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1.
J Cell Sci ; 137(11)2024 06 01.
Article in English | MEDLINE | ID: mdl-38757366

ABSTRACT

Nesprin proteins, which are components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, are located within the nuclear envelope and play prominent roles in nuclear architecture. For example, LINC complex proteins interact with both chromatin and the cytoskeleton. Here, we report that the Drosophila Nesprin MSP300 has an additional function in autophagy within larval body wall muscles. RNAi-mediated MSP300 knockdown in larval body wall muscles resulted in defects in the contractile apparatus, muscle degeneration and defective autophagy. In particular, MSP300 knockdown caused accumulation of cytoplasmic aggregates that contained poly-ubiquitylated cargo, as well as the autophagy receptor ref(2)P (the fly homolog of p62 or SQSTM) and Atg8a. Furthermore, MSP300 knockdown larvae expressing an mCherry-GFP-tagged Atg8a transgene exhibited aberrant persistence of the GFP signal within these aggregates, indicating failure of autophagosome maturation. These autophagy deficits were similar to those exhibited by loss of the endoplasmic reticulum (ER) fusion protein Atlastin (Atl), raising the possibility that Atl and MSP300 might function in the same pathway. In support of this possibility, we found that a GFP-tagged MSP300 protein trap exhibited extensive localization to the ER. Alteration of ER-directed MSP300 might abrogate important cytoskeletal contacts necessary for autophagosome completion.


Subject(s)
Autophagy , Drosophila Proteins , Proteostasis , Animals , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/metabolism , Drosophila melanogaster/genetics , Endoplasmic Reticulum/metabolism , Muscles/metabolism , Larva/metabolism , Larva/genetics , Microfilament Proteins , Muscle Proteins
2.
Dev Biol ; 516: 183-195, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39173814

ABSTRACT

Fibroblast Growth Factors and their receptors (FGFRs) comprise a cell signaling module that can stimulate signaling by Ras and the kinases Raf, MEK, and ERK to regulate animal development and homeostatic functions. In Caenorhabditis elegans, the sole FGFR ortholog EGL-15 acts with the GRB2 ortholog SEM-5 to promote chemoattraction and migration by the sex myoblasts (SMs) and fluid homeostasis by the hypodermis (Hyp7). Cell-specific differences in EGL-15 signaling were suggested by the phenotypes caused by egl-15(n1457), an allele that removes a region of its C-terminal domain (CTD) known to bind SEM-5. To determine how mutations altered EGL-15 activity in the SMs and Hyp7, we used the kinase reporter ERK-KTR to measure activation of the ERK ortholog MPK-1. Consequences of egl-15(n1457) were cell-specific, resulting in loss of MPK-1 activity in the SMs and elevated activity in Hyp7. Previous studies of Hyp7 showed that loss of the CLR-1 phosphatase causes a fluid homeostasis defect termed "Clear" that is suppressed by reduction of EGL-15 signaling, a phenotype termed "Suppressor of Clear" (Soc). To identify mechanisms that permit EGL-15 signaling in Hyp7, we conducted a genetic screen for Soc mutants in the clr-1; egl-15(n1457) genotype. We report the identification of SOC-3, a protein with putative SEM-5-binding motifs and PH and PTB domains similar to DOK and IRS proteins. In combination with the egl-15(n1457) mutation, loss of either soc-3, the GAB1 ortholog soc-1, or the SHP2 ortholog ptp-2, reduced MPK-1 activation. We generated alleles of soc-3 to test the requirement for the SEM-5-binding motifs, finding that residue Tyr356 is required for function. We propose that EGL-15-mediated SM chemoattraction relies solely on the direct interaction between SEM-5 and the EGL-15 CTD. In Hyp7, EGL-15 signaling uses two mechanisms: the direct SEM-5 binding mechanism; and an alternative, CTD-independent mechanism involving SOC-3, SOC-1, and PTP-2. This work demonstrates that FGF signaling uses distinct, tissue-specific mechanisms in development, and identifies SOC-3 as a potential adaptor that facilitates Ras pathway activation by FGFR.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Receptors, Fibroblast Growth Factor , Signal Transduction , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Signal Transduction/genetics , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Fibroblast Growth Factor/genetics , Mutation/genetics , Mitogen-Activated Protein Kinase 1
3.
Proc Natl Acad Sci U S A ; 119(32): e2203531119, 2022 Aug 09.
Article in English | MEDLINE | ID: mdl-35921437

