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1.
BMC Prim Care ; 25(1): 128, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658808

RESUMO

BACKGROUND: Patients' ideas, concerns, and expectations are three important concepts in consultation techniques. Limited studies on these concepts include responses from both health care providers and care recipients of the same consultation. Highlighting both perspectives provides an increased understanding of the consultation. This study aims to explore the perspectives of patients and health care professionals about patients' expectations of primary health care during consultations with primary care physicians and compare the two sets of perspectives. METHODS: A cross-sectional study. Patients (n = 113) and physicians (n = 67) from five primary health care centers completed a questionnaire after planned consultations. Their responses to open-ended questions about patients' expectations, from patients' and physicians' perspectives were analyzed with qualitative content analyses. RESULTS: The patients expected a personal journey, through the primary health care system where they were the subject of interest. A journey, with ready access to a health care provider followed by a consultation with the physician, medical measures administered, their outcomes discussed, and a plan developed for continued health care. The physicians observed patients' expectations to concern the responsibilities placed on primary health care where patients were the object of interest. Patients' short-term expectations were described in a similar way by both patients and physicians. Patients expressed their long-term expectations as more personal and interpersonal whereas physicians observed them from a more professional and organizational standpoint. CONCLUSIONS: Patients and physicians have different views of what patients expect of primary health care. While patients' short-term expectations were perceived by physicians, their long-term expectations were not. Patients expected more of a personal journey through the primary health care system while physicians observed patients' expectations to concern the responsibilities placed on primary health care. Identifying and meeting patients' expectations is an important part of patient-centered care, and a better understanding of patients' expectations is needed to improve health professionals' consultation skills.


Assuntos
Atitude do Pessoal de Saúde , Satisfação do Paciente , Relações Médico-Paciente , Atenção Primária à Saúde , Humanos , Masculino , Estudos Transversais , Feminino , Inquéritos e Questionários , Pessoa de Meia-Idade , Adulto , Pesquisa Qualitativa , Idoso
3.
Acta Oncol ; 63: 44-50, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38380845

RESUMO

BACKGROUND: Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous mastocytosis (CM). The epidemiology of mastocytosis remains incompletely understood. OBJECTIVE: To estimate the incidence, prevalence, overall survival (OS) and burden of comorbidities in adult mastocytosis patients identified in Swedish population-based registries. METHODS: Individuals (≥ 20 years of age) with a mastocytosis diagnosis in the National Patient Register (NPR) and/or the Swedish Cancer Register (SCR) between 2001 and 2018, were identified. In a matched cohort design, for each case five randomly selected mastocytosis-free comparators matched on age, sex, and county of residence were chosen from the Population Register. The Kaplan-Meier method was used to compare OS between individuals with mastocytosis and comparators. Information on concomitant disease at baseline was assessed by use of the Charlson Comorbidity Index (CCI). RESULTS: We identified 2,040 adults with a mastocytosis diagnosis yielding an annual incidence of 1.56 per 100,000 (95% CI 1.29-1.87) and a prevalence of 23.9 per 100,000 (95% CI 22.8-25.0). The comorbidity burden was higher, and the OS lower, in patients with mastocytosis compared to comparators. INTERPRETATION: We found a higher incidence and prevalence of mastocytosis compared to assessments in other settings and confirmed that the prognosis generally is favorable. Of special note was evidence of a higher comorbidity burden in mastocytosis patients compared to the background population. LIMITATIONS: Underreporting and inconsistencies in the use of diagnostic codes.


Assuntos
Mastocitose Sistêmica , Mastocitose , Adulto , Humanos , Mastócitos , Mastocitose/epidemiologia , Mastocitose/complicações , Mastocitose/diagnóstico , Mastocitose Sistêmica/epidemiologia , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/diagnóstico , Prognóstico , Suécia/epidemiologia , Adulto Jovem , Masculino , Feminino
4.
Acta Neurochir (Wien) ; 166(1): 90, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38374453

