Three-year clinical performance of posterior monolithic zirconia single crowns.

STATEMENT OF PROBLEM: Monolithic zirconia has become widely used for single crowns, with the advantages of minimal tooth reduction and good esthetics. However, clinical studies evaluating the performance of and patient satisfaction with posterior monolithic zirconia crowns are sparse. PURPOSE: The purpose of this clinical study was to evaluate the clinical performance of and patient satisfaction with posterior monolithic zirconia crowns. MATERIAL AND METHODS: Within a prospective cohort study design, participants were recruited from a university dental clinic if they required 1 posterior monolithic zirconia crown. The clinical performance was evaluated at follow-up appointments 1, 2, and 3 years after insertion. Bleeding on probing and pocket probing depths for the crowned teeth were recorded. Overall patient satisfaction was measured by using a visual analog scale (VAS), and quality of life was measured by using the validated German version of the Oral Health Impact Profile 14 (OHIP-G14). Descriptive statistical methods were applied. Mean values were calculated and compared by using the paired t test (α=.05). RESULTS: Thirty participants received a monolithic zirconia crown (14 premolars, 16 molars). One biologic complication (vertical root fracture) was identified at the 1-year follow-up. Three years after insertion, 22 participants could be examined, and the crowns were still in function. The gingival and the periodontal status of the crowned teeth had not changed significantly over the 3 years. After insertion, a significant improvement in patient satisfaction was measured up to 3 years CONCLUSIONS: Posterior monolithic zirconia crowns led to enhanced patient satisfaction up to 3 years after insertion. They provided good middle-term success and offered a promising alternative to conventional metal-ceramic crowns.

A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform.

UNLABELLED: In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR(-/-))-CD46Ge mice with 2 × 10(5) 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice. IMPORTANCE: Although MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV.

Trans-amplifying RNA expressing functional miRNA mediates target gene suppression and simultaneous transgene expression.

The co-delivery of microRNAs (miRNAs) and protein-coding RNA presents an opportunity for a combined approach to gene expression and gene regulation for therapeutic applications. Protein delivery is established using long mRNA, self-, and trans-amplifying RNA (taRNA), whereas miRNA delivery typically uses short synthetic oligonucleotides rather than incorporating it as a precursor into long RNA. Although miRNA delivery into the cell cytoplasm using long genomes of RNA viruses has been described, concerns have remained regarding low processing efficiency. However, miRNA precursors can be released from long cytoplasmic alphaviral RNA by a cytoplasmic fraction of Drosha. taRNA, a promising vector platform for infectious disease vaccination, uses a nonreplicating mRNA expressing an alphaviral replicase to amplify a protein-coding short transreplicon-RNA (STR) in trans. To investigate the possibility of simultaneously delivering protein expression and gene silencing, we tested whether a taRNA system can carry and release functional miRNA to target cells. Here, we show that mature miRNA is released from STRs and silences specific targets in a replication-dependent manner for several days without compromising the expression of STR-encoded proteins. Our findings suggest that incorporating miRNAs into the taRNA vector platform has the potential for gene regulation alongside the expression of therapeutic genes.

Oral enzyme combination with bromelain, trypsin and the flavonoid rutoside reduces systemic inflammation and pain when used pre- and post-operatively in elective total hip replacement: a randomized exploratory placebo-controlled trial.

Background: Early mobilization after total hip replacement (THR) is key for fast recovery but is often limited by pain. Oral enzyme combinations (OECs) have demonstrated anti-inflammatory and pain-relieving effects. Objectives and design: This prospective, randomized, double-blind, placebo-controlled exploratory trial evaluated the effects of pre- and post-operative use of OEC (90 mg bromelain, 48 mg trypsin, 100 mg rutoside) following elective THR, on post-operative recovery. Methods: Candidates for primary elective cementless THR owing to osteoarthritis were eligible for participation [age ⩾50 years, body mass index 25-35 kg/m2, C-reactive protein (CRP) ⩽6 mg/L]. Following randomization to OEC or placebo, intervention started pre-operatively and continued onwards until day 42. Main outcomes included post-operative CRP levels (days 1-7), self-reported hip pain at rest (by 0-10 cm visual analogue scale on post-operative days 1-42), post-operative analgesic use [by cumulative analgesic consumption score (CACS) days 7-42], tolerability and adverse events. Results: Patients (N = 34) were recruited from a tertiary orthopaedic hospital in the Czech Republic, of whom 33 completed the study (OEC/placebo: n = 15/18). Baseline characteristics across the groups were comparable. Compared with placebo, the OEC group had numerically lower CRP levels on post-operative days 1-7, including peak level [mean (standard deviation) OEC versus placebo: 81.4 (28.3) versus 106.7 (63.3) mg/L], which translated into a significant 32% lower CRP area under the curve (p = 0.034). The OEC group reported significantly less pain during post-operative days 1-7 versus placebo (analysis of variance treatment × visit [F(4) = 3.989]; p = 0.005). Analgesic use was numerically reduced as assessed through an accumulated CACS. No deleterious effects on haemorheological parameters were observed in either group. Conclusions: Pre- and post-operative use of OEC significantly reduced CRP levels and patient self-reported pain. OEC may be an efficacious and safe treatment option to facilitate post-operative recovery following THR. Trial registration: EudraCT number 2016-003078-41.

Combination of Enzymes and Rutin to Manage Osteoarthritis Symptoms: Lessons from a Narrative Review of the Literature.

Osteoarthritis is the most common joint disorder affecting over 300 million people worldwide. It typically affects the knees and the hips, and is characterized by a loss in normal joint movement, stiffness, swelling, and pain in patients. The current gold standard therapy for osteoarthritis targets pain management using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with several potentially serious side effects, the most common being gastrointestinal perforation and bleeding. Owing to the side effects, NSAID treatment doses need to be as low as possible and should be continued for the shortest duration possible, which is problematic in a chronic condition like osteoarthritis, which requires long-term management. Numerous clinical trials have examined oral enzyme combinations as a potential new approach in managing pain in patients with osteoarthritis. Oral enzyme combinations containing bromelain in combination with trypsin, both proteolytic enzymes, as well as the plant flavonoid rutin, may be an effective alternative to typical NSAIDs. The aim of this narrative review is to summarize and discuss the evidence on the efficacy of oral enzyme combinations compared to the gold standard (NSAID) in the management of osteoarthritis symptoms. Nine randomized controlled trials identified in this review assessed the efficacy and safety of the oral enzyme combination containing bromelain, trypsin, and rutin in patients with osteoarthritis. Most of the studies assessed the impact of the oral enzyme combination on the improvement of the Lequesne Algofunctional index score, treatment-related pain intensity alterations and adverse events compared to patients receiving NSAIDs. Although largely small scale, the study outcomes suggest that this combination is as effective as NSAIDs in the management of osteoarthritis, without the adverse events associated with NSAID use. INFOGRAPHIC.

PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation.

PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target.

Clinical Fit of Monolithic Zirconia Single Crowns.

PURPOSE: To analyze the clinical fit of monolithic zirconia single crowns (MZSCs) in a prospective cohort study. MATERIALS AND METHODS: A total of 30 posterior teeth were restored with MZSCs. Silicone replicas were made to measure the clinical fit using a stereomicroscope. Measurements were conducted at 17 points per crown at the marginal and occlusal surfaces. RESULTS: The mean clinical fit was 0.104 mm at the crown margin and 0.101 mm at the occlusal surface. Measured distances at the marginal and occlusal surfaces were comparable. CONCLUSION: MZSCs showed acceptable clinical fit.

Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis.