ABSTRACT

We show that a Bose-Einstein condensate consisting of dark excitons forms in GaAs coupled quantum wells at low temperatures. We find that the condensate extends over hundreds of micrometers, well beyond the optical excitation region, and is limited only by the boundaries of the mesa. We show that the condensate density is determined by spin-flipping collisions among the excitons, which convert dark excitons into bright ones. The suppression of this process at low temperature yields a density buildup, manifested as a temperature-dependent blueshift of the exciton emission line. Measurements under an in-plane magnetic field allow us to preferentially modify the bright exciton density and determine their role in the system dynamics. We find that their interaction with the condensate leads to its depletion. We present a simple rate-equations model, which well reproduces the observed temperature, power, and magnetic-field dependence of the exciton density.

4.
Cell Tissue Res ; 395(3): 313-326, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38240845

ABSTRACT

Mosquitoes are significant vectors of various pathogens. Unlike vertebrates, insects rely solely on innate immunity. Hemocytes play a crucial role in the cellular part of the innate immune system. The gaseous radical nitric oxide (NO) produced by hemocytes acts against pathogens and also functions as a versatile transmitter in both the immune and nervous systems, utilizing cyclic guanosine monophosphate (cGMP) as a second messenger. This study conducted a parallel comparison of NO synthase (NOS) expression and NO production in hemocytes during Escherichia coli K12 infection in four vector species: Aedes aegypti, Aedes albopictus, Culex pipiens molestus, and Culex pipiens quinquefasciatus. Increased NOS expression by NADPH diaphorase (NADPHd) staining and NO production by immunofluorescence against the by-product L-citrulline were observed in infected mosquito hemocytes distributed throughout the abdomens. NADPHd activity and citrulline labeling were particularly found in periostial hemocytes near the heart, but also on the ventral nerve chord (VNC). Pericardial cells of Ae. aegypti and Cx. p. molestus showed increased citrulline immunofluorescence, suggesting their involvement in the immune response. Oenocytes displayed strong NADPHd and citrulline labeling independent of infection status. This comparative study, consistent with findings in other species, suggests a widespread phenomenon of NO's role in hemocyte responses during E. coli infection. Found differences within and between genera highlight the importance of species-specific investigations.


Subject(s)
Aedes , Culex , Animals , Nitric Oxide , Hemocytes , Citrulline , Escherichia coli , Mosquito Vectors
5.
Prehosp Emerg Care ; : 1-7, 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39212368

ABSTRACT

OBJECTIVES: Elder mistreatment (EM), encompassing abuse and neglect, is a significant public health issue, affecting up to 10% of community-dwelling older adults annually. Elder mistreatment is a growing concern with a higher prevalence in institutional settings and substantial associated healthcare costs. Prehospital clinicians (PHCs) such as emergency medical technicians and paramedics are uniquely positioned to detect and report EM during their interactions with older adults in their homes. The objective of the study is to describe the rate and characteristics of EM documented by PHCs using the National Emergency Medical Services Information System (NEMSIS) database. METHODS: This study analyzed data from NEMSIS, which includes standardized information about PHC emergency response encounters across the United States. In 2018, 22,532,890 activations were included from 9,599 agencies in 43 states and US territories. Elder mistreatment was identified using specific International Classification of Diseases (ICD) codes related to EM. Demographic data, injury location, and associated physical findings were also examined. RESULTS: Out of 9,605,522 EMS encounters for patients aged ≥60, EM was coded in 1,765 encounters (0.02%). Most EM cases were listed as the cause of injury (64%), followed by the clinician's first impression (25.4%). Physical abuse was the most common type of mistreatment reported (20.8%), followed by sexual abuse (18.2%), neglect (9.7%), and psychological/emotional abuse (0.34%). The median age of patients with documented EM was 72, and 62.3% were female. The most common anatomic locations of injuries were the lower extremities, head, and upper extremities. CONCLUSIONS: Despite the high prevalence of EM, PHCs infrequently document EM in their encounters with older adults. Additional training and comprehensive protocols are needed to improve the identification and reporting of EM, mainly elder neglect. Empowering PHCs through education and protocol development can significantly impact the detection and intervention of EM.

