Publications by authors named "Alan Payne"

76 Publications

Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives.

Chem Biol Drug Des 2021 Feb 26. Epub 2021 Feb 26.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.

Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC  ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlights its potential to treat DS M. tb.
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http://dx.doi.org/10.1111/cbdd.13836DOI Listing
February 2021

Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis.

Bioorg Chem 2021 Jan 19;106:104486. Epub 2020 Nov 19.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia. Electronic address:

The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 - 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775894PMC
January 2021

Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents.

RSC Adv 2020 Feb 19;10(13):7523-7540. Epub 2020 Feb 19.

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia. Email:

Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) () strain. Naphthamide derivatives and were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds and had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. It is worth noting that the two most active compounds and also exhibited the highest selective activity towards DS, MDR and XDR strains over mammalian cells [IC (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
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http://dx.doi.org/10.1039/c9ra10663dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497412PMC
February 2020

Sox6 as a new modulator of renin expression in the kidney.

Am J Physiol Renal Physiol 2020 02 25;318(2):F285-F297. Epub 2019 Nov 25.

Department of Medicine/Clinical Pharmacology Division, Vanderbilt University Medical Center, Nashville, Tennessee.

Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal mesenchymal stromal cells (MSCs) differentiate from JG cells. JG cells undergo expansion and smooth muscle cells redifferentiate to express renin along the afferent arteriole. Gene expression profiling comparing resident renal MSCs with JG cells indicates that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin-producing cells. In vivo, Sox6 expression is upregulated after a low-Na diet and furosemide. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin-expressing cells normally seen during a low-Na diet and furosemide as well as the typical increase in renin. Furthermore, Sox6 ablation in renin-expressing cells halts the recruitment of smooth muscle cells along the afferent arteriole, which normally express renin under these conditions. These results support a previously undefined role for Sox6 in renin expression.
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http://dx.doi.org/10.1152/ajprenal.00095.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052657PMC
February 2020

Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis.

Curr Mol Pharmacol 2019 ;12(1):27-49

School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia.

Background: Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human's, there have been some early drug discovery efforts towards developing potent and selective inhibitors.

Objective: Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors.

Conclusion: Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.
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http://dx.doi.org/10.2174/1874467211666181025141114DOI Listing
June 2019

Interventions for replacing missing teeth: attachment systems for implant overdentures in edentulous jaws.

Cochrane Database Syst Rev 2018 10 11;10:CD008001. Epub 2018 Oct 11.

Private practice, Northland Prosthodontics Ltd, 17 Rust Avenue, Town Centre, Whangarei, Northland, New Zealand, 0110.

Background: Implant overdentures are one of the most common treatment options used to rehabilitate edentulous patients. Attachment systems are used to anchor the overdentures to implants. The plethora of attachment systems available dictates a need for clinicians to understand their prosthodontic and patient-related outcomes.

Objectives: To compare different attachment systems for maxillary and mandibular implant overdentures by assessing prosthodontic success, prosthodontic maintenance, patient preference, patient satisfaction/quality of life and costs.

Search Methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 24 January 2018); Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (searched 24 January 2018); MEDLINE Ovid (1946 to 24 January 2018); and Embase Ovid (1980 to 24 January 2018). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials on 24 January 2018. No restrictions were placed on the language or date of publication when searching the electronic databases.

Selection Criteria: All randomised controlled trials (RCTs), including cross-over trials on maxillary or mandibular implant overdentures with different attachment systems with at least 1 year follow-up.

Data Collection And Analysis: Four review authors extracted data independently and assessed risk of bias for each included trial. Several corresponding authors were subsequently contacted to obtain missing information. Fixed-effect meta-analysis was used to combine the outcomes with risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (95% CI). We used the GRADE approach to assess the quality of evidence and create 'Summary of findings' tables.

Main Results: We identified six RCTs with a total of 294 mandibular overdentures (including one cross-over trial). No trials on maxillary overdentures were eligible. Due to the poor reporting of the outcomes across the included trials, only limited analyses between mandibular overdenture attachment systems were possible.Comparing ball and bar attachments, upon pooling the data regarding short-term prosthodontic success, we identified substantial heterogeneity (I = 97%) with inconsistency in the direction of effect, which was unexplained by clinical or methodological differences between the studies, and accordingly we did not perform meta-analyses for this outcome. Short-term re-treatment (repair of attachment system) was higher with ball attachments (RR 3.11, 95% CI 1.68 to 5.75; 130 participants; 2 studies; very low-quality evidence), and there was no difference between both attachment systems in short-term re-treatment (replacement of attachment system) (RR 1.18, 95% CI 0.38 to 3.71; 130 participants; 2 studies; very low-quality evidence). It is uncertain whether there is a difference in short-term prosthodontic success when ball attachments are compared with bar attachments.Comparing ball and magnet attachments, there was no difference between them in medium-term prosthodontic success (RR 0.84, 95% CI 0.64 to 1.10; 69 participants; 1 study; very low-quality evidence), or in medium-term re-treatment (repair of attachment system) (RR 1.75, 95% CI 0.65 to 4.72; 69 participants; 1 study; very low-quality evidence). However, after 5 years, prosthodontic maintenance costs were higher when magnet attachments were used (MD -247.37 EUR, 95% CI -346.32 to -148.42; 69 participants; 1 study; very low-quality evidence). It is uncertain whether there is a difference in medium-term prosthodontic success when ball attachments are compared with magnet attachments.One trial provided data for ball versus telescopic attachments and reported no difference in prosthodontic maintenance between the two systems in short-term patrix replacement (RR 6.00, 95% CI 0.86 to 41.96; 22 participants; 1 study; very low-quality evidence), matrix activation (RR 11.00, 95% CI 0.68 to 177.72; 22 participants; 1 study; very low-quality evidence), matrix replacement (RR 1.75, 95% CI 0.71 to 4.31; 22 participants; 1 study; very low-quality evidence), or in relining of the implant overdenture (RR 2.33, 95% CI 0.81 to 6.76; 22 participants; 1 study; very low-quality evidence). It is uncertain whether there is a difference in short-term prosthodontic maintenance when ball attachments are compared with telescopic attachments.In the only cross-over trial included, patient preference between different attachment systems was assessed after only 3 months and not for the entire trial period of 10 years.

