Formulation and Evaluation of Topically Retained Hydrogels Loaded with Timolol Maleate Microspheres for Extended Release in Treating Glaucoma

Conventional aqueous eye drop formulations have a shorter retention period and wash out of the precorneal region more easily. In this study, biodegradable microsphere-loaded hydrogels were developed to extend the time of residence and improve the drug bioavailability. The prepared microspheres were fabricated using PLGA as the biodegradable polymer and PVA as the surfactant. Hydrogels were prepared using Carbopol 940 and Gellan gum as gelling agents. Methods: The microspheres were created through a technique known as double emulsion solvent evaporation method. Evaluation included for its percentage yield, entrapment efficiency, particle size and surface morphology of the prepared microspheres. Timolol Maleate microsphere loaded hydrogel underwent assessments for pH, spreadability, rheological behaviour, sterility, antimicrobial efficacy, in vitro release studies, drug release kinetics and ocular irritation. Results: FTIR analysis confirmed compatibility between the drug and polymer. SEM observations indicated spherical microspheres with sizes ranging from 1 to 12 µm, suitable for ocular application. All formulations exhibited pH values between 4.2 and 5.0, with gelation occurring at 35°C to 38°C. Formulation F3 demonstrated optimal viscosity (1486 – 1850 cps) and good spreadability. Sterility tests were successful, and F3 displayed a drug release of 82.6% after 24 hours. Antimicrobial studies exhibited inhibition zones, and ocular tests on rabbits revealed no irritation. Stability analysis indicated no significant changes in pH or clarity. Conclusion: Based on physiological, rheological, and in vitro evaluations F3 was identified as the most suitable formulation for extended Timolol Maleate release via hydrogel, holding promise for effective glaucoma treatment

HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype

Phenotypic expression of the common p.C282Y/p.C282Y HFE-related hemochromatosis genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors. Haptoglobin has a crucial role in free hemoglobin iron recovery, and exists as three major types: Hp1-1, Hp2-1 and Hp2-2. Hp2-2 favors endocytosis of hemoglobin iron in monocytes/macrophages, resulting in partial iron retention and increased intracellular ferritin levels. This situation is generally not expected to severely affect iron homeostasis, but was found to correlate with elevated serum iron indices in healthy men. Whether the Hp2-2 genotype acts as a modifier in HFE-related hemochromatosis is unclear. In this study we investigated influence of Hp2-2 and of potential confounders on the iron indices of 351 p.C282Y homozygous patients. We conclude that there is a cause-and-effect relationship between the Hp2-2 genotype and increased iron indices in p.C282Y homozygous patients. The Hp2-2 effect is, however, limited and only apparent in males

Investigation Into the Antidiabetic Effects of a Developed Polyherbal Nanosuspension and Its Assessment

This study focuses on the development and evaluation of a nanosuspension containing ethanolic extracts of Tinospora cordifolia and Syzygium cumini for managing Diabetes mellitus. The main objective is to create an effective polyherbal nanosuspension by combining Tinospora cordifolia and Syzygium cumini with an optimal concentration of chitosan polymer to address Diabetes mellitus. Furthermore, both in vitro and in vivo assessments of the synthesized nanosuspensions were conducted to determine the best formulation. Methods and Findings: The ethanolic extracts of the mentioned plants were obtained using a maceration technique, followed by preliminary phytochemical screening, HPTLC analysis, and FTIR-based incompatibility assessments. The nanosuspension was prepared using the ionic gelation method by varying the chitosan polymer concentration. Comprehensive in vitro assessments were carried out, including measurements of pH, viscosity, drug content, entrapment efficiency, loading capacity, and in vitro release profiles for different formulations. The formulation with the highest drug content and optimal release characteristics was selected for further analysis of particle size, zeta potential, and surface morphology. Subsequently, the antidiabetic efficacy of the polyherbal nanosuspension was evaluated using wistar albino rats. Discussion: FTIR analysis indicated no significant interaction between the drug and the polymer. The in vitro drug release and kinetic analyses suggested that the F5 formulation exhibited superior drug release and an improved release mechanism. The particle size was determined to be approximately 420nm, and SEM imaging revealed particles that were nearly spherical in shape. Stability assessments of formulation F5 demonstrated consistent physical and chemical parameters over time

