonecrosis of the jaw (ONJ) has emerged in association with antiresorptive therapies. The pathophysiology of ONJ is unknown and no established cure currently exists. Our objective was to determine the effect of intermittent PTH administration on early osseous healing in the jaw and long bones of rats receiving bisphosphonate and steroid treatment. METHODS: Ovariectomized rats received the combination therapy of alendronate and dexamethasone (ALN/DEX) for 12 weeks. Osseous wounds were created in the jaw and tibia. PTH was administered intermittently and healing at 2 weeks post-op was compared between the jaw and tibia by microcomputed tomography and histomorphometric analyses. RESULTS: ALN/DEX treatment was associated with necrotic open wounds in the jaw but had no negative effects on healing and promoted bone fill in tibial defects. PTH therapy prevented the development of necrotic lesions in the jaw and promoted healing of the tibial defects. PTH therapy was associated with the promotion of osteocyte survival in osseous wounds both in the jaw and tibia. CONCLUSIONS: Wound healing was impaired in the jaw in rats on a combined bisphosphonate and steroid regimen, and PTH therapy rescued necrotic lesions. These findings suggest that PTH therapy could be utilized to prevent ONJ from occurring in patients on combination antiresorptive and steroid therapy.

Intra-oral PTH administration promotes tooth extraction socket healing.

Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH.

Parathyroid hormone applications in the craniofacial skeleton.

Parathyroid hormone (PTH) is known for its ability to 'build' bone, with research in this area centered on its use as an osteoporosis therapeutic. Recent interest has developed regarding its potential for regenerative applications such as fracture healing and osseous defects of the oral cavity. Many years of investigation using murine gene-targeted models substantiate a role for signaling at the PTH/PTH-related protein (PTHrP) receptor (PPR) in intramembranous bone formation in the craniofacial region as well as in tooth development. Pre-clinical studies clearly support a positive role of intermittent PTH administration in craniofacial bones and in fracture healing and implant integration. A few human clinical studies have shown favorable responses with teriparatide (the biologically active fragment of PTH) administration. Favorable outcomes have emerged with teriparatide administration in patients with osteonecrosis of the jaw (ONJ). New delivery strategies are in development to optimize targeted application of PTH and to help maximize local approaches. The promising host-modulating potential of PTH requires more information to further its effectiveness for craniofacial regeneration and osseous wound-healing, including a better delineation of cellular targets, temporal effects of PTH action, and improved approaches for local/targeted delivery of PTH.

The impact of vitamin D status on periodontal surgery outcomes.

Vitamin D regulates calcium and immune function. While vitamin D deficiency has been associated with periodontitis, little information exists regarding its effect on wound healing and periodontal surgery outcomes. This longitudinal clinical trial assessed outcomes of periodontal surgery and teriparatide administration in vitamin-D-sufficient and -insufficient individuals. Forty individuals with severe chronic periodontitis received periodontal surgery, daily calcium and vitamin D supplements, and self-administered teriparatide or placebo for 6 wks to correspond with osseous healing time. Serum 25(OH)D was evaluated at baseline, 6 wks, and 6 mos post-surgery. Clinical and radiographic outcomes were evaluated over 1 yr. Placebo patients with baseline vitamin D deficiency [serum 25(OH)D, 16-19 ng/mL] had significantly less clinical attachment loss (CAL) gain (-0.43 mm vs. 0.92 mm, p < 0.01) and probing depth (PPD) reduction (0.43 mm vs. 1.83 mm, p < 0.01) than vitamin-D-sufficient individuals. Vitamin D levels had no significant impact on CAL and PPD improvements in teriparatide patients at 1 yr, but infrabony defect resolution was greater in teriparatide-treated vitamin-D-sufficient vs. -deficient individuals (2.05 mm vs. 0.87 mm, p = 0.03). Vitamin D deficiency at the time of periodontal surgery negatively affects treatment outcomes for up to 1 yr. Analysis of these data suggests that vitamin D status may be critical for post-surgical healing. (ClinicalTrials.gov number, CT00277706).

Osteoclasts and odontoclasts: signaling pathways to development and disease.

