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1.
J Clin Invest ; 134(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38557487

RESUMO

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.


Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus , Imunidade Humoral , Interleucina-6 , Antivirais , Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Imunoglobulina G , Interleucina-6/metabolismo , Animais , Camundongos
2.
Cureus ; 16(2): e54717, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38524083

RESUMO

Lateral abdominal wall hematoma is a rare clinical entity but a great mimicker of other diseases' clinical presentations. In this case report, we present a 42-year-old male patient with a constellation of signs and symptoms that were mistaken for aortic dissection before the lateral abdominal wall hematoma diagnosis was confirmed with computed tomography (CT) imaging. Uncontrolled hypertension and persistent cough were most likely predisposing factors; the patient was managed conservatively and discharged in a stable condition.

3.
BMJ Open ; 14(3): e077196, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453199

RESUMO

OBJECTIVES: Remote monitoring of health has the potential to reduce the burden to patients of face-to-face appointments and make healthcare more efficient. Apps are available for patients to self-monitor vision at home, for example, to detect reactivation of age-related macular degeneration (AMD). Describing the challenges when implementing apps for self-monitoring of vision at home was an objective of the MONARCH study to evaluate two vision-monitoring apps on an iPod Touch (Multibit and MyVisionTrack). DESIGN: Diagnostic Test Accuracy study. SETTING: Six UK hospitals. METHODS: The study provides an example of the real-world implementation of such apps across health sectors in an older population. Challenges described include the following: (1) frequency and reason for incoming calls made to a helpline and outgoing calls made to participants; (2) frequency and duration of events responsible for the tests being unavailable; and (3) other technical and logistical challenges. RESULTS: Patients (n=297) in the study were familiar with technology; 252/296 (85%) had internet at home and 197/296 (67%) had used a smartphone. Nevertheless, 141 (46%) called the study helpline, more often than anticipated. Of 435 reasons for calling, all but 42 (10%) related to testing with the apps or hardware, which contributed to reduced adherence. The team made at least one call to 133 patients (44%) to investigate why data had not been transmitted. Multibit and MyVisionTrack apps were unavailable for 15 and 30 of 1318 testing days for reasons which were the responsibility of the app providers. Researchers also experienced technical challenges with a multiple device management system. Logistical challenges included regulations for transporting lithium-ion batteries and malfunctioning chargers. CONCLUSIONS: Implementation of similar technologies should incorporate a well-resourced helpline and build in additional training time for participants and troubleshooting time for staff. There should also be robust evidence that chosen technologies are fit for the intended purpose. TRIAL REGISTRATION NUMBER: ISRCTN79058224.


Assuntos
Degeneração Macular , Aplicativos Móveis , Telemedicina , Humanos , Smartphone , Degeneração Macular/terapia
4.
Perspect Public Health ; : 17579139231185481, 2023 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-37544328

RESUMO

BACKGROUND: In the UK, most smokers choosing e-cigarettes to quit smoking will access vaping via commercial routes. In recent years, however, a shift towards medicalisation of vaping has become apparent, with public health guidance supporting e-cigarettes for smoking cessation and increased partnership working between healthcare professionals and the vaping industry. To achieve the UK's Smokefree 2030 target, the UK Government has set out measures to use e-cigarettes in National Health Service (NHS) settings and to move towards streamlining processes to make e-cigarettes available to a million smokers. This article aims to understand acceptability of different approaches by seeking perspectives of people with lived experience of e-cigarette use for smoking cessation. METHODS: Mixed methods data collected between March 2018 and March 2019 as part of a broader study of e-cigarette use trajectories (ECtra study). Data here relate to the views of partnership working and medicalisation of vaping extracted from 136 interviews/extended surveys of people who had used e-cigarettes to try to stop smoking. Qualitative data were thematically analysed. Participant ratings of interventions were presented descriptively, and differences in participant characteristics and ratings were reported. RESULTS: Three qualitative themes were identified: pro-partnership, anti-partnership and medicalisation dissonance. Medicalisation was discussed for its potential to reassure smokers about e-cigarette harms and its potential to reach smokers from disadvantaged backgrounds. Concerns were raised about cost-effectiveness, quality of support, conflicts of interest and limiting product choice. Most participants rated interventions involving partnership working as potentially helpful in switching from smoking to vaping. There were no statistically significant associations between age, gender and socioeconomic status, and helpfulness ratings. CONCLUSION: Both commercial and medical routes to vaping offer perceived benefits to vapers and may complement and reinforce each other to support smoking cessation.