Authors' Conclusions: For mandibular overdentures, there is insufficient evidence to determine the relative effectiveness of different attachment systems on prosthodontic success, prosthodontic maintenance, patient satisfaction, patient preference or costs. In the short term, there is some evidence that is insufficient to show a difference and where there was no evidence was reported. It was not possible to determine any preferred attachment system for mandibular overdentures.For maxillary overdentures, there is no evidence (with no trials identified) to determine the relative effectiveness of different attachment systems on prosthodontic success, prosthodontic maintenance, patient satisfaction, patient preference or costs.Further RCTs on edentulous cohorts must pay attention to trial design specifically using the same number of implants of the same implant system, but with different attachment systems clearly identified in control and test groups. Trials should also determine the longevity of different attachment systems and patient preferences. Trials on the current array of computer-aided designed/computer-assisted manufactured (CAD/CAM) bar attachment systems are encouraged.
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http://dx.doi.org/10.1002/14651858.CD008001.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516946PMC
October 2018

Insights from molecular signature of in vivo cardiac c-Kit(+) cells following cardiac injury and β-catenin inhibition.

J Mol Cell Cardiol 2018 10 29;123:64-74. Epub 2018 Aug 29.

Mandel Center for Heart and Vascular Research, The Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, United States. Electronic address:

There is much interest over resident c-Kit(+) cells in tissue regeneration. Their role in cardiac regeneration has been controversial. In this study we aim to understand the in vivo behavior of cardiac c-Kit(+) cells at baseline and after myocardial infarction and in response to Sfrp2. This approach can accurately study the in vivo transcript expressions of these cells in temporal response to injury and overcomes the limitations of the in vitro approach. RNA-seq was performed with c-Kit(+) cells and cardiomyocytes from healthy non-injured mice as well as c-Kit(+) cells from 1 day post-MI and 12 days post-MI mice. When compared to in vivo c-Kit(+) cells isolated from a healthy non-injured mouse heart, cardiomyocytes were enriched in transcripts that express anion channels, cation channels, developmental/differentiation pathway components, as well as proteins that inhibit canonical Wnt/β-catenin signaling. Myocardial infarction (MI) induced in vivo c-Kit(+) cells to transiently adopt the cardiomyocyte-specific signature: expression of a number of cardiomyocyte-specific transcripts was maximal 1 day post-MI and declined by 12 days post-MI. We next studied the effect of β-catenin inhibition on in vivo c-Kit(+) cells by administering the Wnt inhibitor Sfrp2 into the infarct border zone. Sfrp2 both enhanced and sustained cardiomyocyte-specific gene expression in the in vivo c-Kit(+) cells: expression of cardiomyocyte-specific transcripts was higher and there was no decline in expression by 12 days post-MI. Further analysis of the biology of c-Kit(+) cells identified that culture induced a significant and irreversible change in their molecular signature raising questions about reliability of in vitro studies. Our findings provide evidence that MI induces in vivo c-Kit(+) cells to adopt transiently a cardiomyocyte-specific pattern of gene expression, and Sfrp2 further enhances and induces sustained gene expression. Our approach is important for understanding c-Kit(+) cells in cardiac regeneration and also has broad implications in the investigation of in vivo resident stem cells in other areas of tissue regeneration.
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http://dx.doi.org/10.1016/j.yjmcc.2018.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192834PMC
October 2018

Electrochemical Behavior and Detection of Sulfated Sucrose at a Liquid|Organogel Microinterface Array.

Anal Chem 2018 09 17;90(17):10256-10262. Epub 2018 Aug 17.

The electrochemical behavior and detection of sulfated carbohydrates were investigated at an array of microinterfaces between two immiscible electrolyte solutions where the organic phase was gelled. It was found that the electrochemical signal was dependent on the organic phase electrolyte cation. Cyclic voltammetry (CV) of sucrose octasulfate (SOS) with bis(triphenylphosphoranylidene)ammonium BTPPA as the organic phase cation did not provide a response to a 10 μM SOS concentration. However, when the organic phase cation was tetradodecylammonium TDDA, a distinct peak was present in the CV at ca. -0.47 V, indicative of a desorption process following adsorption during the preceding scan. This detection peak shifted to ca. -0.28 V when tridodecylmethylammonium TDMA was the organic phase cation, indicating an increased binding strength between this alkylammonium cation and SOS. By combining electroadsorption with TDMA as the organic phase electrolyte cation, detection limits of 0.064 μM SOS in 10 mM LiCl and 0.16 μM in a synthetic urine aqueous phase were achieved. The detection limit was improved to 0.036 μM SOS (10 mM LiCl) when the electroadsorption time was increased to 180 s, indicating the analytical capability for the detection of SOS and related sugars by ion-transfer adsorptive stripping voltammetry.
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http://dx.doi.org/10.1021/acs.analchem.8b01710DOI Listing
September 2018

Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF.

Cell Signal 2018 06 28;46:113-119. Epub 2018 Feb 28.