RESUMO

PURPOSE: The purpose of this study was to evaluate patient-reported outcome measures (PROMS) on dysphagia, health-related quality of life (HRQoL) and return to work after occipitocervical fixation (OCF). Postoperative radiographic measurements were evaluated to identify possible predictors of dysphagia. METHODS: All individuals (≥ 18 years) who underwent an OCF at the study center or were registered in the Swedish spine registry (Swespine) between 2005 and 2019, and were still alive when the study was conducted, were eligible for inclusion. There was no overlap between the cohorts. Prospectively collected data on dysphagia (Dysphagia Short Questionnaire DSQ), HRQoL (EQ5D-3L) and return to work were used. Radiological and baseline patient data were retrospectively collected. In addition, HRQoL data of a matched sample of individuals was elicited from the Stockholm Public Health Survey 2006. RESULTS: In total, 54 individuals were included. At long-term follow-up, 26 individuals (51%) had no dysphagia, and 25 (49%) reported some degree of dysphagia: 11 (22%) had mild dysphagia, and 14 (27%) had moderate to severe dysphagia. On a group level, the OCF sample scored significantly lower EQVAS and EQ-5Dindex values compared to the general population (60.0 vs. 80.0, p = 0.016; 0.43 vs. 0.80, p < 0.001). Individuals working preoperatively returned to work after surgery. Of those responding, 88% stated that they would undergo the OCF operation if it was offered today. No predictors of dysphagia based on radiographic measurements were identified. CONCLUSION: Occipitocervical fixation results in a high frequency of long-term dysphagia. The HRQoL of OCF patients is significantly reduced compared to matched controls. However, most patients are satisfied with their surgery. No radiographic predictors of long-term dysphagia could be identified. Future prospective and systematic studies with larger samples and more objective outcome measures are needed to elucidate the causes of dysphagia in OCF.


Assuntos
Transtornos de Deglutição , Fusão Vertebral , Humanos , Estudos Retrospectivos , Transtornos de Deglutição/etiologia , Qualidade de Vida , Retorno ao Trabalho , Fusão Vertebral/métodos , Vértebras Cervicais/cirurgia
5.
BMC Cardiovasc Disord ; 24(1): 27, 2024 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172659

RESUMO

BACKGROUND: Automated measurement of blood pressure (BP) in designated BP kiosks have in recent years been introduced in primary care. If kiosk blood pressure (BP) monitoring provides results equivalent to in-office BP or daytime ambulatory BP monitoring (ABPM), follow-up of adult patients could be managed primarily by self-checks. We therefore designed a comparative trial and evaluated the diagnostic performance of kiosk- and office-based BP (nurse- versus physician-measured) compared with daytime ABPM. METHODS: A trial of automated BP monitoring in three settings: a designated BP kiosk, by nurses and physicians in clinic, and by ABPM. The primary outcome was systolic and diastolic BP, with respective diagnostic thresholds of ≥135 mmHg and/or ≥ 85 mmHg for daytime ABPM and kiosk BP and ≥ 140 mmHg and/or ≥ 90 mmHg for office BP (nurse- and physician-measured). RESULTS: Compared with daytime ABPM, mean systolic kiosk BP was higher by 6.2 mmHg (95% confidence interval [CI] 3.8-8.6) and diastolic by 7.9 mmHg (95% CI 6.2-9.6; p < 0.001). Mean systolic BP taken by nurses was similar to daytime ABPM values (+ 2.0 mmHg; 95% CI - 0.2-4.2; p = 0.071), but nurse-measured diastolic values were higher, by 7.2 mmHg (95% CI 5.9-9.6; p < 0.001). Mean systolic and diastolic physician-measured BPs were higher compared with daytime ABPM (systolic, by 7.6 mmHg [95% CI 4.5-10.2] and diastolic by 5.8 mmHg [95% CI 4.1-7.6]; p < 0.001). Receiver operating characteristic curves of BP monitoring across pairs of systolic/diastolic cut-off levels among the three settings, with daytime ABPM as reference, demonstrated overall similar diagnostic performance between kiosk and nurse-measured values and over the curve performance for physician-measured BP. Accuracy with nurse-measured BP was 69.2% (95% CI 60.0-77.4%), compared with 65.8% (95% CI 56.5-74.3%) for kiosk BP. CONCLUSIONS: In this study kiosk BP monitoring was not comparable to daytime ABPM but could be an alternative to in-office BP monitoring by trained nurses. The diagnostic performance of kiosk and nurse-measured BP monitoring was similar and better than that of physician-measured BP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04488289) 27/07/2020.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Hipertensão , Adulto , Humanos , Pressão Sanguínea , Determinação da Pressão Arterial/métodos , Hipertensão/diagnóstico , Autocuidado
6.
BMJ Open ; 13(12): e072037, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38056945