5.
Soc Sci Med ; 332: 116080, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37451941

RESUMO

The COVID-19 pandemic and associated 'lockdowns' profoundly impacted people's lives in 2020-2021 and beyond. This study sought to understand unique person-centred insights into health and wellbeing during the restrictive measures in the United Kingdom and to enable us to remember and give testimony to these lived experiences. Using photo-methods, participants from a larger cohort study which tracked people's behaviours during the pandemic were invited to share photographs and short text to visually illustrate their ephemeral and unique COVID-19 experiences. In total 197 participants shared 398 photographs. Using a critical realist approach in our design and analysis, we sought to gain an alternative viewpoint on what 'lockdown' and the pandemic meant. Our major findings revealed starkly contrasting experiences illustrated in our two major themes. Firstly loss, including ambiguous losses and a sense of loss, loss of freedoms and death. Secondly, salutogenesis (what makes us well) whereby participants were able to draw on assets which helped to keep them well by maintaining social connection, 'making the best of it', reconnecting with nature and appreciating the outdoors, creativity for pleasure and faith. Our findings illuminate widely differing experiences and indicate the powerful effect of assets that were perceived by our participants to protect their wellbeing. Understanding differential vulnerability will be essential going forward to target resources appropriately to those who have the least control over their lives, those with the greatest vulnerabilities and least assets which in turn could support a self-perpetuating recovery.

6.
Int J Aging Hum Dev ; 97(1): 65-80, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36259123

RESUMO

Insomnia symptoms are prevalent in older adults with mild cognitive impairment (MCI) and can pose treatment challenges. We tested the feasibility, acceptability, and preliminary efficacy of assisted relaxation therapy (ART) to improve insomnia symptoms in community-dwelling older adults with MCI. In this pilot RCT, 25 participants were assigned to intervention or control groups for 2 weeks. The final sample (n = 20) consisted of all Black, primarily female (70%) older adults (mean age 69.10; SD = 7.45) with mean Montreal Cognitive Assessment scores of 21.10 (SD = 2.49). Recruitment was timely; attrition was low (80%). Participants were able to use ART (average use 7.00; SD = 5.07 days). Participants in the ART group improved on Insomnia Severity Index (ISI) (- 7.10; 95% CI [-11.63, -2.55]; p = .004) compared to baseline. There were clinically meaningful mean change scores on ISI for the intervention group compared to the control (- 7.10 vs. - 4.33). Results provide justification for testing ART in a fully powered clinical trial.


Assuntos
Disfunção Cognitiva , Distúrbios do Início e da Manutenção do Sono , Feminino , Humanos , Idoso , Terapia de Relaxamento , Projetos Piloto , Distúrbios do Início e da Manutenção do Sono/terapia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/terapia , Vida Independente
7.
Neuropsychologia ; 174: 108339, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-35921869

RESUMO

Accumulating evidence indicates two cortical regions, the left ventral premotor cortex (PMv) and left intraparietal sulcus (IPS), are involved in spoken verb production. Some evidence also indicates these regions may be differentially engaged by transitive (i.e., object-oriented) versus intransitive actions. We explored the role of these regions during action picture naming in two experiments, each employing high frequency (10 Hz) online repetitive Transcranial Magnetic Stimulation (rTMS) in 20 participants. In Experiment 1, participants named intransitive action pictures (e.g., LAUGH) accompanied by active and sham rTMS to the left PMv, left IPS, and right superior parietal lobule (SPL; control site). Application of rTMS to PMv resulted in slower naming latencies compared to sham and control site stimulation, whereas stimulation of the IPS did not result in any significant effects. Experiment 2 employed active and sham rTMS identical to Experiment 1 with transitive action pictures (e.g., PUSH). Stimulation of both regions induced changes in naming latencies compared to sham and control site stimulation, with rTMS applied to PMv slowing responses and IPS stimulation facilitating them. Surprisingly, stimulation of the right SPL control site also slowed naming compared to sham across both Experiments. Overall, these findings indicate different roles for PMv and IPS during action picture naming. Specifically, the divergent effects of PMv and IPS stimulation in the transitive action naming task indicate different processes likely operate in the two regions during verb production. Involvement of the right SPL across both transitive and intransitive action naming might reflect visuospatial or general attention mechanisms rather than language processes per se.