Duke Cardiovascular Research Center, and Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, NC 27710, USA. Electronic address:

The development of biased agonist drugs is widely recognized to be important for the treatment of many diseases, including cardiovascular disease. While GPCR biased agonism has been heavily characterized there is a distinct lack of information with respect to RTK biased agonism both in the identification of biased agonists as well as their attendant mechanisms. One such RTK, the Insulin-like Growth Factor 1 Receptor (IGF1R) plays an important role in a range of biological and disease processes. The micropeptide LL37 has been described as a biased agonist of the IGF1R. We were interested to further understand the mechanism by which LL37 promotes biased signaling through the IGF1R. We found that LL37 biased agonism is dependent on β-arrestin 2. Moreover, BRET assays indicated that LL37 biased agonism is explained by the inability of LL37 to promote the recruitment of IRS1 to the IGF1R compared to IGF1. LL37 promotes an altered association of IGF1R with GRK6, which could also serve as an explanation for bias. We also demonstrated a functional consequence of this bias by showing that while LL37 can promote cell proliferation, it does not induce protein synthesis, unlike IGF1, which does both. We have recently identified HASF, a natural protein released by mesenchymal stem cells, as a novel ligand of the IGF1R. HASF is a paracrine factor with potent cardioprotective and cardio-regenerative properties which also acts via IGF1R biased signaling, preferentially activated ERK over Akt.
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http://dx.doi.org/10.1016/j.cellsig.2018.02.013DOI Listing
June 2018

Non-invasive characterization of hemodynamics in adult out-of-hospital cardiac arrest patients soon after return of spontaneous circulation.

Resuscitation 2018 Apr 6;125:99-103. Epub 2018 Feb 6.

Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond, VA, United States.

Background: Little is known about hemodynamics in adult, out-of-hospital (OHCA) patients following return of spontaneous circulation (ROSC). A 1994 study when "high-dose epinephrine" use was common showed consistently elevated systemic vascular resistance (SVR) lasting ≥6 h in 49 adult patients after return of spontaneous circulation (ROSC).

Study Aim: To characterize hemodynamic abnormalities in adult OHCA patients soon after ROSC. Our hypothesis was that, unlike the consistently high SVR values reported when "high-dose" epinephrine was in common use, there would be a more heterogenous distribution of SVR values using current adrenergic therapy.

Methods: We included adult, OHCA patients transported by paramedics to the Emergency Department (ED) post-ROSC. Children, prisoners, pregnant women, and those with ongoing CPR or arrest due to traumatic injury were excluded. Hemodynamics were recorded non-invasively as soon as feasible after ED arrival but were not used to influence therapy, which was guided by clinical judgment of treating ED physicians.

Results: Hemodynamics were recorded on 30 patients 20 [16,25] minutes after ED arrival: 50% had a normal SVR, 30% had a high SVR, and 20% had a low SVR. There was no difference in survival to admission among groups, although there was a difference among groups in survival to discharge. Comparing the low SVR group vs the combined normal and high group revealed a trend for fewer 0/6 (0%) low vs. 10/24 (42%) normal or high SVR patients surviving to hospital discharge (p = .053).

Conclusion: A heterogeneous range of hemodynamic states exist post-ROSC rather than consistent vasoconstriction. Adequately powered, randomized clinical trials will be needed to determine whether noninvasively-derived, hemodynamic-directed therapy can play a role in improving neurologically-intact survival following OHCA in adults.
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http://dx.doi.org/10.1016/j.resuscitation.2018.02.001DOI Listing
April 2018

HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor.

Biochem J 2017 02 20;474(5):771-780. Epub 2017 Feb 20.

Mandel Center for Hypertension and Atherosclerosis Research, Duke University Medical Center, Durham, NC, U.S.A.

We have recently shown that hypoxia and Akt-induced stem cell factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effects, the receptor mediating these effects was unknown. Here, we undertook studies to identify the HASF receptor. A yeast two-hybrid screen identified a partial fragment of insulin-like growth factor 1 receptor (IGF1R) as a binding partner of HASF. Subsequent co-immunoprecipitation experiments showed that HASF bound to full-length IGF1R. Binding assays revealed a high affinity of HASF for IGF1R. The treatment of neonatal ventricular cardiomyocytes with HASF resulted in the phosphorylation of IGF1R and other proteins known to be involved in IGF1R-mediated signaling pathways. HASF-mediated ERK activation was abrogated by IGF1R pharmacological inhibitors and siRNAs that targeted IGF1R. However, siRNA-mediated knockdown of either IGF2R or the insulin receptor had no effect on HASF-induced cell signaling. Additionally, pharmacologic inhibition of IGF1R impeded HASF's ability to induce cardiomyocyte proliferation. Finally, we documented that deletion of the IGF1R completely abolished the ability of HASF to promote cardiomyocyte proliferation in an overexpression mouse model providing further evidence that the IGF1R is the functional receptor for HASF.
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http://dx.doi.org/10.1042/BCJ20160976DOI Listing
February 2017

Maxillary Three-Implant Overdentures Opposing Mandibular Two-Implant Overdentures: 10-Year Prosthodontic Outcomes.

Int J Prosthodont 2016 Jul-Aug;29(4):327-36

Purpose: This study aimed to evaluate the 10-year prosthodontic outcomes with splinted and unsplinted designs for maxillary overdentures on three implants opposing mandibular two-implant overdentures.

Materials And Methods: Using two similar implant systems, 40 edentulous participants with existing mandibular two-implant overdentures were randomly allocated to two prosthodontic treatment groups (splinted design with bar units; unsplinted design with ball attachments). Participants had three narrow-diameter implants placed in their edentulous maxillae using a one-stage surgical procedure, and they were conventionally loaded with overdentures. Prosthodontic maintenance events were documented at 1-, 2-, 5-, 7-, and 10-year recalls.

Results: Progressive attrition of the cohort resulted in 36 participants being seen for the 1-year recall, 31 participants for the 2-year recall, 30 participants for the 3-year recall, 28 participants for the 5-year recall, 26 participants for the 7-year recall, and 23 participants (nearly 60%) for the 10-year recall. Data showed no significant differences in prosthodontic maintenance or success associated with patrices, matrices, or other aspects of the overdentures using the different attachment systems and designs.

