Shaul Beyth

Inhibition of NF‐κB cellular function via specific targeting of the IκB‐ubiquitin ligase

Activation of the transcription factor NF‐κB is a paradigm for signal transduction through the ubiquitin–proteasome pathway: ubiquitin‐dependent degradation of the transcriptional inhibitor IκB in response to cell stimulation. A major issue in this context is the nature of the recognition signal and the targeting enzyme involved in the proteolytic process. Here we show that following a stimulus‐dependent phosphorylation, and while associated with NF‐κB, IκB is targeted by a specific ubiquitin‐ligase via direct recognition of the signal‐dependent phosphorylation site; phosphopeptides corresponding to this site specifically inhibit ubiquitin conjugation of IκB and its subsequent degradation. The ligase recognition signal is functionally conserved between IκBα and IκBβ, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF‐κB activation in response to TNFα and the consequent expression of E‐selectin, an NF‐κB‐dependent cell‐adhesion molecule. Inhibition of NF‐κB function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.

Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study.

Distal tibial fractures tend towards delayed- or nonunion. The purpose of this study was to evaluate the safety and efficacy of early minimally invasive intervention (MII) in the treatment of these fractures. A total 24 consecutive patients who underwent operative treatment for distal tibial fractures were randomized into a control and an intervention group. MII entailed aspirating iliac crest bone marrow and peripheral blood, yielding mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) respectively, that were mixed with demineralized bone matrix (DBM) and injected under fluoroscopic control into the fracture site. No complications occurred in either group. The median time to union was 1.5 months in the MII group and 3 months in the control group. MII was found to be a safe and efficient procedure.

Phage therapy against Enterococcus faecalis in dental root canals

Antibiotic resistance is an ever-growing problem faced by all major sectors of health care, including dentistry. Recurrent infections related to multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant enterococci (VRE) in hospitals are untreatable and question the effectiveness of notable drugs. Two major reasons for these recurrent infections are acquired antibiotic resistance genes and biofilm formation. None of the traditionally known effective techniques have been able to efficiently resolve these issues. Hence, development of a highly effective antibacterial practice has become inevitable. One example of a hard-to-eradicate pathogen in dentistry is Enterococcus faecalis, which is one of the most common threats observed in recurrent root canal treatment failures, of which the most problematic to treat are its biofilm-forming VRE strains. An effective response against such infections could be the use of bacteriophages (phages). Phage therapy was found to be highly effective against biofilm and multidrug-resistant bacteria and has other advantages like ease of isolation and possibilities for genetic manipulations. The potential of phage therapy in dentistry, in particular against E. faecalis biofilms in root canals, is almost unexplored. Here we review the efforts to develop phage therapy against biofilms. We also focus on the phages isolated against E. faecalis and discuss the possibility of using phages against E. faecalis biofilm in root canals.

Antibacterial activity of bone cement containing quaternary ammonium polyethyleneimine nanoparticles