FUSE (Fuzzy Similarity Measure) - A measure for determining fuzzy short text similarity using Interval Type-2 fuzzy sets

Measurement of the semantic and syntactic similarity of human utterances is essential in developing language that is understandable when machines engage in dialogue with users. However, human language is complex and the semantic meaning of an utterance is usually dependent on context at a given time and also based on learnt experience of the meaning of the perception based words that are used. Limited work in terms of the representation and coverage has been done on the development of fuzzy semantic similarity measures. This paper proposes a new measure known as FUSE (FUzzy Similarity mEasure) which determines similarity using expanded categories of perception based words that have been modelled using Interval Type-2 fuzzy sets. The paper describes the method of obtaining the human ratings of these words based on Mendel’s methodology and applies them within the FUSE algorithm. FUSE is then evaluated on three established datasets and is compared with two known semantic similarity algorithms. Results indicate FUSE provides higher correlations to human ratings

Effects of the Non-Equipartition of Electrons and Ions in the Outskirts of Relaxed Galaxy Clusters

(abridged) We have studied the effects of electron-ion non-equipartition in the outer regions of relaxed clusters for a wide range of masses in the \LambdaCDM cosmology using one-dimensional hydrodynamic simulations. The effects of the non-adiabatic electron heating efficiency, \beta, on the degree of non-equipartition are also studied. Using the gas fraction f_gas = 0.17 (which is the upper limit for a cluster), we give a conservative lower limit of the non-equipartition effect on clusters. Beyond the virial radius, the non-equipartition effect depends rather strongly on \beta, and such a strong dependence at the shock radius can be used to distinguish shock heating models or constrain the shock heating efficiency of electrons. We have also studied systematically the signatures of non-equipartition on X-ray and SZ observables. We have calculated the effect of non-equipartition on the projected temperature and X-ray surface brightness profiles using the MEKAL emission model. The non-equipartition effect can introduce a ~10% bias in the projected temperature at R_vir for a wide range of \beta. We also found that the effect of non-equipartition on the projected temperature profiles can be enhanced by increasing metallicity. We found that for our model in the \LambdaCDM Universe, the integrated SZ bias, Y_{non-eq}/Y_{eq}, evolves slightly (at a percentage level) with redshift, which is in contrast to the self-similar model in the Einstein-de Sitter Universe. This may introduce biases in cosmological studies using the f_gas technique. We discussed briefly whether the equipartition and non-equipartition models near the shock region can be distinguished by future radio observations with, for example, ALMA.Comment: 28 pages, 19 figures, accepted for publication in the Astrophysical Journal. Typos corrected in version

Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data

BACKGROUND: Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. METHODS: We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. RESULTS: In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10(-5)), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004). CONCLUSION: This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients

Application of Fuzzy Semantic Similarity Measures to Event Detection Within Tweets

This paper examines the suitability of applying fuzzy semantic similarity measures (FSSM) to the task of detecting potential future events through the use of a group of prototypical event tweets. FSSM are ideal measures to be used to analyse the semantic textual content of tweets due to the ability to deal equally with not only nouns, verbs, adjectives and adverbs, but also perception based fuzzy words. The proposed methodology first creates a set of prototypical event related tweets and a control group of tweets from a data source, then calculates the semantic similarity against an event dataset compiled from tweets issued during the 2011 London riots. The dataset of tweets contained a proportion of tweets that the Guardian Newspaper publically released that were attributed to 200 influential Twitter users during the actual riot. The effects of changing the semantic similarity threshold are investigated in order to evaluate if Twitter tweets can be used in conjunction with fuzzy short text similarity measures and prototypical event related tweets to determine if an event is more likely to occur. By looking at the increase in frequency of tweets in the dataset, over a certain similarity threshold when matched with prototypical event tweets about riots, the results have shown that a potential future event can be detected

A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy

Objective: To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis. Methods: We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay. Results: WES analysis identified two novel variants in the EIF2B5 gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that ~20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant. Conclusion: We report two novel variants in EIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype