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Bone Morphogenetic Protein-Based Therapeutic Approaches
No full textBone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-β family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation
Community Centers\u27 Effects on the Determinants of Health: Improving Community Mental Health
No full textThermosensitive Hydrogels Physically Linked with Chitosan-β-Cyclodextrin Loaded with Curcumin Nanoparticles for Drug Delivery to Treat Rheumatoid Arthritis
No full textImpulse Oscillometry Pulmonary Function Abnormalities in Sickle Cell Disease
No full textContext: Sickle Cell Disease (SCD) is characterized by an inherited point mutation in the hemoglobin (Hgb) HBB gene, which results in hemoglobin polymerization and red blood cell sickling when not fully oxygenated. Inflammatory responses to intravascular hemolysis may be the cause of abnormal pulmonary function found in sickle cell disease. Objective: Our goal was to determine if Impulse Oscillometry (IOS), a measure of pulmonary function, is a sensitive tool to detect a subpopulation of sickle cell patients at increased risk of sickle cell related complications. Design: We conducted a case control study of subjects with SCD, hemolytic anemia controls with other Hemoglobinopathies and Hereditary Spherocytosis (HS), and Hgb AA/AS controls. Setting: Our study took place at Children’s Hospital of Los Angeles in the outpatient setting. Methods: We collected each subject’s self-reported medical history, and blood samples to measure markers of hemolysis and inflammation. IOS was performed to measure airway reactance (AX) and total airway resistance at an oscillation frequency of 5Hz (R5). Results: 22 SCD, 20 Control, and 19 Hemoglobinopathy and HS subjects were studied. The percentage of abnormal R5 readings were high in all populations with no significant difference between the populations (SCD: 37% Controls: 40% Hemoglobinopathies and HS:32%; p\u3e.05). There was, however, a significant difference in AX between SCD, Controls, and Hemoglobinopathies and HS (p\u3c.05). Conclusion: Our study demonstrates a high rate of pulmonary function abnormalities in sickle cell disease subjects and the control populations. Analysis will be done to determine the relationship between the level of hemolysis amongst the SCD subjects with normal R5 and AX readings compared to SCD with abnormal readings. IOS may be a more sensitive measure of airway obstruction but would need to be correlated with complete spirometry and plethysmography with pre and post bronchodilator pulmonary function testing
Advancements in the Treatment of Opioid Abuse Disorder
No full textOver the past twenty years, opioid drug use has increased, causing an epidemic of opioid abuse that is killing tens of thousands of people every year. Current treatment options for opioid abuse disorder include alternative medications for patient’s addiction and pain, as well as different cognitive and behavioral therapies. However, the addiction medication alternatives are often other opioids, and the alternative pain medication are often not as effective as analgesics. The future of treatment for opioid abuse disorder lies in the development of vaccines that prevent addiction to begin with. However, the vaccines currently in development block not only the addiction potential, but also the analgesic effect, so more effective non-opioid pain medications are also being established. This paper explores the current and future treatment options for opioid abuse disorder, as well as defines who is most likely to be affected, public policy created to treat and prevent opioid abuse disorder, and why stigma against patients with opioid abuse disorder is hindering individuals from seeking help and receiving successful treatment
Dominic of Flanders’ Critique of John Duns Scotus’ Primary Argument for the University of Being
No full textThis article considers the attempt by a prominent fifteenth-century follower of Thomas Aquinas, Dominic of Flanders (a.k.a. Flandrensis, 1425-1479), to address John Duns Scotus’ most famous argument for the univocity of being. According to Scotus, the intellect must have a concept of being that is univocal to substantial and accidental being, and to finite and infinite being, on the grounds that an intellect cannot be both certain and doubtful through the same concept, but an intellect can be certain that something is a being while doubting whether it is a substance or accident, finite or infinite. The article shows how Flandrensis’ reply in defence of analogy of being hinges on a more fundamental disagreement with Scotus over the division of the logically one. It also shows how Flandrensis’ answer to this question commits him to a position on the unity of the concept of being that lies between the positions of Scotus and of Flandrensis’ earlier Thomistic sources