Sir, A bone cement mantle is commonly used in orthopaedic surgery, and creates an ideal environment for bacterial growth. Bacterial infection following joint replacement surgery is a catastrophic complication. It is estimated that infections occur in up to about 2% of primary hip and knee replacements, whereas revision surgery carries a 2–3-fold higher risk. The most common bacteria isolated from infected joints are Grampositive cocci (Staphylococcus epidermidis, Staphylococcus aureus and Streptococcus spp.) followed by Gram-negative bacteria and, less frequently, mixed and fungal infections. Addition of antibiotics to the cement has been advocated, especially in revision surgery. However, several studies describe the decreasing potency of common antibiotics in treating the infecting organisms and a parallel rise in the prevalence of resistant strains. As the implant itself lacks a blood supply, it is inherently susceptible to colonization by bacteria, which are less likely to be eradicated than in viable tissue. Therefore, efforts are focused on prevention of implant colonization. However, attempts to protect the implants using an antibiotic coating as well as the addition of antibiotics to the cement in the cemented implant have not proved successful. A novel strategy involves the use of antibacterial molecules that are bound to the implant or to the surrounding cement and are not released but remain functional for long periods of time. Quaternary amine residues proved to have excellent antibacterial properties. – 7 The purpose of this study was to modify a commonly used bone cement to obtain a safe and long-lasting antibacterial effect using quaternary ammonium polyethyleneimine (QPEI) nanoparticles. QPEI nanoparticles were synthesized as previously described. The tested materials were prepared by adding the synthesized powder to clinically available bone cement [SimplexTM P Bone Cement: 75% methyl methacrylate–styrene copolymer, 15% polymethylmethacrylate (PMMA) plus 10% barium; Stryker, Kalamazoo, MI, USA]. QPEI nanoparticles were added at 0%, 1%, 2% or 3% (w/w) to the bone cement and homogeneously mixed according to the manufacturer’s instructions. An antimicrobial effect against S. aureus ATCC 8325-4 and Enterococcus faecalis (a clinical isolate from the Maurice and Gabriela Goldschleger School of Dental Medicine at Tel Aviv University, Israel) was tested using the direct contact test (DCT) and agar diffusion test (ADT). Biocompatibility was tested on human primary polymorphonuclear cells as previously described. Cell viability was measured using the XTT assay (Biological Industries) and levels of tumour necrosis factor-a (TNF-a) in the supernatant were measured using an ELISA kit (Biolegend, San Diego, CA, USA). Additionally, physical properties of the cements were evaluated. Testing was performed using a Controlled Teststore 25 Tons MTS Device (Minneapolis, MN, USA) and results were analysed using MPT software (Multi-Purpose Testware 793.10, MTS System Corporation, Eden Prairie, MN, USA). Strain (1) and Young’s modulus (E) were calculated for each specimen. A strong antibacterial effect after an ageing period of 4 weeks was evident (P,0.05) in all the bone cement samples in which the QPEI nanoparticles were incorporated compared with bone cement samples with no additives, which showed no antibacterial effect. The DCT showed significant antibacterial activity against both bacteria for at least 4 weeks (Figure 1); the ADT revealed no inhibition halo in the agar plates for both tested bacteria, indicating that the nanoparticles are retained in the PMMA and do not diffuse into the agar. Moreover, QPEI nanoparticles did not change the biocompatibility properties of PMMA. Addition of the nanoparticles at all tested percentages didnot result inasignificant change in cell viability compared with that of the bone cement group; incorporation of 0%, 1%, 2% and 3% QPEI Research letters

Myositis ossificans circumscripta of the sacrotuberous ligament: a case report and review of the literature.

Soft tissue ossification is a well-known phenomenon in various pathologic conditions. Myositis ossificans circumscripta refers to posttraumatic calcification of soft tissue, including various ligaments. However, posttraumatic calcification of ligaments in the pelvis is a rare complication described only anecdotally in the past. We present a rare case of posttraumatic calcification of the sacrotuberous ligament in a patient, several months after suffering a pelvic trauma. This is one of the differential diagnoses of soft tissue pain and tenderness after trauma.

Evidence for the Adverse Effect of Starvation on Bone Quality: A Review of the Literature

Malnutrition and starvations possible adverse impacts on bone health and bone quality first came into the spotlight after the horrors of the Holocaust and the ghettos of World War II. Famine and food restrictions led to a mean caloric intake of 200–800 calories a day in the ghettos and concentration camps, resulting in catabolysis and starvation of the inhabitants and prisoners. Severely increased risks of fracture, poor bone mineral density, and decreased cortical strength were noted in several case series and descriptive reports addressing the medical issues of these individuals. A severe effect of severely diminished food intake and frequently concomitant calcium- and Vitamin D deficiencies was subsequently proven in both animal models and the most common cause of starvation in developed countries is anorexia nervosa. This review attempts to summarize the literature available on the impact of the metabolic response to Starvation on overall bone health and bone quality.

Biceps Tenotomy Does not Affect the Functional Outcomes of Patients Treated with Spacer Implantation Due to Massive Irreparable Rotator Cuff Tears

Background: Lesions of the long head of the biceps (LHB) tendon are frequently associated with massive rotator cuff tears (RCT) and may be responsible for shoulder pain and disability. Objective: This study aimed to evaluate functional outcomes of arthroscopic biodegradable spacer implantation with or without biceps tenotomy as treatment for persistent shoulder dysfunction and pain due to a massive irreparable RCT. Methods: A total of 48 patients were implanted with the subacromial spacer using arthroscopic approach with or without biceps tenotomy. All patients were assessed for up to 12 months post-implantation and 18 patients were assessed for at least 24 months (and a maximum of 40 months). Improvement in shoulder function was assessed using Constant score. Results: Subacromial spacer implantation was performed arthroscopically in 48 patients. The mean total Constant score increased from 36 at baseline to 67 points at 12 months post implantation. Patients who underwent LHB tenotomy in addition to the subacromial spacer presented similar improvement of their shoulder function and score compared to the group that was treated with the spacer alone. Conclusion: Current study demonstrates that spacer implantation in this patient population provides significant improvement in function and decreases the pain. Additional LHB tenotomy did not influence the postoperative results during the follow-up.