Conclusion: Maxillary three-implant overdentures are a viable treatment option for edentulous patients wearing opposing mandibular two-implant overdentures. There were no differences in prosthodontic maintenance and success between the splinted (bar) and unsplinted (ball) designs.
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http://dx.doi.org/10.11607/ijp.4631DOI Listing
December 2016

Selenium Augments microRNA Directed Reprogramming of Fibroblasts to Cardiomyocytes via Nanog.

Sci Rep 2016 Mar 15;6:23017. Epub 2016 Mar 15.

Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. However, direct reprogramming strategies are inefficient and slow. Moving towards the eventual goal of clinical application it is necessary to develop new methodologies to overcome these limitations. Here, we report the identification of a specific media composition, reprogramming media (RM), which augmented the effect of miR combo by 5-15-fold depending upon the cardiac marker tested. RM alone was sufficient to strongly induce cardiac gene and protein expression in neonatal tail-tip as well as cardiac fibroblasts. Expression of pluripotency markers Nanog, Oct4, Sox2, and Klf4 was significantly enhanced by RM, with miR combo augmenting the effect further. Knockdown of Nanog by siRNA inhibited the effect of RM on cardiac gene expression. Removal of insulin-transferrin-selenium completely inhibited the effect of reprogramming media upon cardiac gene expression and the addition of selenium to standard culture media recapitulated the effects of RM. Moreover, selenium enhanced the reprogramming efficiency of miR combo.
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http://dx.doi.org/10.1038/srep23017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792153PMC
March 2016

Multicentre prospective evaluation of implant-assisted mandibular removable partial dentures: surgical and prosthodontic outcomes.

Clin Oral Implants Res 2017 Jan 22;28(1):116-125. Epub 2016 Jan 22.

Oral Implantology Research Group, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.

Objective: To determine implant survival and prosthodontic maintenance of implant-assisted mandibular removable partial dentures in a multicentre prospective study up to 10 years.

Materials And Methods: Forty-eight participants with mandibular distal extension partial dentures were selected. A control group of 12 New Zealand participants had new conventional mandibular partial dentures made. Three test groups of 36 participants in New Zealand (n = 12), the Netherlands (n = 12) and Colombia (n = 12) had bilateral distal implants placed. Surgical and prosthodontic outcomes were documented with only healing caps placed (Stage 1) and with an attachment system (Stage 2).

Results: No implants failed after 3 years. Four late implant failures in three participants occurred in New Zealand (two unilateral implant failures after 5 and 8 years and two bilateral implant failures in the same participant after 6 and 10 years); two unilateral late implant failures occurred in the Netherlands and no late failures in Colombia. Implant survival rate was 92% by 10 years. Resonance frequency measurements were taken at surgery implant stability quotient (ISQ) 62.44 ± 7.46; range 40 - 79), baseline (ISQ 63.22 ± 6.17; range 50 - 74) and after 3 years (ISQ 66.38 ± 6.77; range 55 - 83). In New Zealand and Colombia, measured crestal bone levels were 2.03 ± 0.71 mm and 2.20 ± 0.81 mm, respectively, at baseline and 3 years. For Stage I, principal prosthodontic maintenance issues were loose healing caps among 10 New Zealand participants, four Colombian participants and one Netherlands participant. For Stage 2, matrix activation and overdenture puncture fractures resulted in 41 events (25 participants) in New Zealand over 10 years, whilst over 3 years, there were 14 events in nine Colombian participants and six events in five Netherlands participants.

Conclusion: This clinical multicentre research complements previous case reports, case series, retrospective and prospective studies on the notion of implant-assisted removable partial dentures for partially edentulous patients. Late implant failures and increased prosthodontic maintenance when an attachment system is used identify the need for further research, including more robust statistical analyses.
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http://dx.doi.org/10.1111/clr.12769DOI Listing
January 2017

Synthesis and Diels-Alder Reactivity of Substituted [4]Dendralenes.

J Org Chem 2016 Feb 29;81(4):1461-75. Epub 2016 Jan 29.

Research School of Chemistry, The Australian National University , Canberra, ACT 2601, Australia.

The first synthesis of all five possible monomethylated [4]dendralenes has been achieved via two distinct synthetic strategies. The Diels-Alder chemistry of these new dendralenes (as multidienes) with an electron poor dienophile, N-methylmaleimide (NMM), has been studied. Thus, simply upon mixing the dendralene and an excess of dienophile at ambient temperature in a common solvent, sequences of cycloadditions result in the rapid generation of complex multicyclic products. Distinct product distributions are obtained with differently substituted dendralenes, demonstrating that dendralene substitution influences the pathway followed, when a matrix of mechanistic possibilities exists. Dendralene site selectivities are traced to electronic, steric and conformational effects, thereby allowing predictive tools for applications of substituted dendralenes in future synthetic endeavors.
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http://dx.doi.org/10.1021/acs.joc.5b02583DOI Listing
February 2016

Inhibition of Wnt6 by Sfrp2 regulates adult cardiac progenitor cell differentiation by differential modulation of Wnt pathways.

J Mol Cell Cardiol 2015 Aug 10;85:215-25. Epub 2015 Jun 10.

Division of Cardiology, Department of Medicine, Duke University Medical Center & Duke Cardiovascular Research Center, Durham, NC 27710, USA; Duke Cardiovascular Research Center, Durham, NC 27710, USA.

Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progenitor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation.
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http://dx.doi.org/10.1016/j.yjmcc.2015.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838816PMC
August 2015

Interventions for replacing missing teeth: alveolar ridge preservation techniques for dental implant site development.

Cochrane Database Syst Rev 2015 May 28(5):CD010176. Epub 2015 May 28.

Private practice, Burns House Dental Specialists, Level 7, Burns House, 10 George Street, Dunedin, Otago, New Zealand, 9016.

Background: Alveolar bone changes following tooth extraction can compromise prosthodontic rehabilitation. Alveolar ridge preservation (ARP) has been proposed to limit these changes and improve prosthodontic and aesthetic outcomes when implants are used.

Objectives: To assess the clinical effects of various materials and techniques for ARP after tooth extraction compared with extraction alone or other methods of ARP, or both, in patients requiring dental implant placement following healing of extraction sockets.

Search Methods: The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 22 July 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2014, Issue 6), MEDLINE via OVID (1946 to 22 July 2014), EMBASE via OVID (1980 to 22 July 2014), LILACS via BIREME (1982 to 22 July 2014), the Meta Register of Current Controlled Trials (to 22 July 2014), ClinicalTrials.gov (to 22 July 2014), the World Health Organization International Clinical Trials Registry Platform (to 22 July 2014), Web of Science Conference Proceedings (1990 to 22 July 2014), Scopus (1966 to 22 July 2014), ProQuest Dissertations and Theses (1861 to 22 July 2014) and OpenGrey (to 22 July 2014). A number of journals were also handsearched. Trial authors were contacted to identify unpublished randomised controlled trials. There were no restrictions regarding language and date of publication in the searches of the electronic databases.

Selection Criteria: We included all randomised controlled trials (RCTs) on the use of alveolar ridge preservation techniques with at least six months of follow-up. Outcome measures were: changes in the bucco-lingual/palatal width of alveolar ridge, changes in the vertical height of the alveolar ridge, complications, the need for additional augmentation prior to implant placement, aesthetic outcomes, implant failure rates, peri-implant marginal bone level changes, changes in probing depths and clinical attachment levels at teeth adjacent to the extraction site, and complications of future prosthodontic rehabilitation.

Data Collection And Analysis: Two review authors extracted data independently and assessed risk of bias for each included trial. Corresponding authors were contacted to obtain missing information. Results were combined using random-effects models with mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (95% CI). We constructed 'Summary of findings' tables to present the main findings.

Main Results: A total of 50 trials were potentially eligible for inclusion, of which 42 trials were excluded. We included eight RCTs with a total of 233 extraction sites in 184 participants. One trial was judged to be at unclear risk of bias and the remaining trials were at high risk of bias. From two trials comparing xenograft with extraction alone (70 participants, moderate quality evidence), there was some evidence of a reduction in loss of alveolar ridge height (MD -2.60 mm; 95% CI -3.43 to -1.76) and width (MD -1.97 mm; 95% CI -2.48 to -1.46). This was also found in one trial comparing allograft with extraction (24 participants, low quality evidence): ridge height (MD -2.20 mm; 95% CI -0.75 to -3.65) and width (MD - 1.40 mm; 95% CI 0.00 to -2.80) and height. From two RCTs comparing alloplast versus xenograft no evidence was found that either ridge preservation technique caused a smaller reduction in loss of ridge height (MD -0.35 mm; 95% CI -0.86 to 0.16) or width (MD -0.44 mm; 95% CI -0.90 to 0.02; two trials (55 participants); moderate quality evidence). There was insufficient evidence to determine whether there are clinically significant differences between different ARP techniques and extraction based on the need for additional augmentation prior to implant placement, complications, implant failure, or changes in peri-implant marginal bone levels and probing depths of neighbouring teeth. We found no trials which evaluated parameters relating to clinical attachment levels, specific aesthetic or prosthodontic outcomes.

Authors' Conclusions: There is limited evidence that ARP techniques may minimise the overall changes in residual ridge height and width six months after extraction. There is also lack of evidence of any differences in implant failure, aesthetic outcomes or any other clinical parameters due to the lack of information or long-term data. There is no convincing evidence of any clinically significant difference between different grafting materials and barriers used for ARP. Further long term RCTs that follow CONSORT guidelines (www.consort-statement.org) are necessary.
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http://dx.doi.org/10.1002/14651858.CD010176.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464392PMC
May 2015

Maxillary Three-Implant Overdentures Opposing Mandibular Two-Implant Overdentures: 10-Year Surgical Outcomes of a Randomized Controlled Trial.

Clin Implant Dent Relat Res 2016 Jun 1;18(3):527-44. Epub 2015 Apr 1.

Private Practice, Whangarei, New Zealand.

Background: The surgical placement of four maxillary implants for overdentures may not be obligatory when opposing mandibular two-implant overdentures.

Purpose: To determine 10-year surgical outcomes and implant success of three narrow diameter implants in edentulous maxillae with conventional loading.

Materials And Methods: Forty participants with mandibular two-implant overdentures were randomly allocated for surgery for maxillary overdentures. Using osteotomes, three implants of similar systems were placed with a one-stage procedure and 12-week loading with splinted and unsplinted prosthodontic designs. Marginal bone and stability measurements were done at surgery, 12 weeks, 1-, 2-, 5-, 7-, 10 years.

Results: One hundred seventeen implants were placed in 39 participants, with 35 being seen at 1 year; 29 at 2 years; 28 at 5 years; 26 at 7 years; and 23 (59%) at 10 years. Marginal bone loss was 1.35 mm between surgery and 12 weeks; 0.36 mm between 12 weeks and 1 year; 0.48 mm between 1 and 5 years; and 0.22 mm between 5 and 10 years. Implant stability quotients were 56.05, 57.54, 60.88, 58.80, 61.17 at surgery, 12 weeks, 1 year, 5 years, and 10 years. Four-field tables by implant showed success rates of 82% at 1 year; 69.2% at 2 years; 66.7% at 5 years; 61.5% at 7 years; 51.3% at 10 years. Data showed no differences between surgical technique, systems, or prosthodontic designs.

Conclusions: Surgical placement with osteotomes of three narrow diameter implants for maxillary overdentures, opposing mandibular two-implant overdentures, is an acceptable approach, subject to strict patient selection. Implant success is independent of prosthodontic design.
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http://dx.doi.org/10.1111/cid.12325DOI Listing
June 2016

Salt restriction leads to activation of adult renal mesenchymal stromal cell-like cells via prostaglandin E2 and E-prostanoid receptor 4.