Assuntos
Córtex Motor , Nomes , Humanos , Idioma , Lobo Parietal/fisiologia , Estimulação Magnética Transcraniana/métodos
8.
Front Immunol ; 13: 892534, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757719

RESUMO

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.


Assuntos
Doenças Autoimunes , Imunoglobulina G , Doenças Autoimunes/tratamento farmacológico , Homeostase , Humanos , Imunoglobulina G/metabolismo , Recém-Nascido , Receptores Fc , Albumina Sérica/metabolismo
9.
Aust Crit Care ; 35(2): 210-216, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33902987

RESUMO

INTRODUCTION: Impaired respiratory and swallow function in patients with intensive care unit-acquired deconditioning, such as associated with massive tissue loss, is not uncommon and can require prolonged rehabilitation. AIM: The aim of the study was to examine the effect of combined inspiratory and expiratory respiratory muscle strength training (RMST) on respiratory and swallow function in two critical care patients with marked deconditioning after massive tissue loss. METHODS: Case 1 was a 19-year-old male patient with 80% body surface area burns; case 2 was a 45-year-old man with group A streptococcus myositis necessitating quadruple amputation. Both required prolonged intensive care and mechanical ventilation. Both received routine intensive pulmonary and swallow rehabilitation before the trial; however, chronic aspiration and poor secretion clearance remained. At 25 and 26 weeks after initial injury, RMST was performed using EMST150 (expiratory) and Threshold IMT (inspiratory) devices, respectively. At baseline and throughout treatment, data collected included peak expiratory flow (PEF), anthropometry measures, aspiration risk (Penetration-Aspiration Scale [PAS]), pharyngeal clearance (Yale Pharyngeal Residue Scale), secretions (New Zealand Secretion Scale [NZSS]), and functional diet (Functional Oral Intake Scale [FOIS]) via endoscopy. RESULTS/DISCUSSION: At baseline, the PEF score of case 1 was 41% (predicted age-height norm) and the PEF score of case 2 was 14%, indicating severe expiratory compromise. Both had extreme energy requirements (3300 kcal/day; 3500 kcal/day). The baseline swallowing scores of case 1 and 2 were as follows: PAS, 8 and 8; Yale, 9 and 10; NZSS, 4 and 7; and FOIS, 1 and 1, respectively, indicating profound dysphagia. At week 3 of 7 of RMST, swallow function improved to allow both to commence oral intake, followed by tracheostomy decannulation. At weeks 10 and 11, full dysphagia resolution was achieved (FOIS = 7; PAS = 1, Yale = 2, NZSS = 0), with PEF at 70% and 48% predicted respectively. Both patients continued RMST, and at discharge from the acute facility, PEF was 84% and 80% predicted respectively. CONCLUSION: The addition of RMST assisted swallow and pulmonary rehabilitation in both cases and was clinically viable to deliver. Controlled validation trials are now required.


Assuntos
Transtornos de Deglutição , Treinamento de Força , Adulto , Exercícios Respiratórios , Deglutição/fisiologia , Transtornos de Deglutição/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Respiratórios , Adulto Jovem
10.
Br J Dermatol ; 186(3): 429-439, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34608631

RESUMO

BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. OBJECTIVES: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. METHODS: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg-1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). RESULTS: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg-1 and 13 of 15 (87%) patients receiving 25 mg kg-1 , with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg-1 per day (range 0·06-0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. CONCLUSIONS: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.


Assuntos
Anticorpos Monoclonais Humanizados , Pênfigo , Anticorpos Monoclonais Humanizados/efeitos adversos , Autoanticorpos , Desmogleína 1 , Estudos de Viabilidade , Antígenos de Histocompatibilidade Classe I , Humanos , Imunoglobulina G , Recém-Nascido , Pênfigo/tratamento farmacológico , Prednisona/administração & dosagem , Receptores Fc
11.
MAbs ; 13(1): 1976705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34592895

RESUMO

The prolonged in vivo persistence of antibodies results in high background and poor contrast during their use as molecular imaging agents for positron emission tomography (PET). We have recently described a class of engineered Fc fusion proteins that selectively deplete antigen-specific antibodies without affecting the levels of antibodies of other specificities. Here, we demonstrate that these Fc fusions (called Seldegs, for selective degradation) can be used to clear circulating, radiolabeled HER2-specific antibody during diagnostic imaging of HER2-positive tumors in mice. The analyses show that Seldegs have considerable promise for the reduction of whole-body exposure to radiolabel and improvement of contrast during PET.


Assuntos
Neoplasias , Tomografia por Emissão de Pósitrons , Animais , Anticorpos , Linhagem Celular Tumoral , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Receptor ErbB-2
12.
J Neurol Sci ; 430: 118074, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34563918

RESUMO

The neonatal Fc receptor (FcRn) is an MHC class I-like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining immunoglobulin G (IgG) and albumin levels through rescuing these molecules from lysosomal degradation. IgG autoantibodies are associated with many autoimmune diseases, including myasthenia gravis (MG), a rare neuromuscular autoimmune disease that causes debilitating and, in its generalized form (gMG), potentially life-threatening muscle weakness. IgG autoantibodies are directly pathogenic in MG and target neuromuscular junction proteins, causing neuromuscular transmission failure. Treatment approaches that reduce autoantibody levels, such as therapeutic plasma exchange and intravenous immunoglobulin, have been shown to be effective for gMG patients but are not indicated as ongoing maintenance therapies and can be associated with burdensome side effects. Agents that block FcRn-mediated recycling of IgG represent a rational and promising approach for the treatment of gMG. Blocking FcRn allows targeted reduction of all IgG subtypes without decreasing concentrations of other Ig isotypes; therefore, FcRn blocking could be a safe and effective treatment strategy for a broad population of gMG patients. Several FcRn-blocking antibodies and one antibody Fc fragment have been developed and are currently in various stages of clinical development. This article describes the mechanism of FcRn blockade as a novel approach for IgG-mediated disease therapy and reviews promising clinical data using such FcRn blockers for the treatment of gMG.


Assuntos
Imunoglobulina G , Miastenia Gravis , Animais , Autoanticorpos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Miastenia Gravis/tratamento farmacológico
13.
MAbs ; 13(1): 1870059, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33435811

RESUMO

In a scientific career that spanned over three decades, Dr. Jeff Foote made seminal contributions to antibody humanization and the biophysical aspects of antibody recognition. In this Perspective, we discuss his life and work.

14.
Dysphagia ; 36(6): 1019-1030, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33386482

RESUMO

Difficulty swallowing has been reported following whiplash injury; however, the reasons remain poorly understood. A possible factor may be the observed changes in pharyngeal volume. The current exploratory study was designed to examine the prevalence of self-reported dysphagia after whiplash and the relationship with recovery status and change in pharyngeal volume. Data were available from a longitudinal study of adults with whiplash. Data included magnetic resonance imaging (MRI) of the cervical spine, the Dysphagia Handicap Index (DHI), and Neck Disability Index (NDI) collected over four timepoints (< 1 week, 2 weeks, 3 months, and 12 months post-injury). Initial cross-sectional analysis examined 60 patients with DHI data from at least one timepoint. A second, longitudinal analysis was conducted on 31 participants with MRI, NDI, and DHI data at both early (< 1-2 weeks) and late (3-12 months) timepoints. The pharynx was contoured on axial T2-weighted MRI slices using OsiriX image processing software and pharyngeal volume (mm3) was quantified. In the 60-patient cohort, prevalence of self-reported dysphagia (DHI ≥ 3) was observed in 50% of participants at least once in 12 months (M = 4.9, SD 8.16, range 0-40). In the longitudinal cohort (n = 31), mean total DHI significantly (p = 0.006) increased between early and late stages. There was no relationship (p = 1.0) between dysphagia and recovery status, per the NDI% score. Pharyngeal volume remained stable and there was no relationship between dysphagia and pharyngeal volume change (p = 1.0). This exploratory study supports the need for further work to understand the nature of dysphagia, extent of functional compromise, and the underlying pathophysiology post-whiplash.


