Avascular bone necrosis of the femoral head after renal transplantation: Is it avoidable?

Background: Avascular osteonecrosis (AVN) is a seriousosseous complication after renal transplantation (RT). Itsprevalence clearly decreased from 20% to 4% possiblydue to the use of calcinurin inhibitors (CNI), reduction ofsteroid doses and use of steroid free regimens. The aimof our study was to evaluate the frequency of AVNamong our kidney transplant recipients and to determinethe risk factors for its occurrence.Patients and methods: Among 1785 kidney transplantrecipients who received renal allografts between March1976 and December 2005, 40 patients (2.24%) developedAVN with a mean age of 31.3 10.2 years. Eightykidney transplant recipients without AVN were selectedto be a matched control group. The localization of AVNwas the femoral head in all cases.Results: AVN was diagnosed at a mean of 20.4 monthsafter transplantation. The following risk factors werestatistically significant; sirolimus-based regimen,hypercholesterolemia, overweight with body mass index(BMI)>26 and those with HLA A9, HLA B35 and DRB15.Conclusions: We concluded that the proper managementof hypercholesterolemia, maintenance of ideal bodyweight as well as avoidance of sirolimus-basedimmunosuppressive regimen in genetically predisposedpatients may be an effective preventive strategy to avoidAVN

Nonlinear ABAQUS Simulations for Notched Concrete Beams

The numerical simulation of concrete fracture is difficult because of the brittle, inelastic-nonlinear nature of concrete. In this study, notched plain and reinforced concrete beams were investigated numerically to study their flexural response using different crack simulation techniques in ABAQUS. The flexural response was expressed by hardening and softening regime, flexural capacity, failure ductility, damage initiation and propagation, fracture energy, crack path, and crack mouth opening displacement. The employed techniques were the contour integral technique (CIT), the extended finite element method (XFEM), and the virtual crack closure technique (VCCT). A parametric study regarding the initial notch-to-depth ratio (ao/D), the shear span-to-depth ratio (S.S/D), and external post-tensioning (EPT) were investigated. It was found that both XFEM and VCCT produced better results, but XFEM had better flexural simulation. Contrarily, the CIT models failed to express the softening behavior and to capture the crack path. Furthermore, the flexural capacity was increased after reducing the (ao/D) and after decreasing the S.S/D. Additionally, using EPT increased the flexural capacity, showed the ductile flexural response, and reduced the flexural softening. Moreover, using reinforcement led to more ductile behavior, controlled damage propagation, and a dramatic increase in the flexural capacity. Furthermore, CIT showed reliable results for reinforced concrete beams, unlike plain concrete beams

Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene

Candida albicans is a common human fungal pathogen that causes disease ranging from superficial to lethal infections. C. albicans grows as budding yeast which can transform into hyphae in response to various environmental or biological stimuli. Although both forms have been associated with virulence, the hyphae form is responsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selectively inhibit C. albicans hyphae formation without affecting human cells to afford sufficient safety. The newly designed 5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one derivatives, named SR, showed very specific and effective inhibition activity against C. albicans hyphae formation. SR compounds caused hyphae inhibition activity at concentrations 10-40 fold lower than the concentration required to inhibit Candida yeast and bacterial growths. The anti-hyphae inhibition activities of SR compounds were via activation of the hyphae transcription repressor gene, TUP1. Correlation studies between the expression of TUP1 gene and the activity of SR compounds confirmed that the anti-C. albicans activities of SR compounds were via inhibition of hyphae formation. The newly designed SR compounds showed 10-40% haemolytic activity on human erythrocytes when compared to 100% haemolysis by 0.1% triton employed as positive control. Furthermore, theoretical prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of SR compounds confirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity and significant activity of the newly-designed SR compounds, a future optimization of pharmaceutical formulation may develop a promising inhibitor of hyphal formation not only for C. albicans but also for other TUP1- dependent dimorphic fungal infections

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4′-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand–protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1–5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies

Sirolimus based therapy in live-donor renal transplantation: A prospective randomized study

Background/Aim: Calcineurin inhibitor nephrotoxicity has been one of the major clinical problems in clinical practice after renal transplantation. This study was conducted assuming that the advent of novel, potent and non-nephrotoxic immunosuppressant, sirolimus may counterbalance the calcineurin inhibitor dose reduction or avoidance to guard against nephrotoxicity. Methods: Between May 2001 and June 2002, 80 live donor renal allotransplant recipients were subjected to a prospective, randomized controlled trial where they were divided into two equal demographically matched groups to receive either low dose tacrolimus (0.03 mg/kg/day) {Group A} or mycophenolate mofetil (MMF 2 gm/day) { Group B} in combination with sirolimus (5 and 10 mg/day in group A and B respectively). All patients received steroids, according to local protocol, and basiliximab induction therapy. One year follow up for all patients was carried out including histological evaluation of renal allograft tissue at the end of first year. Results: One-year patient and graft survival rates were not significantly different between group A (97.5%, 94.6%) and group B (100%, 97.4%) respectively. However, group B patients experienced lower incidence of biopsy proven acute rejection, albeit statistically insignificant, being 10% in group B and 25% in group A. Moreover, group B patients demonstrated better renal allograft function as measured by serum creatinine at all studied time points. In addition, 1-year protocol biopsies showed significant lower incidence of tubular atrophy and interstitial fibrosis among group B patients. Conclusion: The present study demonstrates that excellent one year kidney transplant outcome can be achieved by sirolimus administration, especially with avoidance of calcineurin inhibitors

A little tsunami at Ras El-Bar, Nile Delta, Egypt; consequent to the 2023 Kahramanmaraş Turkey earthquakes

From the 6th to 7th of February 2023, a storm surge struck Ras El-Bar, Nile Delta coast and attacked the resort facilities, with a wave height and velocity in deep water of 7.2 m and 12.7 m/sec respectively. The wind speed was 12.84 m/s, blowing from the NW and the WSW quadrants. This was an unwitnessed event revealed from the study of similar time interval from 1998 to 2022. Synchronizing with this event on the 6th of February 2023, was Kahramanmaraş Turkey Earthquakes. Consequently, the shoreline receded for about −30 m and with a drop in sea-level of about −40 cm. Furthermore, considerable changes in the beach morphology from a dissipative to a cuspate-related, intermediate tidal flat transverse bar with a rip profile. These are either related to the change in the morphodynamic or sedimentary budget, and resulting due to seawater scouring of bottom sediments for more than −30 cm. Two days preceding the Earthquakes an isostatic rise in sea-level (+20 cm) at the Turkish coast compared to the Mediterranean records, which is interpreted due to regional underwater seismic activities. The drop in the sea-surface height does not happen due to seawater outflow to the Atlantic Ocean. However, the sea-level regained its normal position because of the refill occurring from the Atlantic Ocean to the Mediterranean Sea. The pumice pieces, organic peat, and starfish distributed at Ras El-Bar coast, and thrown from the Northern Mediterranean indicate that the Egyptian coast was subjected to a little tsunami with average height of 14 cm. It is minimized due to enforced wave shifting from high pressure over Egypt to the low-pressure sinks