Hypertension 2015 May 16;65(5):1047-54. Epub 2015 Mar 16.

From the Mandel Center for Hypertension and Atherosclerosis Research, and the Cardiovascular Research Center (Y.Y., J.A.G., R.P.-M., Z.Z., A.P., R.E.P., M.M., V.J.D.) and Division of Nephrology, Department of Medicine (M.H., T.C.), Duke University Medical Center, Durham, NC; Department of Genetics, University of North Carolina at Chapel Hill (P.R., B.K.); and Henry Ford Hospital, Detroit, MI (W.H.B.).

Despite the importance of juxtaglomerular cell recruitment in the pathophysiology of cardiovascular diseases, the mechanisms that underlie renin production under conditions of chronic stimulation remain elusive. We have previously shown that CD44+ mesenchymal-like cells (CD44+ cells) exist in the adult kidney. Under chronic sodium deprivation, these cells are recruited to the juxtaglomerular area and differentiate to new renin-expressing cells. Given the proximity of macula densa to the juxtaglomerular area and the importance of macula densa released prostanoids in renin synthesis and release, we hypothesized that chronic sodium deprivation induces macula densa release of prostanoids, stimulating renal CD44+ cell activation and differentiation. CD44+ cells were isolated from adult kidneys and cocultured with the macula densa cell line, MMDD1, in normal or low-sodium medium. Low sodium stimulated prostaglandin E2 production by MMDD1 and induced migration of CD44+ cells. These effects were inhibited by addition of a cyclooxygenase 2 inhibitor (NS398) or an E-prostanoid receptor 4 antagonist (AH23848) to MMDD1 or CD44+ cells, respectively. Addition of prostaglandin E2 to CD44+ cells increased cell migration and induced renin expression. In vivo activation of renal CD44+ cells during juxtaglomerular recruitment was attenuated in wild-type mice subjected to salt restriction in the presence of cyclooxygenase 2 inhibitor rofecoxib. Similar results were observed in E-prostanoid receptor 4 knockout mice subjected to salt restriction. These results show that the prostaglandin E2/E-prostanoid receptor 4 pathway plays a key role in the activation of renal CD44+ mesenchymal stromal cell-like cells during conditions of juxtaglomerular recruitment; highlighting the importance of this pathway as a key regulatory mechanism of juxtaglomerular recruitment.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393376PMC
May 2015

Abi3bp regulates cardiac progenitor cell proliferation and differentiation.

Circ Res 2014 Dec 8;115(12):1007-16. Epub 2014 Oct 8.

From the Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, NC.

Rationale: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as a protein important for mesenchymal stem cell biology. Because CPCs share several characteristics with mesenchymal stem cells, we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation.

Objective: To determine whether Abi3bp regulates CPC proliferation and differentiation.

Methods And Results: In vivo, genetic ablation of the Abi3bp gene inhibited CPC differentiation, whereas CPC number and proliferative capacity were increased. This correlated with adverse recovery after myocardial infarction. In vitro, CPCs, either isolated from Abi3bp knockout mice or expressing an Abi3bp shRNA construct, displayed a higher proliferative capacity and, under differentiating conditions, reduced expression of both early and late cardiomyocyte markers. Abi3bp controlled CPC differentiation via integrin-β1, protein kinase C-ζ, and v-akt murine thymoma viral oncogene homolog.

Conclusions: We have identified Abi3bp as a protein important for CPC differentiation and proliferation.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.304216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258122PMC
December 2014

Zirconia implants supporting overdentures: a pilot study with novel prosthodontic designs.

Int J Prosthodont 2013 May-Jun;26(3):277-81

Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand.

Limited clinical research identifies prosthodontic perspectives of novel designs for zirconia implants supporting overdentures. Four pilot study participants were selected before a planned randomized clinical trial on zirconia implants supporting overdentures. Novel designs for maxillary four-implant overdentures (quadrilateral design) and mandibular three-implant overdentures (tripodal design) were used with 28 implants (maxilla, n = 16; mandible, n = 12). Four implants failed to achieve osseointegration prior to loading. At the 1-year follow-up appointment, all implants were surviving, the overdentures were in function, and there were no clinical signs of wear of the attachment system. A proof-of-principle for prosthodontic perspectives of a novel design using one-piece zirconia implants supporting maxillary and mandibular implant overdentures was achieved.
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http://dx.doi.org/10.11607/ijp.2903DOI Listing
July 2013

The prognostic accuracy of resonance frequency analysis in predicting failure risk of immediately restored implants.

Clin Oral Implants Res 2014 Jan 31;25(1):29-35. Epub 2012 Oct 31.

Oral Implantology Research Group, Sir John Walsh Research Institute, School of Dentistry, University of Otago, 310 Great King Street, Dunedin, New Zealand.

Objectives: It is of imperative clinical significance to define a safe threshold for planned immediate implant restoration. The aim of this report was to evaluate the prognostic accuracy of resonance frequency analysis (RFA) measurements recorded at two different times (implant placement and 8-week post-implant placement) and to determine the optimal threshold value for predicting failure risk of immediately restored/loaded implants.

Material And Methods: Twenty-eight 8- or 9-mm-diameter implants were placed in either a fresh molar extraction socket or a healed site. An electronic RFA device was used to record the implant stability quotients (ISQs) at implant placement surgery, 8 weeks and 1 year. Receiver operating characteristic (ROC) analysis was used to identify the optimal cut-off level. Sensitivity and specificity were also determined at the selected cut-off value.

Results: The area under the ROC curve for RFA at 8 weeks was 0.93 with a significant P-value (P = 0.001). The optimum cut-off value for detecting implant stability was 60.5 ISQ measured at 8 weeks, with sensitivity and specificity of 95.2% and 71.4%, respectively.

