Full arch immediate occlusal loading using site specific implants: A clinical series of 10 patients (13 arches).

PURPOSE: Osseointegration of dental endosseous implants has proven to be effective, predictable, and clinically successful. Unloaded healing protocols were originally used in treating edentulous patients. Full arch immediate occlusal loading protocols have been shown to be as effective as unloaded healing protocols. This paper reports on the results, benefits, and limitations of one specific immediate loading protocol using site specific implants for fresh extraction and healed extraction sites. MATERIALS AND METHODS: Ten consecutive patients [{13 arches} (age range: 64-81 years; average: 70.1) (4 males/6 females) were treated by the first 2 authors in private practice settings. Hopeless teeth were scheduled for extraction with immediate implant placement and immediate loading with insertion of full arch, screw-retained, acrylic resin interim prostheses within 24 hours. Implants were also placed into healed edentulous ridges. Insertion torque values for each implant were recorded. Interim prostheses were removed after at least 3 months of healing. Implants were reverse torque tested (35 Ncm) and evaluated for macroscopic mobility. Definitive full arch prostheses were made. Patients were followed for 21 to 48 months postimplant surgery. Panoramic radiographs were taken immediately postimplant placement and 1 year postoperative. RESULTS: Thirteen arches were treated; 11 ultrawide diameter implants were placed into molar sockets, 26 inverted body-shift implants were placed into anterior sockets; 25 standard diameter, tapered implants were placed into edentulous sites; 2 zygomatic implants were placed in one patient. The total number of implants placed was 64 (4 preexisting implants were also used and not included in this study). The minimum implant insertion torque value was 20 Ncm. After 12 to 18 months of function (average 14 months), the implant and prosthetic survival rates were 100%. Eight patients were restored with definitive zirconia or acrylic resin hybrid fixed prostheses. Two patients were restored with bar titanium frameworks and removable overdenture prostheses. No prosthetic complications were reported for the definitive prostheses. CONCLUSIONS: The results of this clinical series with site specific implants and immediate full arch occlusal loading in treating edentulous patients resulted in 100% clinical implant and prosthetic survival rates. According to this study, this protocol can be used with high levels of anticipated success.

Displacement of the Inferior Alveolar Bundle Secondary to Post Coronectomy Root Migration: A Case Report.

Intentional coronectomy has become a commonplace procedure as an alternative to full third molar removal in order to decrease the occurrence of inferior alveolar nerve (IAN) injury. It is well known that one of the sequelae of this procedure is superior root migration. This is usually not a significant problem as the migrated roots may erupt to a position where they are more readily removed. This report presents a case in which a curvature at the apex of the root displaced the IAN causing neurologic symptoms.

Implant-related nerve injuries.

Injuries to branches of the trigeminal nerves are a known complication during dental implant placement. These injuries tend to be more severe than those experienced during other dentoalveolar procedures. This article reviews the types of nerve injuries and areas and situations of which clinicians should be cognizant when placing dental implants. Strategies to avoid injuries, and a management algorithm for suspected nerve injuries, are also discussed.

Pharmacokinetic evaluations of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine.

BACKGROUND AND OBJECTIVE: Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655). METHODS: Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. RESULTS: Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. CONCLUSION: Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.

Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures.

The Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures evidence-based clinical practice guideline was codeveloped by the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association. This guideline replaces the previous AAOS Information Statement, "Antibiotic Prophylaxis in Bacteremia in Patients With Joint Replacement," published in 2009. Based on the best current evidence and a systematic review of published studies, three recommendations have been created to guide clinical practice in the prevention of orthopaedic implant infections in patients undergoing dental procedures. The first recommendation is graded as Limited; this recommendation proposes that the practitioner consider changing the long-standing practice of routinely prescribing prophylactic antibiotic for patients with orthopaedic implants who undergo dental procedures. The second, graded as Inconclusive, addresses the use of oral topical antimicrobials in the prevention of periprosthetic joint infections. The third recommendation, a Consensus statement, addresses the maintenance of good oral hygiene.

Pretreatment data is highly predictive of liver chemistry signals in clinical trials.

PURPOSE: The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. PATIENTS AND METHODS: Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. RESULTS: Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy's law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. CONCLUSION: It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones.

Induction of cyclin D1 by arsenite and UVB-irradiation in human keratinocytes.