6.
J Acoust Soc Am ; 156(2): 1380-1390, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39196104

ABSTRACT

For most of his illustrious career, Ken Stevens focused on examining and documenting the rich detail about vocal tract changes available to listeners underlying the acoustic signal of speech. Current approaches to speech inversion take advantage of this rich detail to recover information about articulatory movement. Our previous speech inversion work focused on movements of the tongue and lips, for which "ground truth" is readily available. In this study, we describe acquisition and validation of ground-truth articulatory data about velopharyngeal port constriction, using both the well-established measure of nasometry plus a novel technique-high-speed nasopharyngoscopy. Nasometry measures the acoustic output of the nasal and oral cavities to derive the measure nasalance. High-speed nasopharyngoscopy captures images of the nasopharyngeal region and can resolve velar motion during speech. By comparing simultaneously collected data from both acquisition modalities, we show that nasalance is a sufficiently sensitive measure to use as ground truth for our speech inversion system. Further, a speech inversion system trained on nasalance can recover known patterns of velopharyngeal port constriction shown by American English speakers. Our findings match well with Stevens' own studies of the acoustics of nasal consonants.


Subject(s)
Speech Acoustics , Speech Production Measurement , Humans , Male , Speech Production Measurement/methods , Adult , Female , Young Adult , Voice Quality , Constriction, Pathologic , Speech/physiology , Endoscopy/methods , Endoscopy/instrumentation
7.
Int J Mol Sci ; 25(11)2024 May 22.
Article in English | MEDLINE | ID: mdl-38891838

ABSTRACT

Nanoparticles (NPs) are becoming increasingly important novel materials for many purposes, including basic research, medicine, agriculture, and engineering. Increasing human and environmental exposure to these promising compounds requires assessment of their potential health risks. While the general direct cytotoxicity of NPs is often routinely measured, more indirect possible long-term effects, such as reproductive or developmental neurotoxicity (DNT), have been studied only occasionally and, if so, mostly on non-human animal models, such as zebrafish embryos. In this present study, we employed a well-characterized human neuronal precursor cell line to test the concentration-dependent DNT of green-manufactured copper sulfide (CuS) nanoparticles on crucial early events in human brain development. CuS NPs turned out to be generally cytotoxic in the low ppm range. Using an established prediction model, we found a clear DNT potential of CuS NPs on neuronal precursor cell migration and neurite outgrowth, with IC50 values 10 times and 5 times, respectively, lower for the specific DNT endpoint than for general cytotoxicity. We conclude that, in addition to the opportunities of NPs, their risks to human health should be carefully considered.


Subject(s)
Copper , Metal Nanoparticles , Neurons , Humans , Copper/toxicity , Metal Nanoparticles/toxicity , Metal Nanoparticles/chemistry , Neurons/drug effects , Sulfides/toxicity , Sulfides/chemistry , Cell Movement/drug effects , Cell Line , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/pathology , Nanoparticles/toxicity , Nanoparticles/chemistry , Neural Stem Cells/drug effects , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Cell Survival/drug effects
8.
J Elder Abuse Negl ; 36(4): 367-383, 2024.
Article in English | MEDLINE | ID: mdl-38602348

ABSTRACT

Elder mistreatment, including elder abuse and neglect, is a difficult diagnosis to make and manage for most providers. To address this, two elder abuse consultation teams were developed for patients in the hospital and emergency department settings. As these teams have developed, the providers involved have obtained specialized training and experience that we believe contributes to a new field of elder abuse geriatrics, a corollary to the well-established field of child abuse pediatrics. Providers working in this field require specialized training and have a specialized scope of practice that includes forensic evaluation, evaluation of cognition and capacity, care coordination and advocacy for victims of abuse, and collaboration with protective services and law enforcement. Here we describe the training, scope of practice, ethical role, and best practices for elder mistreatment medical consultation. We hope this will serve as a starting point for this new and important medical specialty.


