Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines

Burkitt''s lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin''s lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.     

Modified implant surfaces show different biofilm compositions under in vivo conditions

Objective: Plaque accumulation on implant surfaces can result in peri-implantitis with potential implant loss. The aim of the present study was to examine the influence of zirconium nitride (ZrN) as a potential implant surface on the biofilm composition and diversity in vivo .
Material and methods: ZrN- or titanium (Ti)-coated glass specimens and ZrN or roughened Ti discs were used as substrates. Pure glass and polished titanium served as controls. The specimens were mounted on removable intraoral splints in five adults. After 24 h of intraoral exposure, the biofilms were analyzed applying single-strand conformation polymorphism (SSCP analysis) of 16S rRNA genes. Sequence analysis of the dominant bands excised from the SSCP fingerprints allowed to taxonomically describe bacteria derived from biofilm samples.
Results: The highest number of bands was counted on pure glass and Ti 800. ZrN-coated glass and ZrN-coated titanium discs showed the lowest values for species richness. However, no significant differences were observed regarding the diversity of the identified bacterial species among all the surfaces examined. A total of 46 different bacteria were identified. The dominant bands within the fingerprints indicated bacteria belonging to the Streptococcus group as identified by their 16S rDNA sequence.
Conclusion: A coating of glass surfaces with ZrN significantly reduced the species richness in early bacterial colonization but the diversity was not significantly changed. In consideration of the results obtained by this and former studies a ZrN coating appears to rather modify the quantity of early bacterial adherence than the quality of the microbial community structure.     

A comprehensive approach to risk assessment and surveillance guiding public health interventions

Tools are required to identify 'multi-endemic' population segments – in order to benefit the most vulnerable people and to make public health interventions cost-effective. The article suggests a comprehensive risk assessment and surveillance system approach based on a combination of epidemiological, environmental and social determinants. Such a cross-disciplinary approach will combine the advantages of forecasting upcoming disease 'hot spots' with provision of evidence for long-term planning under more stable conditions, and it may in principle apply to any combination of public health problems depending on the local context.     

Epidemiology of periodontal diseases in the study of health in Pomerania

Aim: The aim of this study was to assess the prevalence and extent of periodontal diseases among adults in a province in Eastern Germany.
Material and Methods: The Study of Health in Pomerania is a population-based study conducted during 1997–2001. The net random sample comprised 4310 20–81-year-old subjects. Periodontal status was assessed at four surfaces using a half-mouth recording protocol.
Results: The prevalence of attachment loss 3 mm was 89.7%, with 62.8% of teeth being affected. Probing depths 4 mm were prevalent in 69.7% of subjects, and 29.6% of teeth were affected. 25.3% of all subjects had severe pockets (6 mm). Periodontitis was significantly more prevalent in males. For attachment loss, the prevalence and extent increased significantly with increasing age, whereas probing depth values levelled off after the age of 40. In older subjects, increased recession and attachment loss were found, while the probing depth remained constant. According to the recent CDC classification, 17.6% and 33.3% of persons had severe and moderate periodontitis, respectively. The prevalence of periodontitis increased significantly with age and remained constant after the age of 50–59.
Conclusions: Periodontitis is more prevalent in Pomerania than in the United States or Western Europe. In older subjects, attachment loss steadily increased, while the probing depth remained constant.     

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised,placebo-controlled,blinded trial

Objectives. We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. Methods. Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine cessation proportion, and benzodiazepine withdrawal symptoms. Results. In total, 86 patients (21–74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents; difference between means –2.29; 95% CI –5.78 to 1.21; P = 0.20). Benzodiazepine cessation proportion was 38.1% (16/42) in the melatonin group versus 47.7% (21/44) in the placebo group (OR 0.64; 95% CI 0.26 to 1.56; P = 0.32). Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms. Conclusions. Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction. In this context, prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation.     

Substitution Urethroplasty with Closure Versus Nonclosure of the Buccal Mucosa Graft Harvest Site: A Randomized Controlled Trial with a Detailed Analysis of Oral Pain and Morbidity

Background

Optimal surgical management of the buccal mucosa harvest site in patients with urethral stricture disease during buccal mucosa graft urethroplasty (BMGU) remains controversial.