A role for Sfrp2 in cardiomyogenesis in vivo.

Cardiomyogenesis, the process by which the body generates cardiomyocytes, is poorly understood. We have recently shown that Sfrp2 promotes cardiomyogenesis in vitro. The objective of this study was to determine if Sfrp2 would similarly promote cardiomyogenesis in vivo. To test this hypothesis, we tracked multipotent cKit(+) cells in response to Sfrp2 treatment. In control adult mice, multipotent cKit(+) cells typically differentiated into endothelial cells but not cardiomyocytes. In contrast, Sfrp2 switched the fate of these cells. Following Sfrp2 injection, multipotent cKit(+) cells differentiated solely into cardiomyocytes. Sfrp2-derived cardiomyocytes integrated into the myocardium and exhibited identical physiological properties to preexisting native cardiomyocytes. The ability of Sfrp2 to promote cardiomyogenesis was further supported by tracking EdU-labeled cells. In addition, Sfrp2 did not promote the formation of new cardiomyocytes when the cKit(+) cell population was selectively ablated in vivo using a diphtheria toxin receptor-diphtheria toxin model. Notably, Sfrp2-induced cardiomyogenesis was associated with significant functional improvements in a cardiac injury model. In summary, our study further demonstrates the importance of Sfrp2 in cardiomyogenesis.

Mandibular 3-implant overdenture: A clinical report of a novel design.

OBJECTIVE: To report on the use of a mandibular 3-implant overdenture with a novel implant distribution opposing a maxillary complete denture for the rehabilitation of an older edentulous patient. BACKGROUND: The use of oral implants with attachment systems of various numbers and designs to support removable partial and complete dentures is well documented with success and predictability. MATERIALS AND METHODS: An older edentulous patient with a mandibular implant-assisted removable partial denture was presented with failing remaining dentition. Teeth were extracted and a single midsymphyseal implant was placed. A mandibular overdenture on three implants with ball attachments in a tripod distribution was constructed to oppose a new maxillary complete denture made using a modified impression technique. RESULTS: Over 2 years of follow-up, no significant biological or mechanical complications were reported, and denture retention and stability remained optimum. CONCLUSION: Mandibular overdentures on three implants with ball attachments in a tripod distribution, opposing a maxillary complete denture, could be an alternative treatment option for the older edentulous patients.

Methods used for extraction of plant volatiles have potential to preserve truffle aroma: A review.

Truffles are considered one of the world's most highly prized foods mainly due to their desirable organoleptic properties and rarity. However, truffles are seasonal (harvested mostly in winter from June to August in the Southern Hemisphere and from December to February in the Northern Hemisphere) and extremely perishable. Truffles deteriorate rapidly showing undesirable changes within 10 days from harvest in aroma and visual appearance after harvest. The very short postharvest shelf life (about 7-10 days) limits the potential for export and domestic consumption all year round. Several preservation methods have been studied to prolong their shelf life without the loss of aroma. However, all traditional preservation techniques have their own shortcomings and remain challenging. The extraction of natural truffle aroma volatiles for food applications could be a potential alternative to replace the existing synthetic flavoring used for processed truffle products. Four commonly used extraction methods for recovering volatile compounds from plants, namely, supercritical carbon dioxide extraction, Soxhlet extraction, distillation, and cold pressing, are critically analyzed. Up to date, existing research about the extraction of aroma volatiles from truffles is limited in the literature but based on the volatility of the key truffle volatile compounds, supercritical carbon dioxide extraction may offer the best possibility so that a natural truffle-based product that can be used in food applications throughout the year can be made available.

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

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 [IC50 (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.

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

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. This is an update of the Cochrane Review first published in 2015. 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: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 19 March 2021), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2021, Issue 2), MEDLINE Ovid (1946 to 19 March 2021), Embase Ovid (1980 to 19 March 2021), Latin American and Caribbean Health Science Information database (1982 to 19 March 2021), Web of Science Conference Proceedings (1990 to 19 March 2021), Scopus (1966 to 19 March 2021), ProQuest Dissertations and Theses (1861 to 19 March 2021), and OpenGrey (to 19 March 2021). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. A number of journals were also handsearched. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) on the use of ARP 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: We selected trials, extracted data, and assessed risk of bias in duplicate. Corresponding authors were contacted to obtain missing information. We estimated 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 and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 16 RCTs conducted worldwide involving a total of 524 extraction sites in 426 adult participants. We assessed four trials as at overall high risk of bias and the remaining trials at unclear risk of bias. Nine new trials were included in this update with six new trials in the category of comparing ARP to extraction alone and three new trials in the category of comparing different grafting materials. ARP versus extraction: from the seven trials comparing xenografts with extraction alone, there is very low-certainty evidence of a reduction in loss of alveolar ridge width (MD -1.18 mm, 95% CI -1.82 to -0.54; P = 0.0003; 6 studies, 184 participants, 201 extraction sites), and height (MD -1.35 mm, 95% CI -2.00 to -0.70; P < 0.0001; 6 studies, 184 participants, 201 extraction sites) in favour of xenografts, but we found no evidence of a significant difference for the need for additional augmentation (RR 0.68, 95% CI 0.29 to 1.62; P = 0.39; 4 studies, 154 participants, 156 extraction sites; very low-certainty evidence) or in implant failure rate (RR 1.00, 95% CI 0.07 to 14.90; 2 studies, 70 participants/extraction sites; very low-certainty evidence). From the one trial comparing alloplasts versus extraction, there is very low-certainty evidence of a reduction in loss of alveolar ridge height (MD -3.73 mm; 95% CI -4.05 to -3.41; 1 study, 15 participants, 60 extraction sites) in favour of alloplasts. This single trial did not report any other outcomes. Different grafting materials for ARP: three trials (87 participants/extraction sites) compared allograft versus xenograft, two trials (37 participants, 55 extraction sites) compared alloplast versus xenograft, one trial (20 participants/extraction sites) compared alloplast with and without membrane, one trial (18 participants, 36 extraction sites) compared allograft with and without synthetic cell-binding peptide P-15, and one trial (30 participants/extraction sites) compared alloplast with different particle sizes. The evidence was of very low certainty for most comparisons and insufficient to determine whether there are clinically significant differences between different ARP techniques based on changes in alveolar ridge width and height, the need for additional augmentation prior to implant placement, or implant failure. We found no trials which evaluated parameters relating to clinical attachment levels, specific aesthetic or prosthodontic outcomes for any of the comparisons. No serious adverse events were reported with most trials indicating that the procedure was uneventful. Among the complications reported were delayed healing with partial exposure of the buccal plate at suture removal, postoperative pain and swelling, moderate glazing, redness and oedema, membrane exposure and partial loss of grafting material, and fibrous adhesions at the cervical part of previously preserved sockets, for the comparisons xenografts versus extraction, allografts versus xenografts, alloplasts versus xenografts, and alloplasts with and without membrane. AUTHORS' CONCLUSIONS: ARP techniques may minimise the overall changes in residual ridge height and width six months after extraction but the evidence is very uncertain. There is lack of evidence of any differences in the need for additional augmentation at the time of implant placement, implant failure, aesthetic outcomes, or any other clinical parameters due to lack of information or long-term data. There is no 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.

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

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.

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

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/ß-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 ß-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.

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

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.

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

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 (I2 = 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.

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

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 in vivo deletion of the IGF1R completely abolished the ability of HASF to promote cardiomyocyte proliferation in an overexpression mouse model providing further evidence in vivo that the IGF1R is the functional receptor for HASF.

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

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.

Abi3bp regulates cardiac progenitor cell proliferation and differentiation.

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-ß1, 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.

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

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.

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

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.

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

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.

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

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.

Synthesis and Antitumour Evaluation of Tricyclic Indole-2-Carboxamides against Paediatric Brain Cancer Cells.

Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB1 and CB2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB1 and CB2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways.

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

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.

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

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.

Small Molecule Inhibitors of Human Papillomavirus: A Review of Research from 1997 to 2021.

Human papillomavirus (HPV) infections are the cause of warts, lesions and cancer, with different types of HPV causing different symptoms. HPV infections are the primary cause of cervical cancer. There are over 220 different types of HPV, and only nine of these can currently be vaccinated. There is a need to treat these viral infections without just treating the symptoms of the infection, as is currently the main method. There is a wide range of small molecules that have been used to inhibit various stages of the HPV infectious cycle. This review examined 132 small molecules from 121 studies that specifically target aspects of HPV infections. HPV DNA encodes for six early genes (E1 to E7, skipping E3) and two late genes (L1 and L2). According to the results, these targets for small molecule inhibitors fall into three categories: those targeting E1 and E2, targeting E6 and E7 and, finally, targeting L1 and L2. Inhibitors of E6 and E7 are the most widely studied targets, with the majority of HPV inhibition in this area. While compounds targeting both E1/E2 and E6/E7 have made it to clinical trials, there has been no significant advancement on the topic.