Subject(s)
Elder Abuse , Geriatrics , Humans , Elder Abuse/prevention & control , Elder Abuse/diagnosis , Aged , Referral and Consultation , Specialization , Geriatric Assessment/methods
9.
J Elder Abuse Negl ; 36(4): 339-349, 2024.
Article in English | MEDLINE | ID: mdl-39051637

ABSTRACT

Elder mistreatment is common, serious, and under-recognized, with Emergency Department and hospital clinical encounters offering a potential but currently unrealized opportunity to identify and help older adults experiencing mistreatment. Interdisciplinary emergency department and hospital-based response teams represent a promising care model to address this. This manuscript describes two such teams and introduces a special issue dedicated to this work.


Subject(s)
Elder Abuse , Emergency Service, Hospital , Humans , Elder Abuse/prevention & control , Aged , Consensus , Patient Care Team
10.
J Elder Abuse Negl ; 36(4): 350-366, 2024.
Article in English | MEDLINE | ID: mdl-38117212

ABSTRACT

Interdisciplinary Emergency Department/hospital-based teams represent a promising care model to improve identification of and intervention for elder mistreatment. Two institutions, Weill Cornell Medicine/NewYork-Presbyterian Hospital and the University of Colorado Anschutz Medical Campus have launched such programs and are exploring multiple strategies for effective dissemination. These strategies include: (1) program evaluation research, (2) framing as a new model of geriatric care, (3) understanding the existing incentives of health systems, EDs, and hospitals to align with them, (4) connecting to ongoing ED/hospital initiatives, (5) identifying and collaborating with communities with strong elder mistreatment response that want to integrate the ED/hospital, (6) developing and making easily accessible high-quality, comprehensive protocols and training materials, (7) offering technical assistance and support, (8) communications outreach to raise awareness, and (9) using an existing framework to inform implementation in new hospitals and health systems.


Subject(s)
Elder Abuse , Emergency Service, Hospital , Humans , Elder Abuse/prevention & control , Aged , Emergency Service, Hospital/organization & administration , Patient Care Team/organization & administration , Program Evaluation
11.
Mol Psychiatry ; 26(3): 736-746, 2021 03.
Article in English | MEDLINE | ID: mdl-33159186

ABSTRACT

Although the activities of many signaling pathways are dysregulated during the progression of neurodegenerative and muscle degeneration disorders, the precise sequence of cellular events leading to degeneration has not been fully elucidated. Two kinases of particular interest, the growth-promoting Tor kinase and the energy sensor AMPK, appear to show reciprocal changes in activity during degeneration, with increased Tor activity and decreased AMPK activity reported. These changes in activity have been predicted to cause degeneration by attenuating autophagy, leading to the accumulation of unfolded protein aggregates and dysfunctional mitochondria, the consequent increased production of reactive oxygen species (ROS), and ultimately oxidative damage. Here we propose that this increased ROS production not only causes oxidative damage but also ultimately induces an oxidative stress response that reactivates the redox-sensitive AMPK and activates the redox-sensitive stress kinase JNK. Activation of these kinases reactivates autophagy. Because at this late stage, cells have become filled with dysfunctional mitochondria and protein aggregates, which are autophagy targets, this autophagy reactivation induces degeneration. The mechanism proposed here emphasizes that the process of degeneration is dynamic, that dysregulated signaling pathways change over time and can transition from deleterious to beneficial and vice versa as degeneration progresses.


Subject(s)
Autophagy , Oxidative Stress , Mitochondria/metabolism , Oxidation-Reduction , Reactive Oxygen Species/metabolism
12.
Eur Heart J Suppl ; 24(Suppl B): B23-B27, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35370506