Assuntos
Transtornos de Deglutição , Traumatismos em Chicotada , Estudos Transversais , Deglutição , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Humanos , Estudos Longitudinais , Faringe/diagnóstico por imagem , Autorrelato , Traumatismos em Chicotada/complicações , Traumatismos em Chicotada/diagnóstico por imagem
15.
Dysphagia ; 36(2): 303-315, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32445061

RESUMO

Swallowing and voice complaints after a whiplash injury have been observed and reported in several studies; however, variability in study design complicates current understanding of whether dysphagia and dysphonia should be recognised as potential adverse outcomes. A scoping review was conducted across six databases from 1950 to March 2019. A total of 18 studies were included for review. Data regarding study purpose, design, outcome measures, participant characteristics and outcomes reported were extracted. Level of evidence (LOE) was assessed by the American Speech-Language Language Association (ASHA)'s LOE system. All studies were exploratory, with 68% rated as poor (< 3) on quality ratings. Nearly half (n = 6) were single case reports. Only three studies investigated some type of swallow-related outcome specifically within the study aim/s. Incidence of swallow-related problems ranged from 2 to 29%, with unspecified complaints of "swallowing difficulty", "dysphagia" and fatigue and pain whilst chewing reported. Neither swallowing biomechanics nor the underlying pathophysiology of swallow or voice complaints was investigated in any study. Four case studies presented post-whiplash voice complaints; two of which described loss of pitch range. Others described hoarseness, loss of control and weak phonation. Most studies only mentioned swallow- or voice-related deficits when reporting a wider set of post-injury symptomatology and six did not describe the outcome measure used to identify the swallow and voice-related problems reported. The existing literature is limited and of low quality, contributing to an unclear picture of the true incidence and underlying mechanisms of whiplash-related dysphagia and dysphonia.


Assuntos
Transtornos de Deglutição , Disfonia , Traumatismos em Chicotada , Deglutição , Transtornos de Deglutição/etiologia , Disfonia/etiologia , Rouquidão , Humanos , Traumatismos em Chicotada/complicações
16.
Opt Express ; 29(1): 182-207, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33362108

RESUMO

Single-molecule microscopy allows for the investigation of the dynamics of individual molecules and the visualization of subcellular structures at high spatial resolution. For single-molecule imaging experiments, and particularly those that entail the acquisition of multicolor data, calibration of the microscope and its optical components therefore needs to be carried out at a high level of accuracy. We propose here a method for calibrating a microscope at the nanometer scale, in the sense of determining optical aberrations as revealed by point source localization errors on the order of nanometers. The method is based on the imaging of a standard sample to detect and evaluate the amount of geometric aberration introduced in the optical light path. To provide support for multicolor imaging, it also includes procedures for evaluating the geometric aberration caused by a dichroic filter and the axial chromatic aberration introduced by an objective lens.

17.
Mol Ther ; 29(3): 1312-1323, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33212299

RESUMO

Current treatments for antibody-mediated autoimmunity are associated with lack of specificity, leading to immunosuppressive effects. To overcome this limitation, we have developed a class of antibody-based therapeutics for the treatment of autoimmunity involving antibodies that recognize the autoantigen, myelin oligodendrocyte glycoprotein (MOG). These agents ("Seldegs," for selective degradation) selectively eliminate antigen (MOG)-specific antibodies without affecting the levels of antibodies of other specificities. Seldeg treatment of mice during antibody-mediated exacerbation of experimental autoimmune encephalomyelitis by patient-derived MOG-specific antibodies results in disease amelioration. Consistent with their therapeutic effects, Seldegs deliver their targeted antibodies to Kupffer and liver sinusoidal endothelial cells that are known to have tolerogenic effects. Our results show that Seldegs can ameliorate disease mediated by MOG-specific antibodies and indicate that this approach also has the potential to treat other autoimmune diseases where the specific clearance of antibodies is required.


Assuntos
Anticorpos Monoclonais/metabolismo , Autoanticorpos/imunologia , Autoantígenos/imunologia , Encefalomielite Autoimune Experimental/terapia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de IgG/metabolismo
18.
Bioorg Med Chem ; 28(24): 115808, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33071032

RESUMO

As a versatile reaction for bioconjugation, Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has enormous potential in the synthesis of antibody-drug conjugates (ADCs). In order to optimize CuAAC-based ADC synthesis, we characterized kinetically different formulation processes by mimicking ADC synthesis using small molecules and subsequently revealed unique kinetic behaviors of different combinations of alkyne and azide conditions. Our results indicate that under ADC synthesis conditions, for an alkyne-containing drug, its concentration has minimal impact on the reaction rate when an antibody has a non-metal-chelating azide but is proportional to concentration when an antibody contains a metal-chelating azide; however, for an alkyne-containing antibody, the ADC synthesis rate is proportional to the concentration of a drug with a non-metal-chelating azide but displays almost no dependence on drug concentration with a metal-chelating azide. Based on our results, we designed and tested an optimal "click" formulation strategy that allowed rapid and cost-effective synthesis of a new ADC.


