Preservative-free versus preserved latanoprost eye drops for reducing intraocular pressure: a non-inferiority phase III randomized, multi-center, single-blind, parallel-group controlled trial

Background: The aim of this study was to test the non-inferiority of preservative-free (PF) latanoprost 50 μg/mL multi-dose ophthalmic solution versus the marketed benzalkonium chloride (BAK)-preserved latanoprost 50 μg/mL ophthalmic solution in patients with open-angle glaucoma and patients with ocular hypertension. Methods: This was a prospective, national, randomized, multi-center, observer-blind, parallel-group controlled clinical trial. Patients were randomized to receive either PF or BAK-preserved latanoprost once daily for 12 weeks. The primary endpoint was the change in intraocular pressure (IOP) at 8:00 AM in the affected eye between the end of the treatment (week 12) and the baseline (week 0). Secondary measurements were taken at weeks 2 and 6, with IOP being recorded at 8:00 AM, 12:00 PM, and 4:00 PM. Results: A total of 158 patients were included in the per protocol (PP) population (77 in the PF latanoprost treatment arm and 81 patients in the BAK-preserved latanoprost treatment arm). PF latanoprost was non-inferior to BAK-preserved latanoprost in reducing IOP at 8:00 AM in the study eye from the baseline (week 0) to the end of the treatment (week 12). The point estimate of the between-treatment difference was 0.1 mmHg (95% confidence interval: -0.646, 0.847). Mean between-group differences in IOP reduction from the baseline to each of the secondary measurements were also similar between the two treatment arms. The two treatments were well tolerated and had comparable adverse event profiles. Conclusions: PF latanoprost was non-inferior to BAK-preserved latanoprost in reducing IOP in patients with open-angle glaucoma or ocular hypertension. Both treatments were well tolerated

Non-inferiority evaluation of preservative-free latanoprost/timolol eye drops solution versus preserved latanoprost/timolol eye drops in patients with high intraocular pressure and open-angle glaucoma

Background: This study aimed to evaluate the non-inferiority and safety of a newly developed preservative-free (PF) multi-dose latanoprost/timolol ophthalmic solution, compared with the benzalkonium chloride (BAK)-preserved fixed combination, in patients with open-angle glaucoma and ocular hypertension.Methods: A Phase III randomized multi-center observer-blind parallel-group clinical trial was conducted. A total of 210 adult patients (aged over 18 years) were randomly treated with the PF- or the BAK-preserved latanoprost/timolol solution once daily in the affected eye(s) for 12 weeks. Follow-up visits were scheduled at weeks 2, 6, and 12; intraocular pressure (IOP) was recorded at 8:00 AM, 12:00 PM, and 4:00 PM. The primary efficacy endpoint to prove non-inferiority was the IOP change at 8:00 AM (± 1 hour) from the baseline to the end of treatment (week 12) in the studied eye. Safety parameters were also assessed.Results: In total, 196 patients completed the study. The pressure-lowering effect of the PF eye drops was comparable to that of the preserved formulation at all time points. Latanoprost/timolol PF formulation was non-inferior to the BAK-preserved solution as shown by the change in IOP from day 0 to week 12. The point estimate of the inter-treatment difference was 0.624 mmHg (95% CI: -0.094, 1.341). Both treatments were well-tolerated during the study, and they had similar adverse event profiles.Conclusions: PF-latanoprost/timolol combination was found to be non-inferior to the BAK-preserved formulation based on the efficacy at all times, with similar local tolerance

Расчет, проектирование и монтаж каркаса автостоянки открытого типа

Актуальность работы: в данной выпускной квалификационной работе выполняются расчет и проектирование каркаса автостоянки открытого типа. Целью работы является разработка технологии изготовления каркаса. Целью данного курсового проекта является изучение составных частей изделия, определение марки стали, выбор метода сварки, определение режимов сварки и сварочных материалов, нормализация операций, составление технологического процесса, расчет необходимого количества оборудования и работников.Relevance of work: in this final qualification work, the calculation and design of the open-type carcass frame are performed. The aim of the work is to develop a technology for manufacturing a carcass. The objectives of this course project is to study the component parts of a product, determine the grade of steel, choose a welding method, determine welding modes and welding materials, normalize operations, draw up a process, calculate the required amount of equipment and the number of workers

Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor

Excitotoxicity is thought to play key roles in brain neurodegeneration and stroke. Here we show that neuroprotection against excitotoxicity by trophic factors EFNB1 and brain-derived neurotrophic factor (called here factors) requires de novo formation of 'survival complexes' which are factor-stimulated complexes of N-methyl-D-aspartate receptor with factor receptor and presenilin 1. Absence of presenilin 1 reduces the formation of survival complexes and abolishes neuroprotection. EPH receptor B2- and N-methyl-D-aspartate receptor-derived peptides designed to disrupt formation of survival complexes also decrease the factor-stimulated neuroprotection. Strikingly, factor-dependent neuroprotection and levels of the de novo factor-stimulated survival complexes decrease dramatically in neurons expressing presenilin 1 familial Alzheimer disease mutants. Mouse neurons and brains expressing presenilin 1 familial Alzheimer disease mutants contain increased amounts of constitutive presenilin 1-N-methyl-D-aspartate receptor complexes unresponsive to factors. Interestingly, the stability of the familial Alzheimer disease presenilin 1-N-methyl-D-aspartate receptor complexes differs from that of wild type complexes and neurons of mutant-expressing brains are more vulnerable to cerebral ischaemia than neurons of wild type brains. Furthermore, N-methyl-D-aspartate receptor-mediated excitatory post-synaptic currents at CA1 synapses are altered by presenilin 1 familial Alzheimer disease mutants. Importantly, high levels of presenilin 1-N-methyl-D-aspartate receptor complexes are also found in post-mortem brains of Alzheimer disease patients expressing presenilin 1 familial Alzheimer disease mutants. Together, our data identify a novel presenilin 1-dependent neuroprotective mechanism against excitotoxicity and indicate a pathway by which presenilin 1 familial Alzheimer disease mutants decrease factor-depended neuroprotection against excitotoxicity and ischaemia in the absence of Alzheimer disease neuropathological hallmarks which may form downstream of neuronal damage. These findings have implications for the pathogenic effects of familial Alzheimer disease mutants and therapeutic strategies.This work was supported by National Institutes of Health grants 2RF1AG008200-29; 2R01-NS047229; P50AG05138; and by Grant AARF-17-531426 of the Alzheimer's Association