Conclusions: The implant stability measurements after 8 weeks showed a better accuracy in predicting implants that were at risk of failure than those taken at the time of implant placement.
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http://dx.doi.org/10.1111/clr.12057DOI Listing
January 2014

Insertion torque of immediate wide-diameter implants: a finite element analysis.

Quintessence Int 2012 Oct;43(9):e115-26

Sir John Walsh Research Institute, School of Dentistry, University of Otago, Dunedin, New Zealand.

Objective: To use finite element analysis to investigate the influence of insertion torque on the stress distribution around an immediately placed oral implant.

Method And Materials: Finite element software was used to model a mandibular molar extraction socket. The properties of surrounding cancellous bone and thickness of cortical bone were modified to give four 3D finite element models (I, II, III, and IV). A wide-diameter tapered oral implant was modeled and inserted into the socket. Final insertion torques of 32, 50, and 70 Ncm were applied, and the stress profile in each model was evaluated. The maximum von Mises stresses along the buccal cortical bone adjacent to the implant neck were statistically analyzed to compare the three torque values and four bone models.

Results: At the level of the cortical bone, the greatest von Mises stress levels were generated in model IV and diminished as the bone quality increased. Significant increase in stress values at the crestal bone level was observed in all models after using 70 Ncm compared with 32 Ncm. The maximum von Mises stresses at the cancellous bone were higher in model I and reduced with lower level of bone quality (model IV).

Conclusion: The use of 70 Ncm or more insertion torque during placement of an immediately placed wide-diameter implant substantially increases stresses on the crestal bone. The development of a modified surgical protocol involving moderate insertion torque value (32 to 50 Ncm) may contribute to minimizing the risk of early implant failure in extraction sockets.
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October 2012

Prosthodontic maintenance of maxillary implant overdentures: a systematic literature review.

Int J Prosthodont 2012 Jul-Aug;25(4):381-91

School of Dentistry, University of Otago, Dunedin, New Zealand.

Purpose: The aim of this article is to systematically review the literature on prosthodontic maintenance requirements of maxillary implant overdentures with different prosthodontic designs.

Materials And Methods: A standard approach of searching MEDLINE, PubMed, and Google Scholar databases as well as early online journal articles was followed. Hand-searching identified other relevant articles from the reference lists of the articles found. Selection criteria were details of prosthodontic maintenance related to different prosthodontic designs of maxillary implant overdentures, regardless of the dentition of the opposing arch or prosthesis.

Results: From a total of 58 relevant studies identified, only 18 met the criteria. Several categories were used to document the prosthodontic maintenance of maxillary implant overdentures, usually with four or more splinted or unsplinted implants using different attachment systems. Aspects of patrix and matrix maintenance were primarily reported, although soft tissue complications were described frequently. Subjective information on relines and the rationale for minimizing overdenture fractures was found.

Conclusions: Prosthodontic maintenance requirements of maxillary overdentures are a direct consequence of the attachment system, together with differing numbers and distributions of implants. The reviewed literature does not provide a clear controlled indication of prosthodontic maintenance requirements of maxillary overdentures for different prosthodontic designs and attachment systems. Future standardization of maxillary implant overdenture design is recommended, and universally accepted criteria for reporting maxillary implant overdenture maintenance should be implemented to establish accurate comparative data analysis.
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September 2012

Can resonance frequency analysis predict failure risk of immediately loaded implants?

Int J Prosthodont 2012 Jul-Aug;25(4):326-39

Department of Oral Diagnostic and Surgical Sciences, University of Otago, Dunedin, New Zealand.

Purpose: Resonance frequency analysis (RFA) is used to measure oral implant stability. There is controversy with regard to its accuracy in predicting both implant stability and osseointegration. This systematic review and meta-analysis determined the prognostic accuracy of RFA in predicting implant failure following immediate loading protocols.

Materials And Methods: MEDLINE, EMBASE, the Cochrane Oral Health Group's Trials Register, the United Kingdom National Research Register, the Australian New Zealand Clinical Trials Registry, the Database of Abstracts of Reviews of Effectiveness, and the Conference Proceedings Citations Index were searched to select studies that used RFA in assessing implant stability prior to immediate loading. The sensitivity, specificity, and accuracy of RFA in the selected studies were evaluated using a random effects model. The summary receiver operating characteristic was constructed to summarize the overall test performance.

Results: Fifteen studies with 2,236 immediately loaded implants were identified. The sensitivity of RFA in predicting failure of immediately loaded implants was 0.38 (95% confidence interval [CI]: 0.22 to 0.56), the specificity was 0.73 (95% CI: 0.71 to 0.75), and the diagnostic odds ratio was 2.10 (95% CI: 0.79 to 5.57). The area under the curve was 0.54, suggesting a poor predictive and discriminative ability.

Conclusion: RFA measurement at the time of implant placement is not sufficiently accurate to determine implant stability and osseointegration during immediate loading protocols.
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September 2012

MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.

Circ Res 2012 May 26;110(11):1465-73. Epub 2012 Apr 26.

Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, USA.

Rationale: Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ.

Objective: The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo.

Methods And Results: Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin.

Conclusions: The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.
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http://dx.doi.org/10.1161/CIRCRESAHA.112.269035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380624PMC
May 2012

Immediate single implant restorations in mandibular molar extraction sockets: a controlled clinical trial.

Clin Oral Implants Res 2013 May 26;24(5):484-96. Epub 2012 Jan 26.

Oral Implantology Research Group, Sir John Walsh Research Institute, School of Dentistry, University of Otago, Dunedin, New Zealand.

Background: In the replacement of missing teeth, a paradigm shift is currently observed with immediate implant placement and/or restoration, particularly in the aesthetic zone. In molar sites, however, anatomical, occlusal and biomechanical considerations remain deterrent factors influencing the outcome of this treatment paradigm. The aim of this report was to evaluate immediate placement and immediate restoration of strongly tapered wide-diameter implant in fresh mandibular molar extraction sockets.

