Microarchitecture of medication-related osteonecrosis of the jaw (MRONJ); a retrospective micro-CT and morphometric analysis

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (AR) drugs such as bisphosphonates (BP) and denosumab (Dmab). Although several risk factors are described, the etiology of MRONJ is still not fully elucidated. Bone-strengthening is the primary aim of antiresorptive therapy; however, overly increased bone mass and microcrack accumulation are also discussed in MRONJ etiologies. The aim of this study is to evaluate the microarchitecture of jaw bones with micro?computed tomography (micro-CT) in AR-treated patients with or without MRONJ.Human jaw bone samples of AR-treated patients were separated into 11 groups by AR treatment bisphosphonate (BP), denosumab (Dmab), both (M) and control groups. Subgroups were divided according to the clinical localization as AR-exposed vital jaw bone (BP_exp, Dmab_exp, M_exp), osteonecrosis–margin of a sequestrum (BPO_mar, DmabO_mar, MO_mar) and osteonecrosis–sequestrum (BPO_seq, DmabO_seq, MO_seq). Healthy jaw bone (C_HB) and osteoporotic jaw bone (C_OP) represent control groups. Samples underwent retrospective micro-CT and morphometric analysis in representative units by bone volume fraction (BV/TV), bone surface density (BS/BV), trabecular thickness (Tr.Th.), trabecular number (Tr.N.), trabecular space (Tr.Sp.), Euler characteristic for bone connectivity, bone mineral density (BMD) and tissue mineral density (TMD).A total of 141 samples from 78 patients were analyzed. BV/TV of M_exp group (mean: 0.46 ± 0.27) was significantly higher than in the C_OP group (mean: 0.14 ± 0.05; p = 0.0053). Tr.Th. differed significantly between the BP_exp group (mean: 0.32 ± 0.15) and the M_exp group (mean: 0.57 ± 0.20; p = 0.0452) as well as between the BPO_seq group (mean: 0.25 ± 0.10) and the MO_seq group (mean: 0.39 ± 0.18; p = 0.0417). Signs of trabecular thickening and unorganized trabecular microarchitecture from AR-exposed- to sequestrum groups, were analyzed in 3D reconstructions. However, BS/BV, Tr.N., and Tr.Sp. showed no significant differences. Euler characteristic of the BPO_seq group (median: 7.46) doubled compared to that of the BP_exp group (median: 14.97; p = 0.0064). Mineralization parameters BMD and TMD were similar in all groups.Findings show evidence of enhanced bone mass and suspect microarchitecture in some AR-treated jaw bone compared to osteoporotic jaw bone. Despite increased bone mass, some MRONJ samples showed decreased trabecular connectivity by Euler characteristic compared to AR-treated jaw bone. These samples may indicate extensive ossification and ineffective bone mass with superficially higher bone mass without existing or even reduced mechanical stability, indicated by connectivity loss. This result might also suggest a high risk to microcrack accumulation. At some point, possibly some kind of over-ossification could lead to under-nourishment and microarchitectural weakness, creating instability, subsequently increasing vulnerability to MRONJ.     

Primary dural lymphoma: A novel concept of heterogeneous disease

Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well‐documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an additional case of spinal PDL that, similarly to our previous case, was grade 1–2 follicular B‐cell PDL. Our two cases were diagnosed over a 3‐year interval in a 72‐year‐old female and a 74‐year‐old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B‐cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B‐cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site‐specific lymphoma‐type predilection phenomenon, well‐recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification.     

Nonalcoholic fatty liver disease and cardiovascular concerns: The time for hepatologist and cardiologist close collaboration

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver cell damage worldwide. It is strongly associated with an increased risk of cardiovascular disease (CVD). There are not enough recommendations for screening subjects with nonalcoholic steatohepatitis cirrhosis, who are not candidates for liver transplantation, nor who are asymptomatic with NAFLD without cirrhosis. In the current comprehensive narrative review, we aimed to evaluate the associations between CVD and NAFLD. Distinguishing the mechanisms linking these two disorders offers the opportunity to develop targeted therapies. Moreover, we will discuss screening approaches (whom and how-to) and treatment modalities proposed to reduce cardiovascular risk in patients with NAFLD.     

