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1.
SLAS Discov ; 26(7): 909-921, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34085560

RESUMO

A core aspect of epithelial cell function is barrier integrity. A loss of barrier integrity is a feature of a number of respiratory diseases, including asthma, allergic rhinitis, and chronic obstructive pulmonary disease. Restoration of barrier integrity is a target for respiratory disease drug discovery. Traditional methods for assessing barrier integrity have their limitations. Transepithelial electrical resistance (TEER) and dextran permeability methods can give poor in vitro assay robustness. Traditional junctional complex imaging approaches are labor-intensive and tend to be qualitative but not quantitative. To provide a robust and quantitative assessment of barrier integrity, high-content imaging of junctional complexes was combined with TEER. A scalable immunofluorescent high-content imaging technique, with automated quantification of junctional complex proteins zonula occludens-1 and occludin, was established in 3D pseudostratified primary human bronchial epithelial cells cultured at an air-liquid interface. Ionic permeability was measured using TEER on the same culture wells.The improvements to current technologies include the design of a novel 24-well holder to enable scalable in situ confocal cell imaging without Transwell membrane excision, the development of image analysis pipelines to quantify in-focus junctional complex structures in each plane of a Z stack, and the enhancement of the TEER data analysis process to enable statistical evaluation of treatment effects on barrier integrity. This novel approach was validated by demonstrating measurable changes in barrier integrity in cells grown under conditions known to perturb epithelial cell function.


Assuntos
Epitélio/fisiologia , Junções Intercelulares/metabolismo , Células Cultivadas , Impedância Elétrica , Células Epiteliais , Humanos , Imagem Molecular/métodos , Complexos Multiproteicos , Permeabilidade
2.
S Afr Fam Pract (2004) ; 62(1): e1-e6, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33179951

RESUMO

BACKGROUND: A strategy implemented by the South African Department of Health to manage the high burden of human immunodeficiency virus (HIV) has been to task-shift services to primary health care clinics. Outcomes of paediatric patients with HIV are poorer than those of adults, particularly in rural areas. Viral suppression in paediatric patients at the feeder clinics of a rural South African hospital was anecdotally far below the aim of the Joint United Nations Programme on HIV/AIDS (UNAIDS) of 90%. METHODS: A quality improvement approach was used to conduct a baseline assessment of HIV viral suppression in paediatric patients and other process measures, implement a clinical mentorship intervention and evaluate its effectiveness. RESULTS: An initial audit of 235 clinical folders of paediatric patients with HIV revealed a viral suppression of 55.3%. Other poor measures included prescription accuracy, viral loads performed within schedule and response to successive high viral loads. A clinical mentorship intervention using dedicated doctor outreach was implemented and the audit repeated after 12 months (263 folders). Viral suppression improved to 67.4%, as did most other process measures. CONCLUSION: The quality improvement approach regarding the aim to significantly improve viral suppression in paediatric patients through the implementation of clinical mentorship was successful.


Assuntos
Infecções por HIV , Melhoria de Qualidade , Adulto , Criança , HIV , Infecções por HIV/tratamento farmacológico , Humanos , África do Sul/epidemiologia , Carga Viral
3.
Afr J Prim Health Care Fam Med ; 12(1): e1-e3, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33054266

RESUMO

Early in the course of the coronavirus infection disease 2019 (COVID-19) pandemic in South Africa, the Department of Health implemented a policy of community screening and testing (CST). This was based on a community-orientated primary care approach and was a key strategy in limiting the spread of the pandemic, but it struggled with long turnaround times (TATs) for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction test. The local experience at Symphony Way Community Day Centre (Delft, Cape Town), highlighted these challenges. The first positive tests had a median TAT of 4.5 days, peaking at 29 days in mid-May 2020. Issues that contributed to long TATs were unavailability of viral transport medium, sample delivery and storage difficulties, staffing problems, scarcity of testing supplies and other samples prioritised over CST samples. At Symphony Way, many patients who tested COVID-19 positive had abandoned their self-isolation because of the delay in results. Employers were unhappy with prolonged sick leave whilst waiting for results and patients were concerned about not getting paid or job loss. The CST policy relies on a rapid TAT to be successful. Once the TAT is delayed, the process of contacting patients, and tracing and quarantining contacts becomes ineffective. With hindsight, other countries' difficulties in upscaling testing should have served as warning. Community screening and testing was scaled back from 18 May 2020, and testing policy was changed to only include high-risk patients from 29 May 2020. The delayed TATs meant that the CST policy had no beneficial impact at local level.


Assuntos
Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Acessibilidade aos Serviços de Saúde , Programas de Rastreamento , Pneumonia Viral/diagnóstico , Políticas , Betacoronavirus/crescimento & desenvolvimento , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Coronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Programas de Rastreamento/métodos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , SARS-CoV-2 , Síndrome Respiratória Aguda Grave , África do Sul , Fatores de Tempo
4.
J Antimicrob Chemother ; 71(10): 2767-81, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27494903

RESUMO

BACKGROUND: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. METHODS: In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. RESULTS: The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5-11 µM) of rhinovirus-induced type I IFNß, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. CONCLUSIONS: The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/química , Antivirais/farmacologia , Descoberta de Drogas , Interferons/imunologia , Macrolídeos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Asma/tratamento farmacológico , Brônquios/citologia , Brônquios/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Humanos , Interferon beta/imunologia , Interferons/biossíntese , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucina-8/imunologia , Interleucina-8/metabolismo , Macrolídeos/química , Macrolídeos/uso terapêutico , Proteínas de Resistência a Myxovirus/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Proteínas/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Rhinovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
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