Collapsin response‐mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition

The collapsin response‐mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down‐regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth‐promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule‐associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non‐phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non‐phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase‐3β (GSK‐3β), which can phosphorylate the wildtype protein but not the non‐phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin‐binding property of CRMP5. Therefore, CRMP5‐induced growth inhibition is dependent on T516 phosphorylation through the GSK‐3β pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth.     

Preoperative Prediction of Failure Following Two-Stage Revision for Knee Prosthetic Joint Infections

While two-stage revision is the gold standard for treatment of knee prosthetic joint infection (PJI), it is not without risk. The purpose of this study was to develop a tool to preoperatively predict the probability that a two-stage revision would fail to eradicate knee PJI. 3,809 surgical cases were retrospectively reviewed and data were collected from 314 charts. Overall, 105 (33.4%) cases failed to eradicate PJI using this procedure. Univariate analysis identified multiple variables independently associated with reinfection. Logistic regression was used to generate a model (bootstrap-corrected concordance index of 0.773) predicting failure of infection eradication. Preoperative knowledge of a high probability of failure may improve risk assessment, lead to more aggressive management, and allow for time to consider alternative therapies.     

Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors

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Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis

Objective

To study the role of VDR polymorphisms as risk factor for RA and osteoporosis, and whether osteoporosis complicating RA is due to RA or VDR polymorphisms.

Methods

VDR gene polymorphisms ApaI, TaqI, BsmI and FokI were typed by RFLP for 128 RA patients, 30 postmenopausal osteoporotic females and 150 healthy controls.

Results

Significant differences were found between patients and healthy controls in the frequency of BsmI and TaqI (Pc < 0.05) but no significant associations were found for FokI and ApaI polymorphisms except for aa genotype (Pc < 0.001). Titers of RF were higher with aa and bb genotypes. Anti-CCP and CRP levels were higher with aa genotype and more bone loss was associated with Bb genotype. Ff genotype frequency was higher in RA patients with osteoporosis than those without osteoporosis.

Conclusions

The ApaI, BsmI and TaqI polymorphisms may be a susceptibility risk factors for RA and the Ff genotype may be responsible for development of osteoporosis in RA Egyptian patients. However, the present study needs to be replicated in a large number of patients from allover the Egypt and also in multi-ethnic populations.     

Misoprostol decreases oxidative stress and liver injury in bacterial lipopolysaccharide-induced endotoxemia in mice

The effect of misoprostol, a synthetic prostaglandin E1 analog, on the development of oxidative stress induced in mice with lipopolysaccharide (LPS) endotoxin was investigated. Misoprostol was administered by intraperitoneal route (i.p.) at doses of 10, 100, or 1,000 μg/kg at the time of LPS injection (200 μg/kg, i.p.). Mice were euthanized 4 h later. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH), nitric oxide (nitrite/nitrate) levels as well as paraoxonase activity were measured in brain and liver. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as DNA fragmentation were determined in the liver. The administration of LPS increased oxidative stress both in the brain and liver tissue. There were significantly increased MDA and nitrite and decreased GSH and PON1 activity in the brain and liver, respectively. In addition, LPS was associated with markedly elevated plasma ALT and AST level as well as increased liver DNA fragmentation. The administration of misoprostol at 100 or 1,000 μg/kg decreased brain MDA by 17.6 and 30 %, increased GSH by 29.8 and 33.3 %, and decreased nitric oxide by 21.74 and 42.5 %, respectively, compared with the lipopolysaccharide control group. Liver MDA decreased by 27 %, GSH increased by 47.7 %, and nitric oxide decreased by 37.2 % with misoprostol at 1,000 μg/kg. Paraoxonase activity increased in both the brain and liver by misoprostol administration. The increase in liver AST and ALT and DNA fragmentation after endotoxin administration was normalized by misoprostol. These results indicate that misoprostol can alleviate oxidative stress in the presence of a mild systemic inflammatory illness, indicating a new and potentially important therapeutic application for the drug.     

Effects of surface treatment and artificial aging on the shear bond strength of orthodontic brackets bonded to four different provisional restorations

Objective:To evaluate the combined effects of material type, surface treatment, and thermocycling on the bond strength of orthodontic brackets to materials used for the fabrication of provisional crowns.Materials and Methods:Four materials were included in this study (ProTemp, Trim Plus, Trim II, and Superpont C+B). Sixty cylindrical specimens (1 × 3 cm) were prepared from each material and equally divided into three groups. The first group was ground with silica carbide paper, the second was polished with pumice, and the last group was sandblasted with 50-µm aluminum oxide particles. Stainless-steel maxillary central incisor brackets (Victory Series, 3M) were bonded to the provisional material specimens with Transbond XT light-cured composite resin, and half of the specimens from each group were thermocycled 500 times in 5°C and 55°C water baths. Then the brackets were debonded with shear testing, and the results were statistically analyzed by three-way analysis of variance and Tukey''s multiple-comparison tests at α  =  0.05. Adhesive Remnant Index (ARI) was also identified.Results:Before and after thermocycling, ProTemp materials showed the highest shear bond strength with orthodontic brackets (10.3 and 13.1 MPa, respectively). The statistical analysis indicated an interaction among the three independent variables (P < .05) and statistically significant differences in bond strength among provisional materials (P < .001), surface treatments (P < .001), and thermocycling (P < .05). According to the ARI, most groups demonstrated adhesive failure.Conclusions:The provisional material type, surface treatment, and artificial aging have a significant effect on bond strength. Sandblasting treatment exerts a beneficial effect on shear bond strength.     