Phage Therapy: A New Horizon in the Antibacterial Treatment of Oral Pathogens

Dental diseases are perhaps the most prevalent infection-related diseases in humans. Biofilm is involved in almost every infectious disease compromising oral health, notably caries, periodontal disease, gingivitis, endodontic infections and peri-implantitis. Current therapies of biofilm-derived oral infections lack sensitivity; they are not species-specific and kill pathogenic species as well as commensal species, which are protective against the formation of pathogenic biofilms. Moreover, antibiotics have a limited effect on biofilm and are almost unused in oral diseases. A promising alternative approach is bacteriophage (phage) therapy. Phages play a key role in the natural balance in a predator-prey relationship with bacteria and thus have the potential to be efficient anti-bacterial agents. Phages are highly efficient against biofilm, strain specific and easy to isolate and manipulate. Thus, like in many other medicinal fields, phage therapy offers new horizons to dentistry, both therapeutics and research. The present review presents the etiology of common oral diseases, characterization of the infection and the treatment challenges of phage therapy in dentistry. Recent findings and development in the use of phages for prevention, control, and treatment of oral infections as well as possibilities of engineering the oral microbiome are discussed.

Use of three-dimensional fluoroscopy to determine intra-articular screw penetration in proximal humeral fracture model

BACKGROUND Proximal humeral locking plates have significantly improved the treatment of proximal humeral fractures in recent years; however, they are not devoid of complications. Inadvertent screw penetration into the joint is a well-documented complication. Intraoperative 3-dimensional (3D) imaging may assist in detecting intra-articular implant penetration. This study compared the performance of a standard C-arm fluoroscope with a novel 3D imaging fluoroscope in detecting penetrating implants in a proximal humeral fracture model. METHODS Zinc-sprayed proximal humerus sawbones were affixed with a proximal humeral locking plate. Six different constructs were assembled. In each specimen, 1 screw, 2 screws, or no screws were inserted 2-mm proud of the articular surface. Each specimen was imaged with a conventional fluoroscope and a 3D imaging fluoroscope. Overall, 36 image sets were prepared for each modality. These were evaluated by 2 fellowship-trained surgeons for intraobserver and interobserver reliability as well for the accuracy of detecting prominent implants in the 2 imaging methods. RESULTS Overall accuracy for observer A was 89.9% compared with 100% for C-arm fluoroscopy and 3D imaging fluoroscopy (P < .01) and for observer B was 91.1% and 100% (P = .01), respectively. The κ values were 0.74 with C-arm fluoroscopy and 1.0 for the 3D imaging fluoroscopy for observer A, and 0.93 and 1.0, respectively, for observer B. CONCLUSIONS In a proximal humeral fracture model, C-arm fluoroscopy is a highly accurate imaging modality that can minimize the incidence of penetrating screws into the joint. Further clinical studies are required to establish this modality.

Surface-modified nanoparticles as anti-biofilm filler for dental polymers

The objective of the study was to synthesis silica nanoparticles modified with (i) a tertiary amine bearing two t-cinnamaldehyde substituents or (ii) dimethyl-octyl ammonium, alongside the well-studied quaternary ammonium polyethyleneimine nanoparticles. These were to be evaluated for their chemical and mechanical properties, as well for antibacterial and antibiofilm activity. Samples were incorporated in commercial dental resin material and the degree of monomer conversion, mechanical strength, and water contact angle were tested to characterize the effect of the nanoparticles on resin material. Antibacterial activity was evaluated with the direct contact test and the biofilm inhibition test against Streptococcus mutans. Addition of cinnamaldehyde-modified particles preserved the degree of conversion and compressive strength of the base material and increased surface hydrophobicity. Quaternary ammonium functional groups led to a decrease in the degree of conversion and to low compressive strength, without altering the hydrophilic nature of the base material. In the direct contact test and the anti-biofilm test, the polyethyleneimine particles exhibited the strongest antibacterial effect. The cinnamaldehyde-modified particles displayed antibiofilm activity, silica particles with quaternary ammonium were ineffective. Immobilization of t-cinnamaldehyde onto a solid surface via amine linkers provided a better alternative to the well-known quaternary ammonium bactericides.