ABSTRACT

Transcatheter aortic valve implantation (TAVI) has become a high-volume procedure with increasing demands on hospital resources. Local anaesthesia with sedation supervised by an anaesthesiology team is the current standard of care. We aimed to describe our experience with a simplified, nurse-led sedation (NLS) protocol. This study enrolled 128 consecutive patients who underwent transfemoral TAVI with self-expandable Evolut R prosthesis between November 2019 and April 2021. Operators selected 50% of patients for NLS based on the clinical expectation of lower risk of procedural difficulties. Nurse-led sedation protocol demanded only mild to moderate levels of sedation. The clinical outcomes were determined from the local TAVI registry and the national mortality database. Baseline patient characteristics were similar in the NLS (n = 64) and anaesthesiologist-led sedation (ALS) (n = 64) groups except higher prevalence of diabetes mellitus (48.4% vs. 31.3%, P = 0.035) and peripheral vascular disease (20.3% vs. 7.8%, P = 0.036) in the ALS group. There was a trend for the larger prostheses used in the ALS group (P = 0.058). The procedural results did not differ, and coronary care team backup was rarely needed in the NLS group (6% of patients). The in-hospital outcomes were identical from both clinical and echocardiography perspectives, and 30-day mortality was low in both groups (1.5%). For the NLS group, preparation in the catheterization laboratory was quicker by 6.4 min (P = 0.01), and intensive care unit stay was shorter (2.03 vs. 3.48 days, P = 0.001). In conclusion, the NLS for the selected transfemoral TAVI population seems safe.

13.
J Emerg Med ; 63(2): 143-158, 2022 08.
Article in English | MEDLINE | ID: mdl-35637048

ABSTRACT

BACKGROUND: Burn injuries in geriatric patients are common and may have significant associated morbidity and mortality. Most research has focused on the care of hospitalized patients after admission to burn units. Little is known about the clinical characteristics of geriatric burn victims who present to the emergency department (ED) and their ED assessment and management. OBJECTIVE: Our aim was to describe the clinical characteristics and outcomes of geriatric patients presenting to the ED with burn injuries. METHODS: We performed a comprehensive retrospective chart review on all patients 60 years and older with a burn injury presenting from January 2011 through September 2015 to a large, urban, academic ED in a hospital with a 20-bed burn center. RESULTS: A total of 459 patients 60 years and older were treated for burn injuries during the study period. Median age of burn patients was 71 years, 23.7% were 80 years and older, and 56.6% were female. The most common burn types were hot water scalds (43.6%) and flame burns (23.1%). Median burn size was 3% total body surface area (TBSA), 17.1% had burns > 10% TBSA, and 7.8% of patients had inhalation injuries. After initial evaluation, 46.4% of patients were discharged from the ED. Among patients discharged from the ED, only 1.9% were re-admitted for any reason within 30 days. Of the patients intubated in the ED, 7.1% were extubated during the first 2 days of admission, and 64.3% contracted ventilator-associated pneumonia. CONCLUSIONS: Better understanding of ED care for geriatric burn injuries may identify areas in which to improve emergency care for these vulnerable patients.


Subject(s)
Burn Units , Emergency Medical Services , Aged , Emergency Service, Hospital , Female , Humans , Length of Stay , Male , Retrospective Studies , Water
14.
JAMA ; 328(17): 1730-1739, 2022 11 01.
Article in English | MEDLINE | ID: mdl-36272098

ABSTRACT

Importance: Herpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries. Objective: To inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized. Design, Setting, and Participants: Prospective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment. Exposures: First-episode genital HSV-1 infection. Main Outcomes and Measures: Genital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot. Results: Among the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period. Conclusions and Relevance: Genital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.


Subject(s)
HIV Infections , Herpes Genitalis , Herpes Simplex , Herpesvirus 1, Human , Pregnancy , Female , Humans , Adult , Middle Aged , Male , Herpes Genitalis/virology , Virus Shedding , Herpesvirus 2, Human , Prospective Studies , Genitalia/pathology
15.
Graefes Arch Clin Exp Ophthalmol ; 259(1): 121-128, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32812133