Contribution of Lipid Droplet Breakdown to Coxiella Burnetii Infection
Get PDFCoxiella burnetii is an obligate intracellular bacterium and causative agent of culture-negative endocarditis. Although Coxiella initially infects alveolar macrophages, it is found in lipid droplet (LD)-containing foamy macrophages in endocarditis patients. LDs are host lipid storage organelles containing cholesterol esters (CE) and triacylglycerols (TAG). Our previous studies show that Coxiella actively manipulates host LD metabolism via its Type 4 Secretion System (T4SS), which secretes bacterial effectors in the host cell cytoplasm to manipulate cellular processes. Further, specifically blocking adipose triglyceride lipase (ATGL)-mediated LD breakdown inhibits Coxiella growth suggesting importance of LD-derived lipids for bacterial growth. However, how Coxiella regulates LD breakdown and the composition of LD-derived lipids is unknown. Our preliminary fluorescence microscopy studies using CRISPR knockouts and LD inhibitors indicate presence of TAG-rich LDs in Coxiella-infected cells. ATGL-mediated breakdown of TAG-rich LDs releases arachidonic acids, precursors for lipid immune mediators important for immunomodulation during bacterial infections. Hence we hypothesize that Coxiella manipulates ATGL via its T4SS to initiate TAG-rich LD breakdown and subsequently modulate the immune response to promote bacterial survival. To test this hypothesis, we analyzed ATGL gene expression in differentially infected cells using qRT-PCR. Compared to uninfected and T4SS-infected cells, Coxiella infection increased ATGL expression indicating T4SS-dependent regulation of ATGL. Ongoing studies are elucidating the Coxiella T4SS-ATGL interaction. To identify cellular CE and TAG levels and the breakdown products at different times post-infection, we are performing thin layer chromatography (TLC). Completion of our studies will identify the LD breakdown-derived lipids and how Coxiella regulates LD breakdown of to promote its intracellular survival
Effects of Hypothyroidism on Articular Cartilage in Juvenile Swine
Get PDFContext: This research may provide insight into human articular cartilage development, repair mechanisms, and diseases such as arthritis. Objective: The purpose of this study is to compare the proximal femur articular cartilage from hypothyroid-induced juvenile miniature swine to control animals. Design: This study is a randomized control trial (RCT). Setting: All procedures and housing were IUCUC approved; n=4. Methods: Two juvenile male, 11-week-old miniature swine were administered 6-Propyl-2-thiouracil (PTU) via drinking water to induce hypothyroidism; two control animals were identical in age and sex. The articular cartilage from proximal femurs harvested from 25-week-old animals were analyzed with histology, immunohistochemistry (IHC), and histomorphometry. Histology analyzed tissue morphology and proteoglycan content, IHC assessed types II and X collagen, and histomorphometry measured articular cartilage tissue height and cell density. Nested mixed effects ANOVA with α = 0.05 examined histomorphometry data. Results: Hypothyroid articular cartilage displays increased proteoglycan and decreased type II collagen staining patterns and intensities, compared to controls. Type X collagen is absent in hypothyroid and control articular cartilage, but it is present in control growth plate cartilage. Mean tissue height is increased (2337.0 ± 132.8 μm vs 1076.1 ± 132.7 μm, p = 0.021) and mean cell density is decreased (27.6 ± 1.0 cells/cm2 vs 31.0 ± 1.0 cells/cm2, p = 0.016) in hypothyroid articular cartilage, compared to controls. Conclusions: Hypothyroidism in juvenile miniature swine yielded histomorphometric changes in articular cartilage mean tissue height and mean cell density, and different proteoglycan and type II collagen staining, compared to controls. These data suggest delayed progression of articular cartilage development in hypothyroid animals and support the theory that thyroid hormones are fundamental to articular cartilage growth and development