Assuntos
Química Click , Imunoconjugados/química , Alcinos/química , Anticorpos Monoclonais Humanizados/química , Azidas/química , Catálise , Cobre/química , Reação de Cicloadição , Preparações Farmacêuticas/química
19.
J Environ Qual ; 49(2): 392-403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33016417

RESUMO

Numerous studies have documented the linkages between agricultural nitrogen loads and surface water degradation. In contrast, potential water quality improvements due to agricultural best management practices are difficult to detect because of the confounding effect of background nitrate removal rates, as well as the groundwater-driven delay between land surface action and stream response. To characterize background controls on nitrate removal in two agricultural catchments, we calibrated groundwater travel time distributions with subsurface environmental tracer data to quantify the lag time between historic agricultural inputs and measured baseflow nitrate. We then estimated spatially distributed loading to the water table from nitrate measurements at monitoring wells, using machine learning techniques to extrapolate the loading to unmonitored portions of the catchment to subsequently estimate catchment removal controls. Multiple models agree that in-stream processes remove as much as 75% of incoming loads for one subcatchment while removing <20% of incoming loads for the other. The use of a spatially variable loading field did not result in meaningfully different optimized parameter estimates or model performance when compared with spatially constant loading derived directly from a county-scale agricultural nitrogen budget. Although previous studies using individual well measurements have shown that subsurface denitrification due to contact with a reducing argillaceous confining unit plays an important role in nitrate removal, the catchment-scale contribution of this process is difficult to quantify given the available data. Nonetheless, the study provides a baseline characterization of nitrate transport timescales and removal mechanisms that will support future efforts to detect water quality benefits from ongoing best management practice implementation.


Assuntos
Monitoramento Ambiental , Água Subterrânea , Agricultura , Nitratos/análise , Rios
20.
Dysphagia ; 35(6): 968-977, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32103328

RESUMO

Inhalation injury is predictive of dysphagia post burns; however, the nature of dysphagia associated with inhalation burns is not well understood. This study describes the clinical profile and recovery pattern of swallowing following inhalation burn injury. All patients admitted 2008-2017 with confirmed inhalation burns on laryngoscopy and managed by speech-language pathology (SLP) were included. Initial dysphagia presentation and dysphagia recovery pattern were documented using the FOIS. Co-presence of dysphonia was determined clinically and rated present/absent. Persistent laryngeal/pharyngeal injury at 6 months was documented using laryngoscopy. Data were compared to published data from a large adult burn cohort. All patients with confirmed inhalation burns during the study period received SLP input, enabling review of 38 patients (68% male; m = 40.8 years). Percent Total Body Surface Area burn ranged 1-90%, 100% had head and neck burns, 97% required mechanical ventilation (mean 9.4 days), 18% required tracheostomy and 100% had dysphonia. Comparing to non-inhalation burn patients, the inhalation cohort had significantly (p < 0.01) higher dysphagia incidence (89.47% vs 5.6%); more with severe dysphagia at presentation (78.9% vs 1.7%); increased duration to initiate oral intake (m = 24.69 vs 0.089 days); longer duration of enteral feeding (m = 45.03 vs 1.96 days); and longer duration to resolution of dysphagia (m = 29.79 vs 1.67 days). Persistent laryngeal pathology was present in 47.37% at 6 months. This study shows dysphagia incidence in burn patients with inhalation injury is 16 times greater than for those without inhalation injury. Laryngeal pathology due to inhalation injury increases dysphagia severity and duration to dysphagia recovery.


Assuntos
Transtornos de Deglutição , Adulto , Deglutição , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Feminino , Humanos , Incidência , Masculino , Respiração Artificial , Estudos Retrospectivos , Traqueostomia
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