The effects of micro-implant assisted rapid palatal expansion (MARPE) on the nasomaxillary complex—a finite element method (FEM) analysis

Background

Orthodontic palatal expansion appliances have been widely used with satisfactory and, most often, predictable clinical results. Recently, clinicians have successfully utilized micro-implants with palatal expander designs to work as anchors to the palate to achieve more efficient skeletal expansion and to decrease undesired dental effects. The purpose of the study was to use finite element method (FEM) to determine the stress distribution and displacement within the craniofacial complex when simulated conventional and micro-implant-assisted rapid palatal expansion (MARPE) expansion forces are applied to the maxilla. The simulated stress distribution produced within the palate and maxillary buttresses in addition to the displacement and rotation of the maxilla could then be analyzed to determine if micro-implants aid in skeletal expansion.

Methods

A three-dimensional (3D) mesh model of the cranium with associated maxillary sutures was developed using computed tomography (CT) images and Mimics modeling software. To compare transverse expansion stresses in rapid palatal expansion (RPE) and MARPE, expansion forces were distributed to differing points on the maxilla and evaluated with ANSYS simulation software.

Results

The stresses distributed from forces applied to the maxillary teeth are distributed mainly along the trajectories of the three maxillary buttresses. In comparison, the MARPE showed tension and compression directed to the palate, while showing less rotation, and tipping of the maxillary complex. In addition, the conventional hyrax displayed a rotation of the maxilla around the teeth as opposed to the midpalatal suture of the MARPE. This data suggests that the MARPE causes the maxilla to bend laterally, while preventing unwanted rotation of the complex.

Conclusions

In conclusion, the MARPE may be beneficial for hyperdivergent patients, or those that have already experienced closure of the midpalatal suture, who require palatal expansion and would worsen from buccal tipping of the teeth or maxillary complex.     

Epidemiology,etiology, and outcomes of in-hospital cardiac arrest in Lebanon

BACKGROUNDIn-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality. As data is scarce in the Middle East and Lebanon, we devised this study to shed some light on it to better inform both hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.METHODSWe analyzed retrospective data from 680 IHCA events at the American University of Beirut Medical Center between July 1, 2016 and May 2, 2019. Sociodemographic variables included age and sex, in addition to the comorbidities listed in the Charlson comorbidity index. IHCA event variables were day, event location, time from activation to arrival, initial cardiac rhythm, and the total number of IHCA events. We also looked at the months and years. We considered the return of spontaneous circulation (ROSC) and survival to discharge (StD) to be our outcomes of interest.RESULTSThe incidence of IHCA was 6.58 per 1,000 hospital admissions (95% CI: 6.09−7.08). Non-shockable rhythms were 90.7% of IHCAs. Most IHCA cases occurred in the closed units (87.9%) (intensive care unit, respiratory care unit, neurology care unit, and cardiology care unit) and on weekdays (76.5%). ROSC followed more than half the IHCA events (56%). However, only 5.4% of IHCA events achieved StD. Both ROSC and StD were higher in cases with a shockable rhythm. Survival outcomes were not significantly different between day, evening, and nightshifts. ROSC was not significantly different between weekdays and weekends; however, StD was higher in events that happened during weekdays than weekends (6.7%vs. 1.9%, P = 0.002). CONCLUSIONSThe incidence of IHCA was high, and its outcomes were lower compared to other developed countries. Survival outcomes were better for patients who had a shockable rhythm and were similar between the time of day and days of the week. These findings may help inform hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.

In-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality.^[1] Based on the American Heart Association’s Get With The Guidelines-Resuscitation (GWTG-R) registry data from 2003 to 2007, the approximated incidence of IHCAs in the United States was 211,000 annually or roughly 6 to 7 cardiac arrests per 1,000 hospital admissions.^[2,3] Data from 2008 to 2017 showed the incidence of IHCA increased to 292,000 annually or 9 to 10 IHCAs per 1,000 hospital admissions.^[1,4] In contrast, data from the United Kingdom National Cardiac Arrest Audit showed an incidence of 1.6 IHCAs per 1,000 hospital admissions in the United Kingdom from 2011 to 2013.^[1] Despite progress in resuscitation technology and care, survival outcomes following IHCA remain low at 15%−25% and vary radically between 0% and 42% worldwide.^[5,6] Sandroni, et al.^[5] showed that various patient and healthcare-related factors are associated with the survival outcomes of IHCA. The main patient-related factors are age, sex, initial cardiac rhythm, underlying medical condition, comorbidities, and the time of the IHCA event. In contrast, major healthcare-related factors are the protocols for IHCA care, duration and method of resuscitation, skills of healthcare professionals, time from code activation and the arrival of the code response team, and the location of the IHCA event.^[5,7] The study by Chen, et al.^[8] suggests that improving the quality of resuscitation care and minimizing other healthcare-related risk factors can markedly increase survival outcomes from IHCAs.^[6,9]Consistent and updated estimates of the magnitude and outcomes of IHCA are fundamental for monitoring and improving the delivery and quality of IHCA care in any healthcare setting. In Lebanon, studies have shown low survival rates (5.5%) from out-of-hospital cardiac arrest.^[10]The reported incidence of IHCA in the United Arab Emirates was 11.7 per 1,000 hospital admissions,^[6] and in Saudi Arabia was 7.76 per 1,000 hospital admissions.^[11] The reported survival to hospital discharge in the United States was only 10.4%,^[12] and it was only 7.9% in the United Kingdom.^[13] However, unlike European countries and the United States, the epidemiology of IHCA is unknown in Lebanon, suggesting the need for research in this area. Therefore, this study aimed to produce the first estimates of the incidence, characteristics, and outcomes of IHCA at a tertiary-care hospital in Lebanon.