ABSTRACT

PURPOSE: Chronic graft versus host disease is a major consequence after allogeneic stem cell transplantation (allo-SCT) and has great impact on patients' morbidity and mortality. Besides the skin, liver, and intestines, the eyes are most commonly affected, manifesting as severe ocular surface disease. Treatment protocols include topical steroids, cyclosporine, tacrolimus, and ASED. Since these patients often receive systemic immunosuppressant therapy from their oncologists, a topical re-administration of these drugs via ASED with potentially beneficial or harmful effects is possible. The purpose of the study was to determine whether and to which extent systemic immunosuppressants are detectable in ASED. METHODS: A total of 34 samples of ASED from 16 patients with hemato-oncological malignancies after allo-SCT were collected during the manufacturing process and screened for levels of cyclosporine, mycophenolic acid, everolimus, and tacrolimus via liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. RESULTS: Cyclosporine was found in 18 ASED samples in concentrations ranging from 6.5-105.0 ng/ml (32.0 ± 22.8 ng/ml, mean ± SD). The concentration range of mycophenolic acid in 19 samples was 0.04-25.0 mg/l (4.0 ± 5.4 mg/l, mean ± SD). Everolimus and tacrolimus concentrations were well below the respective limits of quantification (< 0.6 and < 0.5 ng/ml) of the established LC-MS/MS method in all samples. CONCLUSIONS: Our study suggests that orally administered cyclosporine and mycophenolic acid for the treatment of systemic GvHD, but not everolimus and tacrolimus, are distinctly detectable in ASED in relevant concentrations. It is highly likely that these agents affect topical therapy of ocular GvHD. However, the extent of this effect needs to be evaluated in further studies.


Subject(s)
Graft vs Host Disease , Immunosuppressive Agents , Chromatography, Liquid , Cyclosporine , Graft vs Host Disease/diagnosis , Graft vs Host Disease/drug therapy , Humans , Ophthalmic Solutions , Tacrolimus , Tandem Mass Spectrometry
16.
Int J Mol Sci ; 22(12)2021 Jun 08.
Article in English | MEDLINE | ID: mdl-34201218

ABSTRACT

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.


Subject(s)
Antineoplastic Agents/toxicity , Blepharitis/pathology , Cornea/blood supply , Graft vs Host Disease/pathology , Hematopoietic Stem Cell Transplantation/adverse effects , Inflammation/pathology , Lacrimal Apparatus/pathology , Animals , Blepharitis/etiology , Blepharitis/metabolism , Disease Models, Animal , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/metabolism , Inflammation/etiology , Inflammation/metabolism , Lacrimal Apparatus/metabolism , Lymphangiogenesis , Mice , Mice, Inbred C57BL
17.
Exp Eye Res ; 201: 108295, 2020 12.
Article in English | MEDLINE | ID: mdl-33038387

ABSTRACT

The lacrimal functional unit (LFU) regulates tear production, composition, distribution and clearance to maintain a stable protective tear layer that is essential for maintaining corneal epithelial health. Dysfunction of the LFU, commonly referred to as dry eye, leads to increased tear osmolarity and levels of inflammatory mediators in tears that cause ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS). Corneal changes in KCS include glycocalyx loss, barrier disruption, surface irregularity inflammatory cytokine/chemokine production, cornification and apoptosis. These can reduce visual function and the increased shear force on the corneal epithelium can stimulate nociceptors sensitized by inflammation causing irritation and pain that may precede frank clinical signs. Therapy of keratoconjunctivitis sicca should be tailored to improve tear stability, normalize tear composition, improve barrier function and minimize shear forces and damaging inflammation to improve corneal epithelial health.


Subject(s)
Cornea/pathology , Keratoconjunctivitis Sicca/pathology , Tears/metabolism , Humans , Keratoconjunctivitis Sicca/metabolism , Osmolar Concentration
18.
Exp Eye Res ; 197: 108115, 2020 08.
Article in English | MEDLINE | ID: mdl-32561483

ABSTRACT

Tears have a vital function to protect and lubricate the ocular surface. Tear production, distribution and clearance is tightly regulated by the lacrimal functional unit (LFU) to meet ocular surface demands. The tear film consists of an aqueous-mucin layer, containing fluid and soluble factors produced by the lacrimal glands and mucin secreted by the goblet cells, that is covered by a lipid layer. The array of proteins, glycoproteins and lipids in tears function to maintain a stable, well-lubricated and smooth optical surface. Tear factors also promote wound healing, suppress inflammation, scavenge free radicals, and defend against microbial infection. Disease and dysfunction of the LFU leads to tear instability, increased evaporation, inflammation, and blurred and fluctuating vision. The function of tear components and the consequences of tear deficiency on the ocular surface are reviewed.