Osteoclasts are cells essential for physiologic remodeling of bone and also play important physiologic and pathologic roles in the dentofacial complex. Osteoclasts and odontoclasts are necessary for tooth eruption yet result in dental compromise when associated with permanent tooth internal or external resorption. The determinants that separate their physiologic and pathologic roles are not well delineated. Clinical cases of primary eruption failure and root resorption are challenging to treat. Mineralized tissue resorbing cells undergo a fairly well characterized series of differentiation stages driven by transcriptional mediators. Signal transduction via cytokines and integrin-mediated events comprise the detailed pathways operative in osteo/odontoclastic cells and may provide insights to their targeted regulation. A better understanding of the unique aspects of osteoclastogenesis and osteo/odontoclast function will facilitate effective development of new therapeutic approaches. This review presents the clinical challenges and delves into the cellular and biochemical aspects of the unique cells responsible for resorption of mineralized tissues of the craniofacial complex.

Serological analysis of Chlamydophila abortus in Australian sheep and implications for the rejection of breeder sheep for export.

OBJECTIVE: To examine the incidence of positive results in a complement fixation test (CFT) and enzyme-linked immunosorbent assay (ELISA) for Chlamydophila abortus in Australian sheep and how this incidence differs with state of origin, age, sex, breed and property. To examine the consequences in relation to rejection of breeder sheep for export. DESIGN: Collection of blood samples from 891 sheep on 109 properties in southern Australia. All samples had a unique, coded property identification. PROCEDURE: The samples were tested using the Institut Pourquier Chlamydophila abortus antibody ELISA (rELISA) and a CFT. Residual maximum likelihood analyses of the sample to positive ratio of the corrected optical density for the rELISA and generalised linear mixed model analyses of the CFT outcomes were carried out. RESULTS: The sample to positive ratio of the corrected optical density values of the rELISA did not differ between sex, age, breed or state of origin, but differed greatly between properties. The CFT outcome did not differ between age, breed or state of origin, but differed greatly between properties and was more often positive with rams than with ewes. CONCLUSION: Positive outcomes to C. abortus antibody tests are very common in Australia. Rams have a particularly high incidence of positive results with the CFT. Rejection of sheep and property consignments is likely to be very common with all tests and situations examined except for the CFT (at 1:32 dilution) in ewes.

JunB as a potential mediator of PTHrP actions: new gene targets Ephrin B1 and VCAM-1.

Parathyroid hormone-related protein (PTHrP) is an integral mediator of physiologic and pathologic processes and has demonstrated actions in the periodontium. PTHrP functions via AP-1, and specifically through JunB. This study identified JunB-dependent downstream mediators of PTHrP using OCCM cementoblastic transfectants with JunB over- or reduced expression. Over-expressing cells showed an increase in proliferation, while the opposite was seen in siRNA transfected cells. Microarray analysis of over-expressing cells revealed more than 1000 regulated genes. Three genes were investigated in more detail. The PTH/PTHrP receptor (PTHR1) and ephrin B1 (EfnB1) were down-regulated, and vascular cell adhesion molecule-1 (VCAM-1) was up-regulated with JunB over-expression. JunB siRNA transfectants had increased PTHR1, but reduced ephrin B1 and unaltered VCAM-1 in vitro. To validate these targets, parental OCCM cells and primary osteoblasts were treated with PTHrP, resulting in reduced PTHR1 and ephrin B1, and increased VCAM-1. Cell transfectants were implanted subcutaneously in vivo, and microarray analysis and RT-PCR performed. Over-expression of JunB down-regulated PTHR1 and ephrin B1, and increased VCAM-1. JunB siRNA transfectant implants had increased PTHR1 and ephrin B1, but no altered VCAM-1. These data highlight new gene targets for PTHrP and indicate JunB is a critical mediator of PTHrP actions.

Comparison of ELISA and CFT assays for Chlamydophila abortus antibodies in ovine sera.

