51,507 research outputs found

    New treatments in Cystic Fibrosis. Analysis of the first patients treated in Cantabria

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    RESUMEN : La medicina personalizada ha supuesto un gran avance para el tratamiento de numerosas patologías, cambiando de forma radical la evolución y pronóstico de las mismas. La Fibrosis Quística es una de las grandes beneficiadas de este tipo de medicina, siendo la enfermedad autosómica recesiva más frecuente de la raza caucásica. En los últimos años se han aprobado tratamientos moduladores que actúan específicamente sobre el defecto básico de la FQ, pudiendo ser tratados un importante número de pacientes en el Hospital Universitario Marqués de Valdecilla. En este trabajo se analizará el efecto de estas nuevas terapias sobre diversos parámetros, que nos permitirán conocer la eficacia y seguridad de las mismas.ABSTRACT : Personalized medicine has meant a great advance in the treatment of numerous pathologies, radically changing their evolution and diagnosis. Cystic Fibrosis, being the most frequent autosomal recessive disease of the Caucasian race, is one of the great beneficiaries of this type of medicine. In recent years, modulating treatments that act specifically on the basic defect of FQ have been tested, leading to a significant number of patients being able to be treated in HUMV. In this report/work/study, we will analyze the effect of these innovative therapies on several parameters, which will allow us to contrast their efficacy and security.Grado en Medicin

    Prenatal exposure to phthalates accelerates reproductive aging in multiple generations of female mice

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    Phthalates are a group of chemicals that are ubiquitously used in many different consumer products. Phthalates are widely used because of their stability and flexibility in products such as paints, personal care products like perfume, building materials, PVC pipes, children’s toys, car seats, and medical bags and IV tubing. Because phthalates are non-covalently bound to products, they can leach out due to cleaning and heating. Therefore, due to the vast use of products containing phthalates and their leaching capabilities, humans are exposed via ingestion, inhalation, and dermal contact. Phthalates and their metabolites have been found in urine, blood, semen, breast milk, amniotic fluid, umbilical cord blood, and follicular fluid. Additionally, studies have shown that women are exposed to higher levels of phthalates compared to men, most likely from their increased use of personal care products compared to men. Studies have shown that phthalates are endocrine-disrupting chemicals that can cause detrimental effects on reproduction in males and females. Specifically, in females, phthalates have been shown to accelerate primordial follicle recruitment, disrupt estrous cyclicity, inhibit ovarian steroidogenesis, and disrupt fertility. Furthermore, these effects have been observed in a multiple and transgenerational manner in female mice. Recent studies have also shown that phthalates may accelerate reproductive aging. Reproductive aging in females is characterized by biomarkers including a drastic decrease in the ovarian follicle pool, dysregulation of hormones involved in the hypothalamic-pituitary-gonadal (HPG) axis including sex steroids, gonadotropin, and peptide hormones, irregular estrous/menstrual cycles, and together this can lead to infertility. Moreover, the ovary has been shown to exhibit direct signs of aging, including increases in inflammation, oxidative stress, fibrosis, and in rodents an increase in cystic ovaries. This is of concern because if a chemical causes an early depletion of the follicle pool, this would lead to early reproductive senescence or menopause in women. Early reproductive senescence would have negative effects on the overall health of a female, leading to dysregulation of the HPG axis, acyclicity, and decreased time for the possibility of pregnancy. Additionally, dysregulation of the