Arsenic is an environmental pollutant with carcinogenic properties that is found in many regions of the world but that poses a health risk primarily in economically disadvantaged areas. In these areas, arsenic ingestion affects various tissues, especially skin in which it acts as a comutagen with the ultraviolet component of solar radiation. Both epidemiological and experimental evidence indicates that arsenic and ultraviolet radiation act on signaling pathways that effect the expression of cyclin D1. We have previously employed an in vitro model system of human epidermal keratinocytes to study the effects of submicromolar concentrations of sodium arsenite on cyclin D1 expression. Here, we employed this system to demonstrate concordant cyclin D1-related induction profiles of ultraviolet B radiation and arsenite using cDNA microarray analysis. We also show that both of these agents act epigenetically to bring about demethylation of the cyclin D1 promoter.

Spectrum of mitochondrial DNA deletions within the common deletion region induced by low levels of UVB irradiation of human keratinocytes in vitro.

We show that a single low-dose exposure of human epidermal keratinocytes (NHEK) to an FS20 light source in vitro can induce the formation of mitochondrial DNA deletions in a PCR detection assay. We used primer sets specifically designed to exclude amplification of segments containing the common deletion, but which could detect possibly lower abundance deletions generated within the same region of the mitochondrial genome. We characterized eight novel deletions of which six were generated from cut sites within, or adjacent to, short direct repeats. Two deletions involved cut sites in inverted tetrameric repeats; one of these also involved an insertion.

Patterns of persistent DNA damage associated with sun exposure and the glutathione S-transferase M1 genotype in melanoma patients.

Solar radiation can lead to changes affecting DNA metabolism resulting in loss of DNA integrity. Skin specimens obtained from melanoma patients treated at the Memorial Sloan-Kettering Cancer Center were used to study patterns of DNA fragmentation using the comet assay and levels of deletions in mitochondrial DNA (mtDNA) using real-time PCR. Skin specimens were classified according to the glutathione S-transferase M1 (GSTM1) genotype (either wild type [WT] or null) and patient sunburn history. GSTM1 null individuals with a sunburn history showed increased levels of both DNA fragmentation by comet assays and mtDNA deletions relative to GSTM1 WT patients with little or no sunburn history. Microarray analyses identified a number of genes whose expression was upregulated >or=5-fold in cells from GSTM1-null patients or from those reporting histories of sunburn. These genes encoded small molecule transporters, various growth factor/chemokine receptors, transcription factors and tumor suppressors. Of 17 genes directly involved in DNA repair, three DNA ligases were highly upregulated while the RAD23 UV excision repair gene and the Growth Arrest and DNA Damage gene (GADD45) were downregulated. These findings support the idea that exposure to solar radiation early in life may induce long-term cellular changes that lead to persistent DNA damage and altered patterns of gene expression.

Mitochondrial DNA deletions in skin from melanoma patients.

We measured the cellular levels of two types of mitochondrial DNA (mtDNA) deletions--the 4977-bp common deletion and recently identified UVB-induced deletion of 5128 bp--in apparently normal skin obtained from wide excisions in melanoma patients. The number of deleted mtDNAs as well as the total mtDNA copy number was highly variable, but the number of deletions increased with age of the donor almost 12-fold across the age range of the patients. Patients were scored for degree of overall pigmentation and response to sunlight by a phenotypic index (PI). The relative levels of both types of mtDNA deletions were much more abundant in the intermediate PI groups compared with either the low or high PI groups. In the intermediate PI group, melanomas were also seen later in life. Unexpectedly, the complement of total mitochondrial genomes was more than twofold higher in the low PI group than in the other PI groups. This may reflect a proliferative response to DNA damage induced by solar radiation in the high-risk group.

E-cadherin gene alterations in gastric cancers in different ethnic populations.