RESUMO

INTRODUCTION: The individual, societal and economic benefits of stroke prevention are high. Even though most risk factors can be reduced by changes to lifestyle habits, maintaining new and healthy activity patterns has been shown to be challenging.The aim of the study is to evaluate the impact of an interdisciplinary team-based, mHealth-supported prevention intervention on persons at risk for stroke. The intervention is mediated by engaging everyday activities that promote health. An additional aim is to describe a process evaluation that serves to increase knowledge about how the programme leads to potential change by studying the implementation process and mechanisms of impact. METHODS AND ANALYSIS: The study will be a randomised controlled trial including 104 persons at risk for stroke. Persons at risk of stroke (n=52) will be randomised to an mHealth-supported stroke prevention programme. Controls will have ordinary primary healthcare (PHC) services. The 10-week programme will be conducted at PHC clinics, combining group meetings and online resources to support self-management of lifestyle change using engaging everyday activities as a mediator. Primary outcomes are stroke risk, lifestyle habits and participation in health-promoting activities. Assessments will be performed at baseline and at follow-up (11 weeks and 12 months). The effects of the programme will be analysed using inferential statistics. Implementation will be analysed using qualitative and quantitative methods. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethical Review Authority. Study results will be disseminated in peer-reviewed journals and at regional and international conferences targeting mixed audiences. TRIAL REGISTRATION NUMBER: NCT05279508.


Assuntos
Autogestão , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Promoção da Saúde/métodos , Acidente Vascular Cerebral/prevenção & controle , Reabilitação do Acidente Vascular Cerebral/métodos , Qualidade de Vida , Prevenção Primária , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
BMC Med Educ ; 23(1): 935, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066519

RESUMO

BACKGROUND: Clinical practice gives medical students opportunities to develop clinical skills and to gain insight into their future profession as a physician. Students in the medical programme at Karolinska Institutet in Sweden had clinical practice in primary health care in nine of their 11 semesters. The aim of this study was to explore medical students' perceptions of learning from patient encounters in a primary health care context. METHODS: The study was a qualitative inductive interview study. The 21 participating medical students were from their 3rd, 4th and 5th (final year) year of the study programme. A semi-structured interview guide was used. The data analysis was performed with qualitative content analysis. RESULTS: The overarching theme of the study was: The individual patient encounters are the key to learning in primary health care. The patient encounters presented both useful opportunities and challenges that could contribute to the students' professional development. The following four categories were found: 1. Patient encounters in are instructive, rewarding and challenging. Practising in primary health care provided experience in meeting and communicating with a wide variety of patients. Students described it being challenging to trust in their own clinical competence and feeling a responsibility towards the patients. 2. Encounters with patients in primary health care provide opportunities for gradual professional development. Students had the opportunity of increasing independence based on their level of clinical competence. They experienced a progression in their professional development after each period in primary health care. 3. A committed supervisor plays a significant role in learning. Committed supervisors who set aside time for supervision, offered support, and encouraged the student, played an important role in the student's learning. 4. Learning in primary health care and learning in hospitals complement one another. It could be difficult for the students to sort out exactly where they learnt different things as they perceived that learning in primary health care and in hospitals complemented one another. CONCLUSIONS: The students' encounters with authentic patients in primary health care gave them recurring opportunities to develop communication skills and to be trusted to work on their own under supervision, giving them guidance on their way to becoming future physicians.