hypothalamic-pituitary-gonadal axis leads to decreased levels of estradiol, and estradiol is vital to cognitive function, cardiovascular health, and bone health. Many studies focus on exposure to single phthalates, but humans are exposed to mixtures of many different chemicals, including phthalates, on a daily basis. Therefore, studies are needed to examine if an environmentally relevant phthalate mixture may be negatively affecting female reproduction. Also, studies are needed to examine if phthalate mixtures cause multigenerational and transgenerational effects on female reproduction. Lastly, minimal studies have examined if phthalates accelerate reproductive aging and if this can occur in multiple generations. Thus, the goal of my dissertation work was to examine if phthalate exposure accelerates reproductive aging and if this occurs in a multigenerational and transgenerational manner in female mice. Specifically, I examined if prenatal exposure to the single phthalate di(2-ethylhexyl) (DEHP) or an environmentally relevant phthalate mixture accelerated biomarkers of reproductive aging in a multiple and/or transgenerational manner in female mice. Further, I investigated if prenatal exposure to a relevant phthalate mixture accelerated the natural decline in fertility and the direct aging of the ovary in a multigenerational manner in female mice. First, I tested the hypothesis that prenatal exposure to the single phthalate, DEHP, accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice. Biomarkers of reproductive aging in females include a decrease in the ovarian follicle pool, acyclicity, and dysregulation of the HPG axis. Early reproductive aging can lead to accelerated infertility and detrimental effects on non-reproductive health like bone and cardiovascular health. I found that prenatal DEHP exposure altered estrous cyclicity, increased the percentage of cystic ovaries, decreased the primordial follicle pool, and altered hormones involved in the HPG axis in the F1 generation. DEHP exposure altered follicle numbers and decreased sex steroid hormone levels in the F2 generation. Last, I found that prenatal DEHP exposure altered estrous cyclicity, decreased the percentage of ovarian follicles, and dysregulated hormones in the HPG axis in the F3 generation. Next, I tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice. Due to humans being exposed to mixtures of chemicals on a daily basis, it is vital to examine if a phthalate mixture may be accelerating reproductive aging. I found that the phthalate mixture dysregulated hormones involved in the HPG axis in the F1 generation. Next, I found that the mixture decreased the percent of antral follicles and testosterone hormone levels in the F2 generation. Last, I found that prenatal mixture exposure caused irregular estrous cyclicity, altered follicle numbers, and decreased luteinizing hormone levels in the F3 generation. Finally, I tested the hypothesis that prenatal exposure to the phthalate mixture accelerates the natural decline in reproductive capacity and the aging of the ovary in the F1 generation of female mice. Women become infertile as they age, and chemical exposure could accelerate the onset of infertility. Further, the ovary displays direct signs of aging including increased oxidative stress, cell death, and fibrosis. I found that prenatal phthalate exposure decreased the ability of females to carry out their pregnancies and produce pups at 11 and 13 months of age. Further, I found that the phthalate mixture decreased the time spent in proestrus at 11 and 13 months. Last, I found that the mixture did not significantly affect the levels of fibrosis, antioxidants, or apoptotic factors that could contribute to the direct aging of the ovary. Collectively, the research from my doctoral studies shows that prenatal exposure to the single phthalate DEHP or an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging and causes an early decline in reproductive capacity in a multiple and transgenerational manner in female mice.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste

    Purification and EPR Spectroscopy of Sav1866-SMALPs

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    One of the greatest challenges in the field of modern science is based on the study of membrane proteins, which thanks to the evolution in the field of physics, chemistry and engineering, has made it possible to obtain tools that have enabled the study of these proteins. Membrane proteins contribute to the 20-30% of the proteome in all genomes but they are not only numerous, they play a crucial role in the life of the cell, as they take part in various and important functions such that they have earned the nickname of “cellular gate-keeper”. Membrane proteins (MP) are involved in complex process of mediating between cells and their environment. They undertake neurotransmission, sensing, transport of nutrients and drugs in and out of the cell. Many MPs are also enzymes, they are also constituents of large dynamic assemblies, intervening in cellular processes such as endocytosis, cell division and migration. In contradiction to their abundance and importance, only a few MP proteins have been purified and characterized both from the functional and structural point of view. Their importance of this class of protein is underlined by the fact that various diseases are connected with defects in MP and they are also involved in multidrug resistance and failure in chemotherapy. This project focuses its attention on the study of a particular class of membrane proteins, ATP binding cassette (ABC), one of the largest superfamilies of membrane transporters present in eukaryotes and prokaryotes. The choice to study these transporters does not arise only from their abundance, but also for the role they play within the cell and their involvement in drug resistance, one of the greatest challenges in the medical field and in diseases like cystic fibrosis, retinal degeneration and adrenoleukodystrophy. The viability of new techniques to investigate the structure and function of these transporters may constitute a new starting point to fully understand their involvement in these pathologies and the mechanism of import-export of drugs. The ABC transporter chosen for this project is Sav1866, a trans-membrane protein of Staphylococcus aureus, involved in drug resistance. The choice is not due only to the task performed at the level of microorganism, but because studies have shown the similarity of the architecture of this MP to the human multidrug transporter P-glycoprotein. A well characterization of Sav1866 could provide a general and a cheaper model for predict P-glycoprotein structure and behavior. One of the first difficulty encountered in the study of MP is obtaining the proteins themselves. MP are usually present at low levels in biological membranes and it is rare for a single membrane protein to be expressed at levels such as to be a major component of the protein composition of cellular membrane, hence the need to optimize the protocols that lead to overexpression of the proteins of interest. Another difficulty is that MPs are generally not soluble in aqueous solution and need an environment that satisfies their high hydrophobicity. For this purpose, one of the major approaches to isolating MP uses detergents. The amphipathic nature of detergents (polar head and hydrophobic tails) meant that they were widely used for the solubilization of membranes, mimicking the natural environment. However, the use of these surface-active agents is not sufficient to provide an environment that reflects the complexity of lipid bilayer. This derives from the fact that the lipid membrane is made up of a large number and variety of lipids, which contribute to creating a unique environment of its kind. The complexity of the native environment, which has an impact on MP, is lost with the use of detergents, but is maintained for a restricted area if a simple organic copolymer, styrene-maleic acid (SMA) is used to solubilize membrane. SMA extract the proteins from the membrane into nano disks consisting of a central lipid supported by a SMA polymer anulus, this structure is called SMALP. For the characterization of the proteins, the site-directed spin labeling (SDSL) technique was used, coupled with EPR spectroscopy. SDSL is a technique used to investigate the structure and local conformation of proteins using electron spin resonance (EPR). Spin labels are paramagnetic molecular reporters (they have an unpaired electron) and in this technique the aminoacids, in particular a cysteine residue, acts as probe attachment site. Unique cysteine residues can be introduced as recombinant protein by site-directed mutagenesis. At neutral pH, the amino acid thiol group reacts with the functional group of the probe forming a covalent bond. thanks to their sensitivity to motion, it is exploited for EPR spectroscopy. SDSL with EPR can be used to understand the structure of SMALP encapsulated membrane proteins and measure the distance between these probes to determine the conformation assumed by MPs in their native lipid environment

    Bone Disease in Long-Term Lung Transplant Survivors

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    Background: During the first two years after lung transplantation (LTx), the incidence of fragility fractures (FX) is estimated to be 15–50% and it is lower in patients with cystic fibrosis (CF) as compared with other end-stage lung diseases (nCF). The aim of our study is to compare the skeletal outcomes, after the first 2 years post-LTx, in long-term survivors with CF and nCF. Materials and Methods: We evaluated the FX rate, the changes in bone mineral density (BMD) and trabecular bone score (TBS) in 68 patients (38 CF and 30 nCF) who underwent LTx in our center and with a follow-up after LTx longer than 5 years (7.3 ± 2.0 years). Results: After the second year post-LTx: (i) the FX rate was lower than during the first two years post-LTx (4.4 vs. 20.6%, p = 0.004), with no difference between CF and nCF patients (5.3 vs. 3.3%, p = 0.589); (ii) BMD at lumbar spine, femoral neck and total hip remained stable (−1.6 ± 1.0 vs. −1.4 ± 1.1, p = 0.431, −1.8 ± 0.9 vs. −1.9 ± 0.9, p = 0.683, −1.5 ± 0.9 vs. −1.4 ± 0.9, p = 0.678, respectively) as well as TBS (1.200 ± 0.124 vs. 1.199 ± 0.205, p = 0.166). Conclusions: After the second year post-LTx, the skeletal complications become less frequent and have similar incidence in patients with CF and nCF

    Design of Quorum Sensing Inhibitor−Polymer Conjugates to Penetrate Pseudomonas aeruginosa Biofilms