BACKGROUND: Sepsis is still a major cause of death in both human and veterinary medicine. Early diagnosis is essential for appropriate treatment. Identification of patients at risk for developing sepsis is already possible in human medicine through the measurement of plasma interleukin-6 (IL-6) levels. In veterinary medicine, however, this has been investigated only in canine experimental models. OBJECTIVES: The purpose of this study was to measure IL-6 plasma levels in dogs with naturally occurring systemic inflammatory response syndrome (SIRS) and sepsis and to analyze the value of IL-6 as a predictive parameter for severity and mortality. METHODS: Included in the study were 79 dogs that had been admitted to the small animal clinics of Munich and Berlin from July 2004 to July 2005 and that satisfied the diagnostic criteria for SIRS and sepsis as defined using established parameters. Measurement of plasma IL-6 levels on days 0, 1, and 2 was performed by the use of a colorimetric bioassay based on IL-6-dependent cell growth. RESULTS: Septic foci were identified in 43 patients (septic group), and 36 patients were enrolled in the SIRS group. The frequency of positive blood cultures was 11%. The overall mortality rate was 48%. Higher plasma IL-6 levels on the day of admission were significantly correlated with a more severe degree of disease, increased mortality rate, and earlier fatality. CONCLUSIONS: Plasma IL-6 concentration is predictive of outcome in canine SIRS and sepsis and may be a valuable laboratory parameter for assessing critically ill dogs.

Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial.

BACKGROUND: Systemic enzyme therapy may improve symptoms of exhaustive eccentric exercise due to anti-inflammatory properties. METHODS: In a randomised, placebo-controlled, two-stage clinical trial, systemic enzyme therapy (Wobenzym) was administered for 72 hours before and 72 hours following a day on which subjects performed an exhaustive eccentric exercise (isokinetic loading of the quadriceps). Efficacy criteria (maximal strength and pain) and time points were selected to account for the multidimensional nature of exercise-induced muscle damage symptoms. Subjects were randomised in a crossover (stage I, n=28) and parallel group design (stage II, n=44). RESULTS: Analysis of stage I data demonstrated a significant superiority (Mann-Whitney=0.6153; p=0.0332; one sided) for systemic enzyme therapy compared with placebo. Stage II was designed as a randomised controlled parallel group comparison. Heterogeneity (I2>0.5) between stages led to separate analyses of stage I (endurance-trained subjects) and stage II (strength-trained subjects). Combined analysis resulted in no evidence for corresponding treatment effects. Analysis of pooled biomarker data, however, demonstrated significant favourable effects for systemic enzyme therapy in both stages. CONCLUSION: Systemic enzyme therapy before and after exhaustive eccentric exercise resulted in higher maximal concentric strength in the less strength-trained subjects (stage I) and in significant favourable effects on biomarkers (inflammatory, metabolic and immune) in all subjects. The application of these findings needs further evaluation.

CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses. We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2'-deoxycytidine. By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166-74 and CXorf6179-87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166-74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope. In summary, our data confirms this antigen as promising target for T cell based therapies.

Use of C-reactive protein to predict outcome in dogs with systemic inflammatory response syndrome or sepsis.

BACKGROUND: There is a high mortality rate in patients with systemic inflammatory response syndrome (SIRS) or sepsis. Therefore, an early diagnosis and prognostic assessment is important for optimal therapeutic intervention. The objective of the study was to evaluate if baseline values and changes in serum C-reactive protein (CRP) might predict survival in dogs with SIRS and sepsis. DESIGN: Prospective study; July 2004 to July 2005. SETTING: Small Animal Clinic, Berlin, Clinic of Small Animal Medicine, Munich. ANIMALS: Sixty-one dogs. MEASUREMENTS AND MAIN RESULTS: For the CRP analysis blood was drawn on day 0, 1, and 2; CRP was measured using a commercial ELISA test kit. Thirteen dogs suffered from nonseptic SIRS and 48 dogs from sepsis. The 14-day survival rate was 61% (69% nonseptic SIRS, 58% sepsis). Serum CRP was higher in sick dogs compared with controls (P<0.001). Over the 3-day period surviving dogs (n=31) displayed a significantly greater decrease in CRP than nonsurvivors (n=10) (P=0.001). No correlation was found between the initial CRP concentrations and the survival rate. The changes in CRP corresponded to the survival rate (P=0.01). CONCLUSION: There was no significant relationship between the survival rate in dogs with nonseptic SIRS or sepsis and the initial serum CRP concentrations. There was a correlation between decreasing CRP concentrations and recovery from disease. However, the changes in CRP concentrations over a 3-day period correctly predicted survival in 94% of dogs and death in 30% of the dogs (false positive rate 22%).