Assuntos
Médicos , Estudantes de Medicina , Humanos , Pesquisa Qualitativa , Atenção Primária à Saúde , Percepção , Competência Clínica
8.
PLOS Glob Public Health ; 3(10): e0000547, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37851646

RESUMO

Lack of skilled human resources in primary care remains a major concern for policymakers in low- and middle-income countries. There is little evidence supporting the impact of residency training in family medicine in the quality of care, and it perpetuates misconceptions among policymakers that the provision of primary care can be easily done by any physician without special training. This article compares the risk of patients being hospitalized due to Ambulatory care sensitive conditions and the odds of having follow-up visits in primary care after hospital discharge, according to the type of their medical provider: (1) Generalists (reference), (2) Family physicians; and, (3) patients with no consultations prior to the event. Multilevel multivariate binomial regression models estimated the relative risks of a patient being hospitalized in a given month and the relative risks for the occurrence of a follow-up visit in primary care in a retrospective cohort of 636.640 patients between January 2013 and July 2018 in Rio de Janeiro. For all 14 conditions, there was a higher risk of hospitalization when patients had no consultation in primary care prior to the event. Except for Ear, Nose and Throat infections, patients seen by family physicians had a lower risk of being hospitalized, compared to patients seen by Generalists. Follow-up visits were more likely to happen among patients treated by family physicians for almost every condition analyzed. With two years of training in family medicine, Family physicians can reduce the risk of their patients being hospitalized and increase the likelihood of those patients having a follow-up consultation in primary care. Investments in residency training in family medicine should be made to fix the shortage of skilled physicians in primary care, reduce hospitalizations and improve quality and continuity of care.

9.
Scand J Prim Health Care ; 41(3): 343-350, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37561134

RESUMO

PURPOSE: To explore hypertension management in primary healthcare (PHC). DESIGN: Structured interviews of randomly selected PHC centres (PHCCs) from December 2019 to January 2021. SETTING: Seventy-six PHCCs in eight regions of Sweden. MAIN OUTCOME MEASURES: Staffing and organization of hypertension care. Methods of measuring blood pressure (BP), laboratory tests, registration of co-morbidities and lifestyle advice at diagnosis and follow-up. RESULTS: The management of hypertension varied among PHCCs. At diagnosis, most PHCCs (75%) used the sitting position at measurements, and only 13% routinely measured standing BP. One in three (33%) PHCCs never used home BP measurements and 25% only used manual measurements. The frequencies of laboratory analyses at diagnosis were similar in the PHCCs. At follow-up, fewer analyses were performed and the tests of lipids and microalbuminuria decreased from 95% to 45% (p < 0.001) and 61% to 43% (p = 0.001), respectively. Only one out of 76 PHCCs did not measure kidney function at routine follow-ups. Lifestyle, physical activity, food habits, smoking and alcohol use were assessed in ≥96% of patients at diagnosis. At follow-up, however, there were fewer assessments. Half of the PHCCs reported dedicated teams for hypertension, 82% of which were managed by nurses. There was a great inequality in the number of patients per tenured GP in the PHCCs (median 2500; range 1300-11300) patients. CONCLUSIONS: The management of hypertension varies in many respects between PHCCs in Sweden. This might lead to inequity in the care of patients with hypertension.


Hypertension is mainly handled in primary healthcare (PHC), and this study shows important dissimilarities in organization and clinical management.Several variants in techniques and measurements of blood pressure were found between PHC centres.Lifestyle, clinical and laboratory assessments decreased at follow-ups compared to at diagnosis, specifically for lipids, microalbuminuria and electrocardiograms.Nearly half of the PHC centres reported that they had dedicated hypertension teams.


Assuntos
Hipertensão , Atenção Primária à Saúde , Humanos , Suécia , Inquéritos e Questionários , Hipertensão/terapia , Pressão Sanguínea
10.
Front Immunol ; 14: 1151754, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37063885

RESUMO

Mast cells are tissue-resident cells playing major roles in homeostasis and disease conditions. Lung mast cells are particularly important in airway inflammatory diseases such as asthma. Human mast cells are classically divided into the subsets MCT and MCTC, where MCT express the mast cell protease tryptase and MCTC in addition express chymase, carboxypeptidase A3 (CPA3) and cathepsin G. Apart from the disctintion of the MCT and MCTC subsets, little is known about the heterogeniety of human lung mast cells and a deep analysis of their heterogeniety has previously not been performed. We therefore performed single cell RNA sequencing on sorted human lung mast cells using SmartSeq2. The mast cells showed high expression of classical mast cell markers. The expression of several individual genes varied considerably among the cells, however, no subpopulations were detected by unbiased clustering. Variable genes included the protease-encoding transcripts CMA1 (chymase) and CTSG (cathepsin G). Human lung mast cells are predominantly of the MCT subset and consistent with this, the expression of CMA1 was only detectable in a small proportion of the cells, and correlated moderately to CTSG. However, in contrast to established data for the protein, CPA3 mRNA was high in all cells and the correlation of CPA3 to CMA1 was weak.


Assuntos
Mastócitos , Peptídeo Hidrolases , Humanos , Quimases/genética , Quimases/metabolismo , Mastócitos/metabolismo , Catepsina G , Peptídeo Hidrolases/metabolismo , Triptases/genética , Triptases/metabolismo , Pulmão/metabolismo , Análise de Sequência de RNA
11.
J Allergy Clin Immunol Pract ; 11(6): 1706-1717, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36868470

RESUMO

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients.


Assuntos
Mastocitose Sistêmica , Mastocitose , Humanos , Mastocitose/diagnóstico , Mastocitose/terapia , Mastocitose Sistêmica/diagnóstico , Previsões , Mastócitos
12.
J Immunol Res ; 2023: 9393497, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36761882

RESUMO

Background: Asthma is a chronic inflammatory disease with structural changes in the lungs defined as airway remodelling. Mast cell responses are important in asthma as they, upon activation, release mediators inducing bronchoconstriction, inflammatory cell recruitment, and often remodelling of the airways. As guinea pigs exhibit anatomical, physiological, and pharmacological features resembling human airways, including mast cell distribution and mediator release, we evaluated the effect of extracts from two common allergens, house dust mite (HDM) and cat dander (CDE), on histopathological changes and the composition of tryptase- and chymase-positive mast cells in the guinea pig lungs. Methods: Guinea pigs were exposed intranasally to HDM or CDE for 4, 8, and 12 weeks, and airway histology was examined at each time point. Hematoxylin and eosin, Picro-Sirius Red, and Periodic Acid-Schiff staining were performed to evaluate airway inflammation, collagen deposition, and mucus-producing cells. In addition, Astra blue and immunostaining against tryptase and chymase were used to visualize mast cells. Results: Repetitive administration of HDM or CDE led to the accumulation of inflammatory cells into the proximal and distal airways as well as increased airway smooth muscle mass. HDM exposure caused subepithelial collagen deposition and mucus cell hyperplasia at all three time points, whereas CDE exposure only caused these effects at 8 and 12 weeks. Both HDM and CDE induced a substantial increase in mast cells after 8 and 12 weeks of challenges. This increase was primarily due to mast cells expressing tryptase, but not chymase, thus indicating mucosal mast cells. Conclusions: We here show that exposure to HDM and CDE elicits asthma-like histopathology in guinea pigs with infiltration of inflammatory cells, airway remodelling, and accumulation of primarily mucosal mast cells. The results together encourage the use of HDM and CDE allergens for the stimulation of a clinically relevant asthma model in guinea pigs.


Assuntos
Asma , Mastócitos , Animais , Cobaias , Remodelação das Vias Aéreas , Alérgenos , Asma/etiologia , Alérgenos Animais , Modelos Animais de Doenças , Pulmão , Pyroglyphidae , Triptases
15.
Nat Commun ; 13(1): 7483, 2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470868

RESUMO

TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology.


Assuntos
Canabidiol , Canabinoides , Ratos , Humanos , Animais , Canabidiol/farmacologia , Canais de Cátion TRPV/metabolismo , Canabinoides/farmacologia , Probenecid/farmacologia , Ligantes , Microscopia Crioeletrônica
16.
Sci Rep ; 12(1): 18924, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344588

RESUMO

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.


Assuntos
Asma , Mastócitos , Cobaias , Humanos , Animais , Mastócitos/metabolismo , Pyroglyphidae , Monensin/farmacologia , Monensin/metabolismo , Asma/metabolismo , Alérgenos , Inflamação/patologia , Modelos Animais de Doenças
17.
J Lipid Res ; 63(12): 100310, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36370807

