Microparticles as novel biomarkers/effectors in severe sepsis

Microparticles (MP) are submicron structures produced by all cells upon activation or apoptosis that act as a non-soluble means of communication between cells. They ferry proteins, bioactive lipids, RNA and receptors, as well as ridding cells of redundant organelles and toxins. They have been recently investigated for their pathophysiological role and as potential biomarkers/effectors in many diseases. In severe sepsis, studies of MP so far have produced inconsistent and even conflicting results. In this project, it was demonstrated that cell derived MP subsets vary according to the cause of severe sepsis (community acquired pneumonia (CAP) or faecal peritonitis (FP)), where CAP patients had higher levels of circulating MP. Surprisingly, FP patients MP levels were comparable to healthy volunteers. Further stratification of MP subsets according to their expression of the protein alpha-2-macroglobulin (A2M) has yielded better differentiation between the two diseases. The A2M expressing MP were significantly higher in survivors of community acquired pneumonia sepsis, but there was no similar association in patient with FP. Granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon γ (IFN- γ) are being studied as possible adjuvant therapies in sepsis. They seem to reverse the immune-paresis that ensues after the initial insult. MP produced from whole blood stimulated with GM-CSF and IFN- γ were studied in this project. Both GM-CSF and IFN- γ increased MP expressing A2M over control. These MP elicited a pro-inflammatory phenotype when incubated with neutrophils or endothelial cells which may contribute to the potential benefits of GM-CSF and IFN- γ in severe sepsis.HCA internationa

Impact of Total Salpingectomy Versus Tubal Conservation During Abdominal Hysterectomy on Ovarian Function

Background: Hysterectomy is one of the most common surgeries in women worldwide. It is applied for the treatment of various problems, such as pelvic pain, menstrual problems, tumors, and other related diseases. Objective: The aim of this work was to preservation of ovarian function as long as possible to decrease manifestation of menopause in hysterectomized patients. Patients and Methods: The study was case control study included 58 patients attendant in outpatient clinic of Obstetrics and Gynecology department, Zagazig University Hospital, and Banha Teaching Hospital during the period from April 2017 to October 2018. All patients were scheduled to total abdominal hysterectomy without oophorectomy due to benign uterine disease. Patients was classified into two groups randomly: Group 1: included odd number of patients 29 was subjected to total abdominal hysterectomy with bilateral complete excision of the tubes. Group II: included an even numbers of patients (n =29) for whom the classical approach of hysterectomy was performed. Results: There was no significant difference between groups regarding Operation, time Hospital stay and Bleeding. Also regarding number of antral follicle post operatively. While these are significant differences between Ovary size distributions between studied groups at different times. Conclusions: It could be concluded that salpingostomy with abdominal hysterectomy is a safe and convenient treatment that does not have a deleterious effect on ovarian reserve