Subject(s)
Dry Eye Syndromes/metabolism , Glycoproteins/metabolism , Lacrimal Apparatus/metabolism , Mucins/metabolism , Tears/metabolism , Humans
19.
Exp Eye Res ; 201: 108294, 2020 12.
Article in English | MEDLINE | ID: mdl-33039458

ABSTRACT

Most patients with chronic dry eye disease (DED) have episodic flares, which can be triggered by a variety of activities and environmental stresses. These flares are typically associated with rapid exacerbation of discomfort symptoms, followed by prolonged elevation of inflammation. In an acute flare, ocular surface inflammation begins with a nonspecific innate immune response, in some cases followed by a slower but more specific adaptive immune response. At the ocular surface, epithelial cells are central to the innate immune response, and we discuss their role in DED flares alongside the other core components. Epithelial cells and other cells of the innate response (neutrophils, monocytes, macrophages and dendritic cells) trigger flares in response to increased osmolarity, detected via pattern receptors on their cell surface. Ultimately, downstream signaling pathways activate innate and adaptive immune responses, with consequent inflammation and symptoms. In chronic DED, pathogenic T cells have infiltrated the ocular surface tissues. The established adaptive immune response is likely to lead to flare-ups at lower thresholds of stress, with inflammation maintained over a longer period. Increased understanding of the inflammatory cascades activated during a flare may guide management and improve outcomes.


Subject(s)
Cytokines/metabolism , Dry Eye Syndromes/metabolism , Immunity, Innate/physiology , Inflammation/metabolism , T-Lymphocytes/immunology , Conjunctiva/immunology , Conjunctiva/metabolism , Dry Eye Syndromes/immunology , Humans , Inflammation/immunology
20.
Transfusion ; 60(9): 1987-1997, 2020 09.
Article in English | MEDLINE | ID: mdl-32743798

ABSTRACT

Risk assessments of transfusion-transmitted emerging infectious diseases (EIDs) are complicated by the fact that blood donors' demographics and behaviors can be different from the general population. Therefore, when assessing potential blood donor exposure to EIDs, the use of general population characteristics, such as U.S. travel statistics, may invoke uncertainties that result in inaccurate estimates of blood donor exposure. This may, in turn, lead to the creation of donor deferral policies that do not match actual risk. STUDY DESIGN AND METHODS: This article reports on the development of a system to rapidly assess EID risks for a nationally representative portion of the U.S. blood donor population. To assess the effectiveness of this system, a test survey was developed and deployed to a statistically representative sample frame of blood donors from five blood collecting organizations. Donors were directed to an online survey to ascertain their recent travel and potential exposure to Middle East respiratory syndrome coronavirus (MERS-CoV). RESULTS: A total of 7128 responses were received from 54 256 invitations. The age-adjusted estimated total number of blood donors potentially exposed to MERS-CoV was approximately 15 640 blood donors compared to a lower U.S. general population-based estimate of 9610 blood donors. CONCLUSION: The structured donor demographic sample-based data provided an assessment of blood donors' potential exposure to an emerging pathogen that was 63% larger than the U.S. population-based estimate. This illustrates the need for tailored blood donor-based EID risk assessments that provide more specific demographic risk intelligence and can inform appropriate regulatory decision making.


Subject(s)
Blood Donors , Blood Transfusion , Blood-Borne Infections/epidemiology , Communicable Diseases, Emerging/epidemiology , Communicable Diseases, Imported/epidemiology , Coronavirus Infections/epidemiology , Environmental Exposure , Risk Assessment/methods , Surveys and Questionnaires , Travel-Related Illness , Adolescent , Adult , Aged , Aged, 80 and over , Blood Banks , Blood Donors/statistics & numerical data , Blood-Borne Infections/blood , Blood-Borne Infections/prevention & control , Blood-Borne Infections/transmission , Communicable Diseases, Emerging/blood , Communicable Diseases, Emerging/prevention & control , Communicable Diseases, Emerging/transmission , Communicable Diseases, Imported/blood , Communicable Diseases, Imported/prevention & control , Communicable Diseases, Imported/transmission , Coronavirus Infections/blood , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Decision Making , Female , Humans , Male , Middle Aged , Middle East , Middle East Respiratory Syndrome Coronavirus , Sample Size , Sampling Studies , Transfusion Reaction/prevention & control , United States/epidemiology , Young Adult
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