Konrad Neumann

Morphological and bond strength evaluation of different resin cements to root dentin

This study correlated the morphological characteristics with the bond strengths of various resin cements used for bonding fiber posts to root canal dentin. Fifty glass-fiber posts (FRC Postec Plus) were luted into the root canals of extracted human anterior teeth using five resin cements (n = 10): Panavia F 2.0, PermaFlo DC, Variolink II, RelyX Unicem, and Clearfil Core. Before insertion of the post, the adhesive systems were labeled with fluorescein and the resin cement was labeled with rhodamine isothiocyanate. The roots were sectioned into three slices (of 2 mm thickness), and each slice was analyzed using confocal laser scanning microscopy in dual fluorescence mode to determine hybrid layer thickness, the number of resin tags, and the number of broken tags. Bond strengths were measured using a micro push-out test. Bond strengths to root canal dentin, as well as the morphological characteristics, were significantly affected by the materials. However, these factors did not correlate. The self-adhesive resin cement, which showed the formation of a hybrid layer and resin tags only sporadically, had the highest bond strengths. These results indicate that chemical interactions between the adhesive cement and hydroxyapatite may be more crucial for root dentin bonding than the ability of the same material to hybridize dentin.

A frequent functional toll-like receptor 7 polymorphism is associated with accelerated Hiv-1 disease progression

Objectives:Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR7 recognizes RNA of various viruses including HIV. The objective of this study was to examine the influence of individual genetic variations of TLR7 on the susceptibility to and progression of HIV disease. Method:We genotyped a population of 734 HIV-positive adults and 545 healthy controls for three TLR7 single nucleotide polymorphisms. The frequency of TLR7 genetic variations was assessed and related to HIV disease progression. Furthermore, we analyzed peripheral blood mononuclear cells obtained from healthy individuals differing in their TLR7 genotype and assessed their response to a TLR7-specific ligand ex vivo. Results:Presence of the most frequent TLR7 polymorphism, TLR7 Gln11Leu, was associated with higher viral loads and accelerated progression to advanced immune suppression in HIV patients. Furthermore, in women this polymorphism may be associated with increased HIV-1 susceptibility as it was found more frequently among patients as compared with controls. Peripheral blood mononuclear cells from polymorphism carriers secreted significantly less IFN-α following TLR7 activation, whereas IL-6 production remained unaltered. Conclusion:This is the first report of a functional TLR7 variant to be associated with susceptibility to and a more severe clinical course of HIV-1 disease. These results may have implications for the risk assessment of individual patients as well as for HIV-1 therapy and vaccination strategies in the future.

A Functional Toll-Like Receptor 8 Variant Is Associated with HIV Disease Restriction

BACKGROUND Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR8 has been found to recognize RNA derived from various viruses, including human immunodeficiency virus (HIV). Presently, very little is known about the influence of TLR8 genetic variation on susceptibility to and progression of HIV disease. METHODS AND RESULTS We genotyped a population of 782 HIV-positive adults and 550 healthy control subjects for 3 nonsynonymous TLR8 single-nucleotide polymorphisms. We found that the presence of the most frequent TLR8 polymorphism, TLR8 A1G (rs3764880), confers a significantly protective effect regarding progression of the disease. In overexpression assays, we demonstrated that this receptor variant displays impaired NF-kappaB activation in vitro. Furthermore, we analyzed different cell types obtained from individuals differing in their TLR8 genotype and assessed their response to TLR8 ligands in vitro. The presence of the mutated receptor variant was associated with modulation of cytokine secretion profiles and lipid mediator synthesis patterns in monocytes and neutrophils. CONCLUSIONS This first report of a functional TLR8 variant associated with a different clinical course of an RNA viral disease may have implications for the individual risk assessment of patients infected with HIV and other RNA viruses as well as for future HIV vaccine development.