RESUMO

Inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) results in decreased production of proinflammatory PGE2 and can lead to shunting of PGH2 into the prostaglandin D2 (PGD2)/15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) pathway. 15dPGJ2 forms Michael adducts with thiol-containing biomolecules such as GSH or cysteine residues on target proteins and is thought to promote resolution of inflammation. We aimed to elucidate the biosynthesis and metabolism of 15dPGJ2 via conjugation with GSH, to form 15dPGJ2-glutathione (15dPGJ2-GS) and 15dPGJ2-cysteine (15dPGJ2-Cys) conjugates and to characterize the effects of mPGES-1 inhibition on the PGD2/15dPGJ2 pathway in mouse and human immune cells. Our results demonstrate the formation of PGD2, 15dPGJ2, 15dPGJ2-GS, and 15dPGJ2-Cys in RAW264.7 cells after lipopolysaccharide stimulation. Moreover, 15dPGJ2-Cys was found in lipopolysaccharide-activated primary murine macrophages as well as in human mast cells following stimulation of the IgE-receptor. Our results also suggest that the microsomal glutathione S-transferase 3 is essential for the formation of 15dPGJ2 conjugates. In contrast to inhibition of cyclooxygenase, which leads to blockage of the PGD2/15dPGJ2 pathway, we found that inhibition of mPGES-1 preserves PGD2 and its metabolites. Collectively, this study highlights the formation of 15dPGJ2-GS and 15dPGJ2-Cys in mouse and human immune cells, the involvement of microsomal glutathione S-transferase 3 in their biosynthesis, and their unchanged formation following inhibition of mPGES-1. The results encourage further research on their roles as bioactive lipid mediators.


Assuntos
Cisteína , Prostaglandinas , Camundongos , Humanos , Animais , Lipopolissacarídeos/metabolismo , Mastócitos , Prostaglandina-E Sintases/metabolismo , Macrófagos/metabolismo , Ciclo-Oxigenase 2/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Prostaglandina D2/farmacologia
19.
J Autoimmun ; 131: 102857, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35780036

RESUMO

Dysregulated T-cell activation is a hallmark of several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The lymphocyte cytosolic protein 2 (LCP2), also known as SLP-76, is essential for the development and activation of T cells. Despite the critical role of LCP2 in T-cell activation and the need for developing drugs that modify T-cell activation, no LCP2 inhibitors have been developed. This can be explained by the "undruggable" nature of LCP2, lacking a structure permissive to standard small molecule inhibitor modalities. Here, we explored an alternative drug modality, developing antisense oligonucleotides (ASOs) targeting LCP2 mRNAs, and evaluated its activity in modulating T-cell activation. We identified a set of 3' UTR targeting LCP2 ASOs, which knocked down LCP2 in a human T-cell line and primary human T cells and found that these suppressed T-cell receptor mediated activation. We also found that the ASOs suppressed FcεR1-mediated mast cell activation, in line with the role of LCP2 in mast cells. Taken together, our data provide examples of how immunomodulatory ASOs that interfere with undruggable targets can be developed and propose that such drug modalities can be used to treat autoimmune diseases.


Assuntos
Doenças Autoimunes , Oligonucleotídeos Antissenso , Linhagem Celular , Humanos , Ativação Linfocitária , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Linfócitos T
20.
Blood Adv ; 6(15): 4439-4449, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35500226

RESUMO

Mast cell accumulation is a hallmark of a number of diseases, including allergic asthma and systemic mastocytosis. Immunoglobulin E-mediated crosslinking of the FcεRI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages, and controversies remain about whether FcεRI expression appears during the mast cell progenitor stage or during terminal mast cell maturation. Here, we used single-cell transcriptomics analysis to reveal a temporal association between the appearance of FcεRI and the mast cell gene signature in CD34+ hematopoietic progenitors in adult peripheral blood. In agreement with these data, the FcεRI+ hematopoietic progenitors formed morphologically, phenotypically, and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating development of mast cell progenitors. Culture assays showed that interleukin-3 (IL-3) and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust FcεRI downregulation. Taken together, we showed that FcεRI expression appears at the progenitor stage of mast cell differentiation in peripheral blood. We also showed that external stimuli regulate FcεRI expression of mast cell progenitors, providing a possible explanation for the variable FcεRI expression levels during mast cell development.


Assuntos
Mastócitos , Transcriptoma , Adulto , Humanos , Estudos Prospectivos , Receptores de IgE/genética , Receptores de IgE/metabolismo , Células-Tronco/metabolismo
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