International Association of Dental Traumatology guidelines for the management of traumatic dental injuries: 2. Avulsion of permanent teeth

Avulsion of permanent teeth is one of the most serious dental injuries. Prompt and correct emergency management is essential for attaining the best outcome after this injury. The International Association of Dental Traumatology (IADT) has developed these Guidelines as a consensus statement after a comprehensive review of the dental literature and working group discussions. It represents the current best evidence and practice based on that literature search and expert opinions. Experienced researchers and clinicians from various specialties and the general dentistry community were included in the working group. In cases where the published data did not appear conclusive, recommendations were based on consensus opinions or majority decisions of the working group. They were then reviewed and approved by the members of the IADT Board of Directors. The purpose of these Guidelines is to provide clinicians with the most widely accepted and scientifically plausible approaches for the immediate or urgent care of avulsed permanent teeth. The IADT does not, and cannot, guarantee favorable outcomes from adherence to the Guidelines. However, the IADT believes that their application can maximize the probability of favorable outcomes.     

International Association of Dental Traumatology guidelines for the management of traumatic dental injuries: General introduction

Traumatic dental injuries (TDIs) occur most frequently in children and young adults. Older adults also suffer TDIs but at significantly lower rates than individuals in the younger cohorts. Luxation injuries are the most common TDIs in the primary dentition, whereas crown fractures are more commonly reported for the permanent teeth. Proper diagnosis, treatment planning and follow up are very important to assure a favorable outcome. These updates of the International Association of Dental Traumatology's (IADT) Guidelines include a comprehensive review of the current dental literature using EMBASE, MEDLINE, PUBMED, Scopus, and Cochrane Databases for Systematic Reviews searches from 1996 to 2019 and a search of the journal Dental Traumatology from 2000 to 2019. The goal of these guidelines is to provide information for the immediate or urgent care of TDIs. It is understood that some follow‐up treatment may require secondary and tertiary interventions involving dental and medical specialists with experience in dental trauma. As with previous guidelines, the current working group included experienced investigators and clinicians from various dental specialties and general practice. The current revision represents the best evidence based on the available literature and expert opinions. In cases where the published data were not conclusive, recommendations were based on the consensus opinions of the working group. They were then reviewed and approved by the members of the IADT Board of Directors. It is understood that guidelines are to be applied using careful evaluation of the specific clinical circumstances, the clinician's judgment, and the patient's characteristics, including the probability of compliance, finances and a clear understanding of the immediate and long‐term outcomes of the various treatment options vs non‐treatment. The IADT does not, and cannot, guarantee favorable outcomes from adherence to the Guidelines. However, the IADT believes that their application can maximize the probability of favorable outcomes.     

Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing,docking and molecular dynamics simulation study

The outbreak of novel coronavirus, SARS-CoV-2, has infected more than 36 million people and caused approximately 1 million deaths around the globe as of 9 October 2020. The escalating outspread of the virus and rapid rise in the number of cases require the instantaneous development of effectual drugs and vaccines. Presently, there are no approved drugs or vaccine available to treat the infection. In such scenario, one of the propitious therapeutic approaches against viral infection is to explore enzyme inhibitors amidst natural compounds, utilizing computational approaches aiming to get products with negligible side effects. In the present study, the inhibitory prospects of ilimaquinone (marine sponge metabolite) were assessed in comparison with hydroxychloroquine, azithromycin, favipiravir, ivermectin and remdesivir at the active binding pockets of nine different vital SARS-CoV-2 target proteins (spike receptor binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like-protease), employing an in silico molecular interaction based approach. In addition, molecular dynamics (MD) simulations of the SARS-CoV-2 papain-like protease (PLpro)–ilimaquinone complex were also carried out to calculate various structural parameters including root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (R_g) and hydrogen bond interactions. PLpro is a promising drug target, due to its imperative role in viral replication and additional function of stripping ubiquitin and interferon-stimulated gene 15 (ISG15) from host-cell proteins. In light of the possible inhibition of all vital SARS-CoV-2 target proteins, our study has emphasized the importance to study in depth ilimaquinone actions in vivo.