OBJECTIVE: To compare the sensitivity and specificity of Chlamydophila abortus antibody assays, to find a suitable serological assay for testing sheep for export. DESIGN: Comparison of results from known positive and negative sheep populations. PROCEDURE: Fifty-five positive and fifty negative sera were analysed by four enzyme linked immunosorbent assays (ELISA), three using recombinant antigens based on the chlamydial polymorphic outer membrane proteins (POMP90-3, POMP90-4, POMP80-90) and one using a synthetic peptide based on chlamydial major outer membrane proteins (MOMP-P). They were also analysed by complement fixation tests (CFT) using crude antigens from chlamydia isolated from an Australian sheep, a Californian parakeet and a Texan turkey. Assay sensitivity and specificity were expressed as point estimates and 95% confidence intervals. Results were compared using McNemar's test for paired samples. RESULTS: ELISA sensitivity ranged from 70 to 98% and complement fixation test sensitivity from 60 to 96%; with POMP90-3 > POMP90-4 > CFT (parakeet) > CFT (turkey) > POMP80-90 > MOMP-P > CFT (sheep). There was no significant difference from POMP90-3 to POMP80-90 (P > 0.05). ELISA specificity ranged from 88 to 100% and CFT specificity was 100% for all three antigens; with CFT and POMP90-4 > MOMP-P > POMP80-90 > POMP90-3. There was no significant difference from CFT to POMP80-90 (P > 0.05). Changing the CFT cut-off from 1:32 to 1:4 substantially reduced the specificity with little improvement in sensitivity. CONCLUSION: Assays using POMP90-4, POMP80-90, CFT (parakeet) and CFT (turkey) had equivalent sensitivity and specificity; none of the ELISAs were more specific than any CFT. The POMP80-90 ELISA is recommended as an alternative to CFT (parakeet) but as its specificity is not ideal the search for a more specific assay should continue.

Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing.

Stromal derived factor-1 (SDF-1 or CXCL12) controls many aspects of stem cell function including trafficking and proliferation. Previously, it was demonstrated that DNA-damaging agents such as irradiation, cyclophosphamide or 5-fluorouracil increase the expression of SDF-1 by osteoblasts in murine marrow. Here, the production of SDF-1 by osteoblasts in vitro in response to cytokines known to be particularly important in bone physiology was examined using primary human osteoblasts (HOBs), mixed marrow stromal cells (BMSCs), and by, mouse, rat and human osteoblast-like cell lines. From these studies, it was determined that the expression of SDF-1 is an early feature of osteoblastic induction that may be modulated by IL-1beta, PDGF-BB, VEGF, TNF-alpha and PTH. Each of these factors increased SDF-1 synthesis, while TGF-beta1 decreased SDF-1 secretion. Of note, the biodistribution of SDF-1 in culture was equally distributed between the medium and detergent-soluble and -insoluble fractions of the cultures. Immunohistochemistry of developing bones demonstrated that SDF-1 was also a feature of early bone development first beginning in the perichondrium and moving into the marrow cavity of the developing bone analogue. As SDF-1 expression increases in response to PTH in vitro, animals were treated with an anabolic regime of PTH for 21 days. Under these conditions, significant increases in SDF-1 mRNA expression were observed near the growth plate and epiphysis regions of the long bones. Yet, in serum, immunodetectable SDF-1 levels were significantly reduced (24%) in the PTH-treated animals (Vehicle: 408 +/- 25 vs. PTH 308 +/- 20 SDF-1 pg/ml). Together, these data suggest a possible mechanism for localizing stem cells into a developing marrow where increased expression of SDF-1 in the local marrow environment along with decreased SDF-1 in the serum may create a homing gradient.

[Cochrane EPOC group: closing the gap between quality assurance and organization of care research and front line professionals]. / Cochrane EPOC group: chiudere il gap tra ricerca sul miglioramento della qualità dei servizi sanitari e professionisti sul campo.

Keeping physicians informed on an ongoing basis is a new challenge for continuing medical education and quality assurance. In Italy over the last 5 years interest in evidence based literature is growing. This is demonstrated by the launch of an Italian edition of Clinical Evidence and by the growing number of guidelines and systematic reviews produced by Italian authors and institutions. However, there is some uncertainty concerning the familiarity of Italian policy makers and public health physicians with the evidence-based resources, including also how to access them. This article attempts to close this gap, by describing the activities of the Cochrane Collaboration and, within it, of the Cochrane Effective Practice and Organisation of Care Group (EPOC), both aim to prepare and maintaining SR of health care interventions. Specifically, the EPOC group develops systematic reviews of professional, financial, organisational and regulatory interventions that are designed to improve professional practice and the delivery of effective health services. EPOC has 31 reviews and 24 protocols published in Issue 4, 2004 of the Cochrane Library and has developed standard methods to assist people, such as quality criteria for study design specific to health services research. The EPOC specialized register contains details of over 2200 studies that fall within the group's scope. Systematic reviews provide a valuable and efficient source of information for policy makers and health care professionals aimed at implementing effective and efficient strategies to encourage medical behavioural change and deliver of high quality services.