INTRODUCTION: A retrospective study of nucleotide sequence alterations in exons 7-9 of the E-cadherin gene and expression of E-cadherin and beta-catenin in gastric tumors from African American, Asian, Causcasian and Hispanic patients was carried out to determine differences potentially related to race/ethnicity in these groups. METHODS: Paraffin-embedded tissue sections archived at the Memorial Sloan Kettering Cancer Center were used for immunohistochemical staining of sections for membranous E-cadherin protein and nuclear localization of beta-catenin. DNA from tumor tissue extracted from the paraffin sections was used as template for amplification of the E-cadherin gene exonic regions. RESULTS: Sequence analyses of the high-frequency mutation region along E-cadherin exons 7-9 revealed a number sequence alterations in the patient group as a whole, mostly within exon 8. The alterations were mainly single nucleotide insertions, but a palindromic duplication of exon 8 in a Caucasian patient and several extragenic insertions in a Hispanic and an African American patient were also found. Nuclear localization of beta-catenin was correlated with inactivating sequence alterations in three patients. CONCLUSIONS: Exon 8 was found to display the most extensive alterations in all the groups studied. As a group, the most extensive sequence alterations were found in tumors from Caucasian patients. A finding of potential significance as a biomarker related to ethnicity was a C insertion at nt 76,598 found independently in two African American patients.

Timing of trigeminal nerve microsurgery: a review of the literature.

Injury to peripheral branches of the trigeminal nerve is a known sequelae of oral and maxillofacial surgery procedures. The most often studied and reported branches have been the inferior alveolar and lingual nerves. Many questions still remain unanswered concerning the appropriate timing of surgical repair. The literature frequently mentions specific timing guidelines, however, there is scant scientific evidence to support these guidelines. In fact, several authors of clinical series state that although many of their surgical procedures occurred fairly late due to the timing of referral and other issues such as insurance authorization, reasonable clinical results were still achieved in these patients. Various systems of nerve injury evaluation and testing methods make it difficult to draw specific timing recommendations. The consensus of literature reviewed indicates that more research is necessary in this area to better answer these questions.

Induction of cyclin D1 by submicromolar concentrations of arsenite in human epidermal keratinocytes.

Arsenic is a prevalent environmental carcinogen but arsenic is not directly mutagenic and the mechanism by which arsenite brings about oncogenic transformation is poorly understood. To gain insight into the oncogenic properties of arsenic, we studied the expression of cyclin D1 in cultured human epidermal keratinocytes treated with submicromolar concentrations of sodium arsenite. Arsenite at concentrations between 200 and 800 nM over a 3-day period brought about an increase in cell growth rate. Uptake of the vital stain, neutral red, arsenite at 200 and 400 nM concentrations brought about a parallel increase in cell viability over the same treatment period. Analysis of cell cycle parameters by flow cytometry showed that the growth stimulation was accompanied by a concomitant shift from the G1 into the S/G2 cell cycle compartment in the arsenite-treated cells. Real-time PCR analysis of cyclin D1 transcription showed that there was an induction of more than three-fold in cells exposed to 400 nM arsenite for 3 days. Quantitation of cyclin D levels in Western blots showed that arsenite treatment caused a time-dependent induction of cyclin D proteins representing an induction of about 2.0-fold after a 7 day treatment period. Electrophoretic mobility shift assays (EMSA) showed that arsenite also stimulated binding of the transcription factors, AP1 and CREBP to their respective binding motifs within 3 days. This supports a mechanism of oncogenesis based on persistent upregulation of D type cyclins leading to a concomitant loss of G1/S checkpoint control.

Perioperative considerations in the management of pediatric surgical patients.

Pediatric anatomy and physiology differ significantly from those of adults and, therefore, require special considerations in evaluation and perioperative management. This article highlights the anatomic and physiologic differences that influence pediatric management. It also covers specific disease processes that are common in the pediatric population and that may involve special management strategies.

Modulation of sulfur mustard induced cell death in human epidermal keratinocytes using IL-10 and TNF-alpha.

We compared the effects of overexpressing a tightly regulated anti-inflammatory cytokine, interleukin 10 (IL-10), and the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on sulfur mustard induced cytotoxicity in human epidermal keratinocytes. Both cytokines were overexpressed when compared with the cells transfected with the empty vector as determined by quantitative ELISA. Cells overexpressing interleukin 10 suppressed the pro-inflammatory cytokines interleukin 8 and interleukin 6 following exposure to 50-300 microM sulfur mustard. These cells exhibited delayed onset of sulfur mustard induced cell death. On the other hand, cells overexpressing tumor necrosis factor alpha induced a sustained elevation in both interleukin 6 and 8 expression following exposure to 50-300 microM sulfur mustard. These cells were sensitized to the effects of sulfur mustard that resulted in an increased sulfur mustard induced cell death. Normal human epidermal keratinocytes treated with sulfur mustard exhibited elevated levels of tumor necrosis factor alpha expression and increased activity of nuclear factor kappa B. Gene array data indicated that cells overexpressing interleukin 10 induced several genes that are involved in growth promotion and cell-fate determination. We, therefore, identify IL-10 and TNF-alpha signal transduction pathways and their components as possible candidates for early therapeutic intervention against sulfur mustard induced cell injury.