Restoration methods for biomedical images in confocal microscopy

Diese Arbeit stellt neue Loesungen zum Problem Bildrestauration im biomedizinischen Bereich vor. Das Konfokal-Mikroskop ist eine verhaeltnismaessig neue Bildungstechnik, die als Standardwerkzeug in biomedizinischen Studien eingesetzt wird. Diese Technik dient zum Sammeln einer Reihe von 2D Bildern der einzelnen Abschnitte innerhalb eines Probestuecks, um eine 3D Darstellung des Gegenstandes zu erzeugen. Trotz seiner verbesserten Belichtungseigenschaften unterliegen die beobachteten Bilder Stoerungen augrund der begrenzten Groesse der Punktantwort (PSF) und das Poisson-Rauschens. Bildrestaurationstechniken versuchen diese Stoerungen herauszurechnen und das Originalbild zu rekonstruieren. Diese Doktorarbeit beginnt mit der Beschreibung des Konfokal-Mikroskops und den Quellen von Artefakten. Dann werden die vorhandenen Bildwiederherstellungsmethoden vorgestellt und verglichen. Die Arbeit ist in drei Teile gegliedert: Im ersten Teil wird eine neue begrenzte blinde Dekonvolutionsmethode eingefuehrt. Durch eine passende Re-Parametrisierung wird dabei a priori Wissen eingebaut. Fuer die PSF wird ein parametrisches Modell, mit einem begrenzten Satz von Basisunktionen benutzt, um Nicht-Negativitaet, zirkulaaere Symmetrie und Limitierung der Frequenzbandbreite sicher zu stellen. Fuer das Bild stellt die quadratische Re-Parametrisierung die Nicht-Negativitaet sicher. Die Entfaltungsmethode wird anhand von simulierten und realen Konfokal-Mikroskopie Daten ausgewertet. Der Vergleich mit einem nicht-parametrisierten Algorithmus zeigt, dass die vorgeschlagene Methode verbesserte Leistung und schnellere Konvergenz erreicht. Im zweiten Teil der Arbeit wird eine neue Methode eingefuehrt, die versucht die anisotrope tiefabhaengige Unschaerfe zu beheben. Wenn roehrenfoermige Gegenstaende -wie Neuronen- abgebildet werden, sind die aufgenommenen Bilder degradiert und die Extraktion der genauen Morphologie der Neuronen wird erschwert. Es wird eine neue Methode vorgeschlagen, mit der sich die PSF ohne irgendein Vorwissen ueber das Belichtungssystem aus dem augenommenen Bild schaetzen laesst. Diese Methode, die auf der Schaetzung des urspruenglichen Gegenstandes basiert ist fuer Faelle verwendbar, in denen der abgebildete Gegenstand eine bekannte Geometrie hat. Mit der vorgeschlagenen Dekonvolutionsmethode werden geometrische Verzerrungen beseitigt und die wiederhergestellten Bilder sind fuer weitere Analysen besser verwendbar. Im dritten Teil wird eine neue Methode zur adaptiven Regularisierung vorgeschlagen. Diese vorgeschlagene Technik passt ihr Verhalten abhaengig von den lokalen Intensitaetsgradient im Bild an. Die neue Technik wird getestet und mit der ''total variation'' und der Tikhonov Regularisierungtechnik verglichen. Die Experimente zeigen, dass mit dem adaptiven Verahren, die Qualitaet der rekonstruierten Bilder verbessert wird.This thesis introduces new solutions to the problem of image restoration in biomedical fields. The confocal microscope is a relatively new imaging technique that is emerging as a standard tool in biomedical studies. This technique is capable of collecting a series of 2D images of single sections inside a specimen to form a 3D image of the object. Despite of its improved imaging properties, the observed images are blurred due to the finite size of the the point spread function and corrupted by Poisson noise due to the counting nature of image detection. Image restoration techniques aim at reversing the degradation and recovering an estimate of the true image. This thesis starts with the description of the confocal microscope and the sources of degradation. Then, the existing image restoration methods are studied and compared. The work done in this thesis is divided into three parts: In the first part, a new constrained blind deconvolution method is introduced. Re-parameterization is used to strictly enforce prior knowledge. A parametric model based on a set of constrained basis functions is used for the PSF to ensure non-negativity, circular symmetry, and band-limitedness. For the image, quadratic re-parameterization ensures non-negativity. The deconvolution method is evaluated on both simulated and real confocal microscopy data sets. The comparison with non-parameteric algorithms shows that the proposed method exhibits improved performance and faster convergence. In the second part, a new method to correct the anisotropic, depth-variant blur is introduced. When objects of tubular-like structure, like neurons, are imaged, the acquired images are degraded and the extraction of accurate morphology of neurons is hampered. A new method to estimate the PSF from the acquired image, without any prior knowledge about the imaging system, is proposed. This method which is based on the estimation of the original object and is suitable for cases in which, the object being imaged has a known geometry. Using the proposed restoration method, geometric distortions are eliminated and the restored images are more suitable for further analysis. In the third part, a new method for adaptive regularization is proposed. The proposed technique adapts its behavior depending on the local activities in the image, as reflected in the magnitude of the intensity gradient. The new technique is tested and compared to both the total variation and the Tikhonov regularization techniques. Experiments show that, using the adaptive technique, the quality of the restored images is improved

Educational Innovation in the Sultanate of Oman and its Research Requirements: a research Map for the Department of Educational Foundations and Administration

This study intended to provide a research map that shows the most important research issues and educational challenges facing education in the Sultanate of Oman in the light of contemporary educational innovations. A descriptive research method was used. The procedures followed in the study included a review of educational research maps in the colleges of education, conducted a theoretical analysis of the relationship between global changes and their impact on the areas of educational innovation, identify areas of educational innovation in Oman, and Meta analysis of research conducted at the Department of Educational Foundations and Administration. Based on the analysis and interpretation of data collected from 120 research participants, consisting of 10 faculty members, 15 Master students, 20 experts from the Ministry of Education and Ministry of Higher Education, and 75 school principals representing different provinces, a research map, with its objectives, scopes, and mechanics of implementation, was developed

Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2

A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent

Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2

From MDPI via Jisc Publications RouterHistory: accepted 2020-11-21, pub-electronic 2020-11-26Publication status: PublishedA series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a−m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a−m in the presence of phosphorus oxychloride. New compounds 4a−m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52−0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent

Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents

Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion

Aims Ran GTPase is involved in nucleocytoplasmic shuttling of proteins and is overexpressed in several cancers. The expression of Ran in malignant melanoma (MM) and its functional activity have not been described and were investigated in this study.Methods The prognostic value of Ran expression was tested in a series of 185 primary cutaneous MM cases using immunohistochemistry. The functional activity of Ran was investigated in the two melanoma cell lines. Ran expression was knocked down using two siRNAs and the effect on the expression of the c-Met oncogene, a potential downstream target of Ran, was tested. Functional effects of Ran knockdown on cell motility and cell proliferation were also assessed.Results Positive Ran expression was seen in 12.4% of MM and was associated with advanced clinical stage and greater Breslow thickness. Positive expression was an independent marker of shorter overall survival (p=0.023). Knockdown of Ran results in decreased expression of c-Met and the downstream c-met signalling targets ERK1/2. There was a significant reduction in cell migration (p [less than] 0.001) and cell invasion (p [less than] 0.001). c-Met knockdown decreased the expression of Ran through MAPK and PI3K-AKT in A375 cell line, inhibited the cell viability and migration of both A375 and G361 melanoma cell lines while invasion was enhanced.Conclusion Ran is a poor prognostic marker in cutaneous MM. It upregulates expression of the oncogene c-Met and, possibly through this, it promotes cell motility which may in turn promote metastasis