GLUCOCORTICOID RECEPTOR SYNERGISM WITH TRANSCRIPTION FACTORS IN RECEPTOR - REGULATED GENE EXPRESSION

GLUCOCORTICOID HORMONES AND INSULIN REGULATE GENE EXPRESSION IN A COOPERATIVE MANNER. WE SHOW THAT IN RAT HEPATIC CELLS INSULIN ENHANCES SYNERGISTICALLY THEGLUCOCOTRICOID INDUCED EXPRESSION OF CAT. THE PRESENCE OF ACTIVE GLUCOCORTICOID RESPONSE ELEMENTS (GRES) ON CAT PROMOTER IS REQUIRED AND THE INDUCTION DEPENDS ON THE INSULIN CONCENTRATION AND ON THE PRESENCE OF ACTIVE GLUCOCORTICOID RECEPTOR (GR). INSULIN ALTERS NEITHER THE AFFINITY OF GR FOR ITS HORMONE NOR ITS AFFINITY FOR THE DNA. INSULIN ACTS IN A SEQUENCE SPECIFIC MANNER AND AT THE TRANSCRIPTIONAL LEVEL. IT DOES NOT ACT AT THE POST - TRANSCRIPTIONAL OR THEPOST - TRASLATIONAL LEVEL. WE ALSO SHOW THAT IN HUMAN HEPATOMA CELLS A SINGLE COPY OF A GRE ON CAT PROMOTER CAN MEDIATE THE INSULIN ENHANCEMENT OF GLUCOCORTICOID INDUCED CAT EXPRESSION. THE N' - TERMINAL AND THE C' - TERMINAL DOMAINS OF GR ARE NOT INVOLVED IN MEDIATING THE RESPONSE. INSULIN HAD NO EFFECT ONGR BINDING TO GRE AND IT DIDN'T CAUSE THE INTERACTION OF ANY OTHER TRANSCRIPTION FACTOR WITH THE GR ON THE GRE. FINALLY WE SHOW THAT INSULIN AFFECTS BOTH THE NUCLEAR LEVELS AND THE PHOSPHORYLATION STATE OF GR. THE COMBINATORIAL ACTION OF BOTH HORMONES KEEP NUCLEAR GR AT LOW LEVELS WHILE AT THE SAME TIME IT INDUCES THE PHOSPHORYLATION OF NUCLEAR GR. THE PHOSPHORYLATION IS AT SERINE/THEONINE RESIDUES SINCE AT THE SAME TIME WE OBSERVE A DRAMATIC DEPHOSPHORYLATIONAT TYROSINE RESIDUES. THE (ABSTRACT TRUNCATED)ΣΤΗΝ ΠΑΡΟΥΣΑ ΕΡΓΑΣΙΑ ΔΕΙΧΝΕΤΑΙ ΠΩΣ ΟΙ ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΕΙΣ ΟΡΜΟΝΕΣ ΚΑΙ Η ΙΝΣΟΥΛΙΝΗ ΡΥΘΜΙΖΟΥΝ ΤΗ ΓΟΝΑΔΙΑΚΗ ΕΚΦΡΑΣΗ ΚΑΤΑ ΤΡΟΠΟ ΣΥΝΕΡΓΙΣΤΙΚΟ. ΠΑΡΑΤΗΡΟΥΜΕ ΠΩΣ ΣΕΚΥΤΤΑΡΑ ΗΠΑΤΟΣ ΑΡΟΥΡΑΙΟΥ Η ΙΝΣΟΥΛΙΝΗ ΑΥΞΑΝΕΙ ΣΥΝΕΡΓΙΣΤΙΚΑ ΜΕ ΤΗ ΔΕΞΑΜΕΘΑΖΟΝΗΤΗΝ ΕΚΦΡΑΣΗ ΤΟΥ ΓΟΝΙΔΙΟΥ ΤΗΣ ΑΚΕΤΥΛΟΤΡΑΝΣΦΕΡΑΣΗΣ ΤΗΣ ΧΛΩΡΑΜΦΑΙΝΙΚΟΛΗΣ (CAT).ΤΟ ΦΑΙΝΟΜΕΝΟ ΑΥΤΟ ΑΠΑΙΤΕΙ ΤΗΝ ΥΠΑΡΞΗ ΣΤΟΙΧΕΙΩΝ ΑΠΟΚΡΙΝΟΜΕΝΩΝ ΣΤΑ ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΗ (GLUCOCORTICOID RESPONSE ELEMENT, GRE) ΣΤΟΝ ΥΠΟΚΙΝΗΤΗ ΤΗΣ CAT ΚΑΙ ΕΞΑΡΤΑΤΑΙ ΑΠΟ ΤΗ ΣΥΓΚΕΝΤΡΩΣΗ ΤΗΣ ΙΝΣΟΥΛΙΝΗΣ ΚΑΙ ΤΗΝ ΠΑΡΟΥΣΙΑ ΕΝΕΡΓΟΥ ΥΠΟΔΟΧΕΑ ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΩΝ (GLUCOCORTICOID RECEPTOR, GR). Η ΙΝΣΟΥΛΙΝΗ ΔΕΝ ΕΠΙΔΡΑ ΣΤΗ ΣΥΓΓΕΝΕΙΑ ΤΟΥ GR ΓΙΑ ΤΗ ΔΕΞΑΜΕΘΑΖΟΝΗ ΟΥΤΕ ΣΤΗ ΣΥΓΓΕΝΕΙΑ ΤΟΥ GR ΓΙΑ ΤΟ DNA. Η ΡΥΘΜΙΣΗ ΤΗΣ ΕΚΦΡΑΣΗΣ ΤΗΣ CAT ΓΙΝΕΤΑΙ ΣΤΟ ΕΠΙΠΕΔΟ ΤΗΣ ΜΕΤΑΓΡΑΦΗΣ ΚΑΙ ΟΧΙ ΜΕΤΑ - ΜΕΤΑΓΡΑΦΙΚΑ Η ΜΕΤΑ - ΜΕΤΑΦΡΑΣΤΙΚΑ. ΕΝΑ ΚΑΙ ΜΟΝΟ ΣΤΟΙΧΕΙΟ ΑΠΟΚΡΙΣΗΣ ΣΤΑ ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΗ (GRE) ΣΤΟΝ ΥΠΟΚΙΝΗΤΗ ΤΗΣ CAT ΕΙΝΑΙ ΙΚΑΝΟ ΚΑΙ ΑΝΑΓΚΑΙΟ ΓΙΑ ΤΗΝ ΣΥΝΕΡΓΙΣΤΙΚΗ ΑΥΞΗΣΗ ΤΗΣ ΕΚΦΡΑΣΗΣ ΤΗΣ CAT ΑΠΟ ΤΙΣ ΔΥΟ ΟΡΜΟΝΕΣ. ΕΠΙΣΗΣ ΣΤΟ ΣΥΝΕΡΓΙΣΜΟ ΔΕ ΣΥΜΜΕΤΕΧΟΥΝ ΤΟ ΑΜΙΝΟΤΕΛΙΚΟ ΚΑΙ ΤΟ ΚΑΡΒΟΞΥΤΕΛΙΚΟ ΤΜΗΜΑ ΤΟΥ ΜΟΡΙΟΥ GR. Η ΙΝΣΟΥΛΙΝΗ ΔΕΝ ΕΠΑΓΕΙ ΤΗΝ ΑΛΛΗΛΕΠΙΔΡΑΣΗ ΚΑΠΟΙΟΥ ΠΑΡΑΓΟΝΤΑ ΜΕ ΤΟΝ GR ΚΑΤΑ ΤΗ ΣΥΝΔΕΣΗ ΤΟΥΜΕ ΤΟ GRE, ΟΥΤΕ ΜΕΤΑΒΑΛΛΕΙ ΤΗ ΣΤΑΘΕΡΟΤΗΤΑ ΜΕ ΤΗΝ ΟΠΟΙΑ Ο GR ΣΥΝΔΕΕΤΑΙ ΣΤΟ GRE. ΤΕΛΟΣ ΠΑΡΑΤΗΡΟΥΜΕ ΠΩΣ Η ΣΥΝΔΥΑΣΜΕΝΗ ΔΡΑΣΗ ΤΩΝ ΔΥΟ ΟΡΜΟΝΩΝ ΚΡΑΤΑ ΜΕΓΑΛΟ ΜΕΡΟΣ ΤΟΥ GR ΕΞΩ ΑΠΟ ΤΟΝ ΠΥΡΗΝΑ, ΠΡΟΚΑΛΩΝΤΑΣ ΥΠΕΡΦΩΣΦΟΡΥΛΙΩΣΗ ΤΩΝ ΧΑΜΗΛΩΝ ΕΠΙΠΕΔΩΝΠΥΡΗΝΙΚΟΥ GR. ΤΑΥΤΟΧΡΟΝΑ ΠΡΟΚΑΛΕΙΤΑΙ ΑΠΟΦΩΣΦΟΡΥΛΙΩΣΗ ΚΑΤΑΛΟΙΠΩΝ ΤΥΡΟΣΙΝΗΣ, ΠΟΥ ΦΑΙΝΕΤΑΙ ΝΑ ΠΑΙΖΕΙ ΛΕΙΤΟΥΡΓΙΚΟ ΡΟΛΟ ΣΤΗΝ ΕΜΦΑΝΙΣΗ ΤΟΥ ΣΥΝΕΡΓΙΣΜΟΥ