Management of parotid duct injuries.

Injuries to the buccal region of the face can carry multiple complications due to the complex anatomy that lies within. The facial nerve and the parotid duct can be easily injured by sharp or penetrating trauma to the cheek. The purpose of this paper is to present the full spectrum of current treatment modalities available to manage these injuries. The anatomy of the parotid gland and duct are described, and surgical techniques and therapeutic alternatives for the immediate and delayed treatment of the parotid duct injuries are reviewed. Clinical cases are presented to illustrate the treatment options outlined.

National differences in reporting 'pneumonia' and 'pneumonia interstitial': an analysis of the WHO International Drug Monitoring Database on 15 drugs in nine countries for seven pulmonary conditions.

PURPOSE: Increased post-marketing reports of 'interstitial pneumonia' as an adverse drug reaction (ADR) from the use of gefitinib, irinotecan, or leflunomide among patients in Japan have not been noted in other countries. The WHO International Drug Monitoring Database was analyzed to examine Japan's pattern of reporting the term 'pneumonia interstitial' for 15 selected drugs with a mixed history of association with pulmonary ADRs. METHODS: ADR counts from the WHO Database for 1992-2001 were obtained for 15 disparate drugs (three androgen blockers, eight cytotoxics, one proton pump inhibitor, one monoclonal antibody, and two anti-epileptics) from nine countries (Australia, France, Germany, Italy, Japan, Spain, Thailand, U.K., and U.S.A.) for seven pulmonary ADR terms (alveolitis fibrosing, pneumonia, pulmonary fibrosis, lung fibrosis interstitial, pulmonary infiltration, interstitial lung disease, and pneumonia interstitial). Statistical analyses included estimating Poisson-distributed expected rates, observed/expected (O/E) ratios, and 95% confidence intervals (CI). The overlapping nature and changes in definition over time of these terms in medical texts and in the WHO-ART, COSTART, J-ART, and MedDRA coding systems is also noted. RESULTS: Compared to other countries, both Japan and France did not have higher O/E reporting ratios for all seven pulmonary ADRs combined, but did have higher O/E ratios for 'pneumonia interstitial' and lower O/E ratios for 'pneumonia' for the same drugs. CONCLUSIONS: Japan and France were found to preferentially use the term 'pneumonia interstitial' for ADR where other countries used 'pneumonia.' This cultural pattern coincides with the fact that 'pneumonia interstitial' in older versions of COSTART, J-ART, and MedDRA were subsumed under infectious pulmonary diseases.

Immortalized human keratinocytes: A model system to study the efficacy of therapeutic drugs in response to the chemical warfare agent sulfur mustard (HD)

Cytokines have been established as biomarkers to detect exposure of cells to chemical warfare agents such as sulfur mustard (2,2'-dichlorodiethyl sulfide, HD). In this study cultured normal and SV40 immortalized human epidermal keratinocyte (NHEK/IHEK) cells were compared as potential model systems to measure the efficacy of therapeutic drugs against HD. Immortalized human epidermal keratinocytes resemble their primary cell counterparts but have the advantage of being carried through long-term culture. Immortalized cells also provide consistency and durability and are less costly than primary keratinocytes. Immunoassay studies were performed to examine the response of these two cell lines to HD. We found that both normal and immortalized NHEKs secreted the pro-inflammatory mediator interleukin-8 (IL-8) when exposed to HD. However, a major difference was observed between the NHEK cell line 6207 and IHEK cell line 425. IHEK cell line 425 produced higher levels of Interleuken-8 then those of its normal counterpart cell line 6207. This observation is significant since therapeutic drugs such as ibuprofen, which depress cytokine production, may not allow these biomarkers to be detected efficiently in experimental analysis of certain NHEK cell lines. The fact that Il-8 production higher in cell line 425 cell makes this in vitro model a potential screening tool to study the efficacy of drugs that suppress production of cytokine markers.