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    Antimicrobial resistance (AMR) is a global threat to public health with a forecast of a negative financial impact of one trillion dollars per annum, hence novel therapeutics are urgently needed. The resistance of many bacteria against current drugs is further augmented by the ability of these microbes to form biofilms where cells are encased in a slimy extracellular matrix and either adhered to a surface or forming cell aggregates. Biofilms form physiochemical barriers against the penetration of treatments such as small molecule antibacterials, rendering most treatments ineffective. Pseudomonas aeruginosa, a priority pathogen of immediate concern, controls biofilm formation through multiple layers of gene regulation pathways including quorum sensing (QS), a cell-to-cell signaling system. We have recently reported a series of inhibitors of the PqsR QS regulator from this organism that can potentiate the action of antibiotics. However, these QS inhibitors (QSIs) have shown modest effects on biofilms in contrast with planktonic cultures due to poor penetration through the biofilm matrix. To enhance the delivery of the inhibitors, a small library of polymers was designed as carriers of a specific QSI, with variations in the side chains to introduce either positively charged or neutral moieties to aid penetration into and through the P. aeruginosa biofilm. The synthesized polymers were evaluated in a series of assays to establish their effects on the inhibition of the Pqs QS system in P. aeruginosa, the levels of inhibitor release from polymers, and their impact on biofilm formation. A selected cationic polymer–QSI conjugate was found to penetrate effectively through biofilm layers and to release the QSI. When used in combination with ciprofloxacin, it enhanced the biofilm antimicrobial activity of this antibiotic compared to free QSI and ciprofloxacin under the same conditions

    Sustainable Synthesis of FITC Chitosan-Capped Gold Nanoparticles for Biomedical Applications

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    The quest for novel nanoscale materials for different applications necessitates that they are easy to obtain and have excellent physical properties and low toxicity. Moreover, considering the ongoing environmental impact of noxious chemical waste products, it is important to adopt eco-friendly approaches for nanoparticle synthesis. In this work, a natural polymer (medium molecular weight chitosan) derived from chitin was employed as a reducing agent to obtain gold nanoparticles (AuNPs) with a chitosan shell (AuNPs@CS) by a microwave oven. The chitosan is economically viable and cost-competitive in the market showing also nontoxic behavior in the environment and living organisms. The synthesized AuNPs@CS-FITC NPs were fully characterized by spectroscopic and microscopic characterization techniques. The size distribution of NPs was about 15 nm, which is a suitable dimension to use in biomedical applications due to their high tissue penetration, great circulation in blood, and optimal clearance as well as low toxicity. The prepared polymer-capped NPs were further functionalized with a fluorescent molecule, i.e., Fluorescein-5-isothiocyanate (FITC), to perform imaging in the cell. The results highlighted the goodness of the synthesis procedure, as well as the high internalization rate that resulted in an optimal fluorescence intensity. Thus, this work presents a good sustainable/green approach-mediated polymer nanocomposite for various applications in the field of diagnostic imaging

    Wooster Magazine: Spring 2023

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    The spring 2023 issue of Wooster magazine features alumni influencing change in their communities around the world, including John Carwile ’81, career member of the U.S. Foreign Service; Rashmi Ekka ’08, international development consultant; Samira El-Adawy ’13, Special Olympics youth manager in the Middle East and North Africa; Ishtiaq Ghafoor ’00, a diplomat with the British Foreign Service; Sarah Haile ’03, a biostatistician at University of Zurich; Kurt Russell ’94, 2022 National Teacher of the Year; and Lauren Vargo ’13, climate change researcher in New Zealand. Also featured are students who have attended the annual Athens Democracy Forum for the past five years and recent international graduates taking advantage of opportunities to gain experience in STEM fields. The issue also includes an interview with Wooster’s incoming 13th president, Dr. Anne McCall.https://openworks.wooster.edu/wooalumnimag_2011-present/1045/thumbnail.jp

    Case report: A case of fetal umbilical vein varix presenting disseminated intravascular coagulation, polycythemia, and neonatal hepatitis in an extremely low birth weight infant

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    Reports on the clinical course of fetal umbilical vein varix in premature infants are limited. We report a case of an extremely low body weight infant with intra-abdominal umbilical vein varix who developed disseminated intravascular coagulation, polycythemia, and hyperbilirubinemia after birth; late-onset neonatal hepatitis; and fetal thrombotic vasculopathy confirmed by placental histopathology. Ultrasonography after birth showed a dilated portion of the umbilical vein at the hepatic hilum with thrombi inside. We speculate that the umbilical vein varix caused the fetal thrombotic vasculopathy, and the presence of umbilical vein varix and fetal thrombotic vasculopathy in combination with prematurity caused coagulopathy, polycythemia, hyperbilirubinemia, and hepatitis. Despite the favorable outcomes reported in the literature, premature infants with umbilical vein varix may require careful observation and management for coagulopathy and late-onset hepatitis. Furthermore, placental histopathology could aid in the understanding of various clinical outcomes in infants with umbilical vein varices
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