Methods: Twenty-four 8- or 9-mm diameter implants were placed in either a fresh molar extraction socket or a healed site. All the implants received provisional crowns within 48 h. The provisional crowns were replaced with full ceramic crowns after 8 weeks of implant placement.

Results: The overall implant success rate after 1 year of service for the 24 implants in two treatment groups was 75%. Success rates were 83.3% and 66.7% for the delayed and immediate placement groups respectively, with no significant difference observed between the two groups (P = 0.35). Implant stability measurements identified the immediately placed implants to be more stable immediately after surgery than delayed placed implants. In contrast, the delayed placed implants were more stable after 8 week healing time.

Conclusions: The rehabilitation of single missing mandibular molars by immediately placed and restored wide-diameter implants was associated with a relatively high failure rate.
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http://dx.doi.org/10.1111/j.1600-0501.2011.02415.xDOI Listing
May 2013

Multicentre prospective evaluation of implant-assisted mandibular bilateral distal extension removable partial dentures: patient satisfaction.

Clin Oral Implants Res 2013 Jan 24;24(1):20-7. Epub 2011 Nov 24.

Department of Oral Function and Restorative Dentistry, Section of Oral Implantology and Prosthetic Dentistry, Academic Center for Dentistry Amsterdam, Amsterdam, The Netherlands.

Objective: To compare the levels of patient satisfaction with either conventional mandibular bilateral distal extension partial dentures or those assisted by bilateral distal implants.

Materials And Methods: Forty-eight participants who were dissatisfied with their existing conventional mandibular distal extension dentures opposing complete maxillary dentures were selected for a multicentre prospective study in New Zealand, Colombia and the Netherlands. A control group of 12 participants in New Zealand received conventional mandibular partial dentures. Three test groups involving 36 participants in New Zealand (12), Colombia (12) and the Netherlands (12) received bilateral distal implants in the second molar regions. After conventional loading, the test group participants initially had healing caps placed on the distal implants providing support only, followed after approximately 6 months by ball abutments (retentive anchors) for support and retention. Patient outcomes were determined with questionnaires completed at specific stages of the study for up to 3 years.

Results: Visual analogue scale, Likert and oral health impact questionnaires before and after treatment indicated improved results. There were significantly improved parameters of overall satisfaction, stability, chewing and appearance after 3 years (P < 0.05). There were also improvements on stability, chewing and overall satisfaction. Speech also improved, but not significantly. Ball abutments (retentive anchors) on the distal implants, as opposed to healing caps improved patient satisfaction for stability, chewing and overall satisfaction. Changing to ball abutments (retentive anchors) revealed significant improvement by participant response when evaluating parameters of stability, chewing and overall satisfaction (P < 0.05).

Conclusion: Mandibular implant-assisted removable partial dentures are a preferable treatment option for patients with complaints about their conventional distal extension partial dentures.
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http://dx.doi.org/10.1111/j.1600-0501.2011.02367.xDOI Listing
January 2013

Mandibular two-implant overdentures: prosthodontic maintenance using different loading protocols and attachment systems.

Int J Prosthodont 2011 Sep-Oct;24(5):405-16

Purpose: The aim of this research was to determine the long-term prosthodontic maintenance requirements of mandibular two-implant overdentures using different loading protocols and attachment systems.

Materials And Methods: A total of 106 participants were allocated randomly to one of four different implant systems (Steri-Oss, Southern, Straumann, or Branemark). Three different loading protocols (2, 6, and 12 weeks) were used with six different ball abutment patrices and their respective matrices (Steri-Oss rubber, Straumann gold, Straumann titanium, Branemark gold, Southern plastic, and Southern gold/platinum). Prosthodontic maintenance events were documented prospectively from baseline until the 8-year recall according to predefined categories.

Results: After 6 years, 90 participants attended recall and, thereafter, 68 participants were followed for 8 years. No significant differences were found between the number of prosthodontic maintenance events and the loading protocol used. Steri-Oss rubber matrices had the highest mean number of maintenance events at 32.2 ± 14.5 events, followed by the Branemark gold matrices at 28.8 ± 12.6 events. The Southern plastic matrices had a significantly lower mean number of maintenance events (8.7 ± 4.2) when compared with all other groups. Over a 6-year period, the matrices with the best longevity were Straumann gold at 3.9 ± 2.1 years. Straumann gold matrices also lasted significantly longer than all other matrices (P < .05). Southern gold/platinum, Branemark gold, and Southern plastic matrices all lasted significantly longer than the Straumann titanium and Steri-Oss matrices (P < .05). The mean time to reline for overdentures was 3.37 ± 2.06 years; remaking of overdentures peaked by year 7, with a mean time to remake of 5.81 ± 2.04 years.

Conclusion: Early loading protocols do not influence long-term prosthodontic maintenance requirements of unsplinted mandibular two-implant overdentures. By contrast, attachment systems do influence prosthodontic maintenance, particularly with regard to the type of matrices used.
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November 2011

Mandibular two-implant overdentures: three-year prosthodontic maintenance using the locator attachment system.

Int J Prosthodont 2011 Jul-Aug;24(4):328-31

Limited clinical research identifies prosthodontic maintenance requirements of mandibular overdentures using the Locator attachment system. Sixty-five edentulous participants received complete maxillary dentures opposing mandibular two-implant overdentures with either Locator nylon (n = 21), Southern plastic (n = 24), or Straumann gold (n = 20) matrices. Prosthodontic maintenance was recorded prospectively for 3 years using defined categories. Over the 3-year period, a mean 3.52 ± 4.8, 2.08 ± 1.9, and 5.5 ± 4.2 maintenance events occurred for Locator, Southern, and Straumann participants, respectively. Prosthodontic success rates of 90% in the Locator nylon group, 88% in the Southern plastic group, and 75% in the Straumann gold group were achieved. Int J Prosthodont 2011;24:328-331.
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April 2016