Randomized Clinical Trial Comparing the Effects of Post Placement on Failure Rate of Postendodontic Restorations: Preliminary Results of a Mean Period of 32 Months

INTRODUCTION The aim of this randomized clinical trial was to assess whether the placement of a fiber post (DT Light Post) (DT) and the amount of residual coronal dentin affect the time to failure of single-unit postendodontic restorations. METHODS Ninety patients providing 120 teeth were selected. Three groups (n = 40) were defined on the basis of the amount of residual coronal dentin: 2-walls group, 2 or more coronal walls; 1-wall group, 1 coronal wall; no-wall group, no wall exceeding 2 mm above the gingival level. Within each group teeth were randomized and allocated to 2 intervention groups (n = 20), including subgroups no post (no root canal retention) and subgroups post (placement of DT). RESULTS After a mean observation period of 32.4 (13.7) months in subgroups no post, the failure rates were 10%, whereas in subgroups post, failure rates of 7% were observed (P = .318). In no-wall group post placement significantly affected the time to failure of total restorations (P = .029, log-rank test). Teeth without post retention revealed a significantly higher failure rate (31%) compared with teeth restored with post retention (7%). CONCLUSIONS Within the observation time of the present study, fiber post placement was efficacious to reduce failures of postendodontic restorations only with teeth that exhibited no coronal walls. Post insertion for teeth showing a minor substance loss should be critically reconsidered.

Association of TLR7 single nucleotide polymorphisms with chronic HCV‐infection and response to interferon‐a‐based therapy

Summary.  An efficient immune response against hepatitis C virus (HCV) is necessary to clear infection. As HCV is a single‐stranded RNA virus, a role for TLR7 in the immune response against HCV is possible, and early clinical studies have demonstrated an antiviral effect of TLR7 stimulation. We tested the hypothesis that genetic variations of TLR7 are associated with chronic HCV‐infection and outcome of therapy. The prevalence of three TLR7 variations was analysed in 978 patients with chronic HCV‐infection, 898 patients with chronic liver disease of other aetiologies, and in 203 healthy controls. The prevalence of TLR7 variations was correlated with the response to interferon‐α‐based treatment in 544 patients with chronic HCV‐infection. We analysed TLR7 polymorphisms by melting curve analysis and reconstructed haplotypes. The c.32A>T variation was over‐represented in female patients with chronic HCV‐infection compared to patients with other chronic liver diseases and to healthy controls (P < 0.05). In contrast, c.2403 G>A was less prevalent in male patients with chronic HCV‐infection (P < 0.05). No association was observed for the third variant, c.1‐120T>G. Haplotype analysis confirmed the differential distribution of TLR7 variants between the groups. Within the group of female patients with chronic HCV‐infection, c.32T was predictive of an unfavourable outcome of interferon‐α therapy (P < 0.05). This study reports the association of TLR7 variants with chronic HCV‐infection and with the response to interferon‐α therapy in patients with chronic HCV‐infection. Our results suggest that variations of TLR7 impair the immune response to HCV and imply a gender‐specific effect of this X‐chromosomal variation.

Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients.

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1–infected patients represents one possible strategy. Four hundred thirty‐three patients were randomly assigned to receive either 1.5 μg/kg peginterferon alfa‐2b weekly plus 800‐1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18‐48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription‐mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009.)

Escitalopram for the Prevention of Peginterferon-α2a–Associated Depression in Hepatitis C Virus–Infected Patients Without Previous Psychiatric Disease: A Randomized Trial

BACKGROUND Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING 10 university and 11 academic hospitals in Germany. PATIENTS 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE Roche Pharma and Lundbeck.

The broader context of antibiotic resistance: Zinc feed supplementation of piglets increases the proportion of multi-resistant Escherichia coli in vivo

Following the Europe-wide ban of antimicrobial growth promoters, feed supplementation with zinc has increased in livestock breeding. In addition to possible beneficial effects on animal health, feed supplementation with heavy metals is known to influence the gut microbiota and might promote the spread of antimicrobial resistance via co-selection or other mechanisms. As Escherichia coli is among the most important pathogens in pig production and often displays multi-resistant phenotypes, we set out to investigate the influence of zinc feed additives on the composition of the E. coli populations in vivo focusing on phylogenetic diversity and antimicrobial resistance. In a piglet feeding trial, E. coli were isolated from ileum and colon digesta of high dose zinc-supplemented (2500ppm) and background dose (50ppm) piglets (control group). The E. coli population was characterized via pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) for the determination of the phylogenetic background. Phenotypic resistance screening via agar disk diffusion and minimum inhibitory concentration testing was followed by detection of resistance genes for selected clones. We observed a higher diversity of E. coli clones in animals supplemented with zinc compared to the background control group. The proportion of multi-resistant E. coli was significantly increased in the zinc group compared to the control group (18.6% vs. 0%). For several subclones present both in the feeding and the control group we detected up to three additional phenotypic and genotypic resistances in the subclones from the zinc feeding group. Characterization of these subclones suggests an increase in antimicrobial resistance due to influences on plasmid uptake by zinc supplementation, questioning the reasonability of zinc feed additives as a result of the ban of antimicrobial growth promoters.