Design and Construction of a Narrow Pulse, High Power Current Source Circuit to Supply a Diode Laser

71 σ.Σκοπός της διπλωματικής αυτής εργασίας είναι η σχεδίαση και κατασκευή γεννήτριας στενών παλμών υψηλού ρεύματος για την τροφοδοσία διοδικού laser. Το κύκλωμα αυτό μπορεί να αξιοποιηθεί για την ανίχνευση καρκινικών κυττάρων σε ασθενείς. Η ανίχνευση αυτή βασίζεται στο φαινόμενο του φθορισμού. Υπάρχουν ήδη μέθοδοι ανίχνευσης που βασίζονται σε αυτό το φαινόμενο. Tο καινούργιο στοιχείο που μπαίνει είναι η μελέτη της χρονικής μεταβολής της απόκρισης της φθορίζουσας ουσίας μέσα στο σκεδάζον υλικό (που στην προκειμένη περίπτωση είναι βιολογικοί ιστοί), μετά την ακτινοβόληση του καρκινικού ιστού. Η μελέτη της χρονικής μεταβολής του φθορισμού και η πληροφορία που μπορούμε να πάρουμε από αυτήν, μπορεί να αξιοποιηθεί για υπολογισμό με μεγαλύτερη ακρίβεια της θέσης και του βάθους του καρκινικού ιστού. Η φθορίζουσα ουσία στην οποία αναφερόμαστε είναι ένας φωτοευαισθητοποιητής, με συγκεκριμένες ιδιότητες, ο οποίος με την είσοδό του στον οργανισμό, κατακρατείται μόνο από τα καρκινικά κύτταρα, και στην συνέχεια αφού ακτινοβοληθεί, μπορεί να μελετηθεί το φθορισμός του για να γίνει ο εντοπισμός. Για να μπορέσουμε να μελετήσουμε την χρονική μεταβολή του φαινομένου του φθορισμού η ιδέα είναι η κατασκευή κυκλώματος τέτοιου που να οδηγεί το laser, παράγοντας πολύ στενούς παλμούς, μεγάλης έντασης (0,5Α με 2,5Α) ενώ κάθε παλμός παράγεται περίπου κάθε 50μs. Η παρούσα εργασία λοιπόν εστιάζει στο πώς θα κατασκευαστεί αυτό το κύκλωμα, ποια είναι τα προβλήματα που παρουσιάζονται και πώς μπορούν να αντιμετωπιστούν.The purpose of this thesis is to design and construct a narrow pulse, high power current source supply for diode laser. This circuit can be used to detect cancer cells in patients. This detection is based on the fluorescence phenomenon. There are already detection methods based on this phenomenon. The novelty is the study of time variation of the response of the fluorescent substance inside the scattered material (which in this case is biological tissues), after irradiation of the tumor tissue. The study of the temporal change of fluorescence and the information we can get from it can be used to calculate more accurately the location and depth of tumor tissue. The fluorescent substance to which we refer is a photosensitizer, with specific properties, which upon entering the body is retained only by cancer cells, and then after irradiated, its fluorescence can be studied to make the identification. In order to study the time course of the fluorescence phenomenon, the idea is the construction of a circuit to drive the laser, producing very narrow current pulses (0.5 to 2.5A), one every 50us. This thesis therefore focuses on how to build this circuit what problems are encountered and how they can be addressed.Αναστάσιος Π. Γεωργακόπουλο

Increasing the Bandwidth of Wideband Antennas Using the Frequency Pulling Technique

Frequency pulling technique (FPT) is a recently developed method for increasing the bandwidth (BW) of microstrip antennas. It is based on the insertion loss methodology used for the design of bandpass filters. Namely, to apply this technique, the resonators in a bandpass filter are replaced with antennas that have identical equivalent resonant circuits. Also, all the equivalent resonant circuits can represent symmetrical feeding points of a single antenna. Therefore, when these circuits are properly connected in accordance with the FPT rules, they create a matching network that increases the BW of a single antenna. However, prior studies on this method are limited to (1) narrowband antenna designs, (2) antennas with feeding points located at the same plane, and (3) feeding networks implemented as single feeding lines (e.g., microstrip lines) which have introduced several limitations and design complexities. In this work, we address these challenges by (1) extending FPT to wideband designs, (2) using feeding points located at different planes, and (3) designing feeding networks as unequal power dividers. Such networks not only simplify the design complexities associated with the traditional approach but also offer the capability to apply FPT to non-planar designs (e.g., 3D antenna configurations). To demonstrate the latter, we properly engineer a triangular tapered slot antenna, feeding it with a coupled microstrip line. As a result, the bandwidth of our modeled antenna increases from 34.51% to 78.25%, demonstrating excellent agreement between simulated and measured results

3D AFM Nanomechanical Characterization of Biological Materials

Atomic Force Microscopy (AFM) is a powerful tool enabling the mechanical characterization of biological materials at the nanoscale. Since biological materials are highly heterogeneous, their mechanical characterization is still considered to be a challenging procedure. In this paper, a new approach that leads to a 3-dimensional (3D) nanomechanical characterization is presented based on the average Young’s modulus and the AFM indentation method. The proposed method can contribute to the clarification of the variability of the mechanical properties of biological samples in the 3-dimensional space (variability at the x–y plane and depth-dependent behavior). The method was applied to agarose gels, fibroblasts, and breast cancer cells. Moreover, new mathematical methods towards a quantitative mechanical characterization are also proposed. The presented approach is a step forward to a more accurate and complete characterization of biological materials and could contribute to an accurate user-independent diagnosis of various diseases such as cancer in the future

3D AFM Nanomechanical Characterization of Biological Materials

Atomic Force Microscopy (AFM) is a powerful tool enabling the mechanical characterization of biological materials at the nanoscale. Since biological materials are highly heterogeneous, their mechanical characterization is still considered to be a challenging procedure. In this paper, a new approach that leads to a 3-dimensional (3D) nanomechanical characterization is presented based on the average Young’s modulus and the AFM indentation method. The proposed method can contribute to the clarification of the variability of the mechanical properties of biological samples in the 3-dimensional space (variability at the x–y plane and depth-dependent behavior). The method was applied to agarose gels, fibroblasts, and breast cancer cells. Moreover, new mathematical methods towards a quantitative mechanical characterization are also proposed. The presented approach is a step forward to a more accurate and complete characterization of biological materials and could contribute to an accurate user-independent diagnosis of various diseases such as cancer in the future