Inhibitory potential of ilimaquinone (marine sponge metabolite) against nine essential SARS-CoV-2 target proteins, employing a molecular interaction and dynamics simulation approach.     

Design and formulation of polymeric nanosponge tablets with enhanced solubility for combination therapy

Three drugs namely caffeine, paracetamol, and aceclofenac are commonly used for treating various acute and chronic pain related ailments. These 3 drugs have varied solubility profiles, and formulating them into a single tablet did not have the desired dissolution profile for drug absorption. The objective of the present research was to tailor the drug release profile by altering drug solubility. This was achieved by loading the drug into nanosponges. Here, three-dimensional colloidal nanosponges were prepared using β-cyclodextrin with dimethyl carbonate as a cross-linker using the hot-melt compression method. The prepared nanosponges were characterized by FTIR, ¹H NMR spectroscopy, DSC, XRPD studies and SEM. The FTIR and DSC results obtained indicated polymer-drug compatibility. The ¹H NMR spectroscopy results obtained indicated the drug entrapment within nanosponges with the formation of the inclusion complex. XRPD studies showed that the loaded drug had changed crystalline properties altering drug solubility. SEM photographs revealed the porous and spongy texture on the surface of the nanosponge. Box–Behnken experimental design was adopted for the optimization of nanosponge synthesis. Among the synthesized nanosponges containing paracetamol, aceclofenac and caffeine, batch F3–P31, F3–A31 and F3–C31 were considered optimized. Their particle size was 185, 181 and 199 nm with an entrapment efficiency of 81.53, 84.96, and 89.28% respectively. These optimized nanosponges were directly compressed into tablets and were studied for both pre and post-compression properties including in vitro drug release. The prepared tablet showed desired drug dissolution properties compared to the pure drug. The above outcomes indicated the applicability of nanosponges in modulating the drug release with varied solubility for combination therapy.

Polymeric nanosponges as potential carriers for successful combination therapy of poorly soluble drugs (paracetamol, aceclofenac, caffeine).     

Instant and quantitative epoxidation of styrene under ambient conditions over a nickel(ii)dibenzotetramethyltetraaza[14]annulene complex immobilized on amino-functionalized SBA-15

Nickel(ii)dibenzotetramethyltetraaza[14]annulene complex (Nitmtaa) was synthetized and immobilized on post amino-functionalized SBA-15 (N-SBA-15) to obtain a stable and reusable nanocatalyst named as Nitmtaa@N-SBA-15. Here (3-aminopropyl)triethoxysilane (APTES) was first grafted on the surface SBA-15, then Nitmtaa was added and coordinated on the silica surface via APTES amine groups. The structure and morphology, and thermal stability of the prepared nanocatalyst was investigated using SEM, HR-TEM, BET, FT-IR, powder XRD, and TGA. HR-TEM and XRD results revealed a high dispersion of Nitmtaa on the SBA-15 surface. The catalytic activity of this nanocatalyst was evaluated in the epoxidation of styrene, under ambient conditions, using meta-chloroperoxybenzoic acid (m-CPBA) as the oxygen donor. This nanocatalyst showed an immediate and quantitative epoxidation of styrene with high turn-over-frequency ∼31.58 s⁻¹. Moreover, the superior catalytic activity and high stability of Nitmtaa@N-SBA-15 could be maintained after four successive cycles. A possible reaction mechanism is also proposed.

Immediate and quantitative epoxidation of styrene under ambient conditions catalyzed by new nanocatalyst obtained by immobilizing nickel(ii)dibenzotetramethyltetraaza[14]annulene in amino-functionalized SBA-15.