The effect of hospital size and surgical service on case cancellation in elective surgery: results from a prospective multicenter study.

BACKGROUND: Short-term case cancellation causes frustration for anesthesiologists, surgeons, and patients and leads to suboptimal use of operating room (OR) resources. In many facilities, >10% of all cases are cancelled on the day of surgery, thereby causing major problems for OR management and anesthesia departments. The effect of hospital type and service type on case cancellation rate is unclear. METHODS: In 25 hospitals of different types (university hospitals, large community hospitals, and mid- to small-size community hospitals) we studied all elective surgical cases of the following subspecialties over a period of 2 weeks: general surgery, trauma/orthopedics, urology, and gynecology. Case cancellation was defined as any patient who had been scheduled to be operated on the next day, but cancelled after the finalization of the OR plan on the day before surgery. A list of possible cancellation reasons was provided for standardized documentation. RESULTS: A total of 6009 anesthesia cases of 82 different anesthesia services were recorded during the study period. Services in university hospitals had cancellation rates 2.23 (95% confidence interval [CI] = 1.49 to 3.34) times higher than mid- to small-size community hospitals 12.4% (95% CI = 11.0% to 13.8%) versus 5.0% (95% CI = 4.0% to 6.2%). Of the surgical services, general surgical services had a significantly (1.78, 95% CI = 1.25 to 2.53) higher cancellation rate than did gynecology services—11.0% (95% CI = 9.7% to 12.5%) versus 6.6% (95% CI = 5.1% to 8.4%). CONCLUSIONS: When benchmarking cancellation rates among hospitals, comparisons should control for academic institutions having higher incidences of case cancellation than nonacademic hospitals and general surgery services having higher incidences than other services.

Reliability of fiber post bonding to root canal dentin after simulated clinical function in vitro

The aim of this study was to investigate the effect of thermomechanical loading (TML) on the bond strength of fiber posts luted with three different resin cements. Sixty-six extracted human anterior teeth were endodontically treated and restored with fiber posts (RelyX Fiber Posts, 3M ESPE) using three commercially available resin cements and three corresponding core build-up materials (n=22 each): Panavia F 2.0/Clearfil DC Core Automix (Kuraray), Variolink II/Multicore Flow (Ivoclar Vivadent), and RelyX Unicem/Filtek Z250 (3M ESPE). Twelve specimens of each group received all-ceramic crowns and were subjected to TML. The other 10 specimens were stored in saline solution for 24 hours. The roots were sectioned and bond strength was measured using a push-out test. Adhesive interfaces of two specimens of each group subjected to TML were analyzed using field emission scanning electron microscopy (FESEM). Bond strengths of fiber posts were significantly affected by the type of resin cement (p<0.0005) and TML (p<0.0005; two-way analysis of variance). TML significantly reduced bond strengths for all materials ((6.0 (6.2) MPa)) compared with initial bond strengths ((14.9 (10.4) MPa)). RelyX Unicem resulted in significantly higher bond strengths before ((18.3 (10.3) MPa)) and after TML ((9.8 (7.5) MPa)) compared with the other materials (p<0.0005; Tukey HSD). Using FESEM, Variolink II and Panavia F demonstrated a hybrid layer partly detached from the underlying resin cement, whereas no hybrid layer was observed for RelyX Unicem. The decrease in bond strength after TML suggests that retention of fiber posts may be reduced after clinical function. Therefore, endodontically treated teeth that are restored using fiber posts may benefit from additional reinforcement via coronal restorations using adequate ferrules and/or adhesive techniques.