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1.
Clin Infect Dis ; 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38018297
2.
J Urban Health ; 93(6): 923-939, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27726051

RESUMO

Community schools link students, families, and communities to educate children and strengthen neighborhoods. They have become a popular model for education in many US cities in part because they build on community assets and address multiple determinants of educational disadvantage. Since community schools seek to have an impact on populations, not just the children enrolled, they provide an opportunity to improve community health. Community schools influence the health and education of neighborhood residents though three pathways: building trust, establishing norms, and linking people to networks and services. Through such services as school-based health centers, nutrition education, family mental health counseling, violence prevention, and sexuality education, these schools build on the multiple reciprocal relationships between health and education. By developing closer ties between community schools and neighborhood health programs, public health professionals can help to mobilize a powerful new resource for reducing the health and educational inequalities that now characterize US cities. We suggest an agenda for research, practice, and policy that can build the evidence needed to guide such a strategy.


Assuntos
Educação em Saúde , Saúde Pública , Serviços de Saúde Escolar , Instituições Acadêmicas , Pessoal de Saúde , Humanos
3.
Am J Public Health ; 105 Suppl 1: S119-24, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25706006

RESUMO

In this article, we compared the characteristics of public and private accredited public health training programs. We analyzed the distinct opportunities and challenges that publicly funded schools of public health face in preparing the nation's public health workforce. Using our experience in creating a new, collaborative public school of public health in the nation's largest urban public university system, we described efforts to use our public status and mission to develop new approaches to educating a workforce that meets the health needs of our region and contributes to the goal of reducing health inequalities. Finally, we considered policies that could protect and strengthen the distinct contributions that public schools of public health make to improving population health and reducing health inequalities.


Assuntos
Faculdades de Saúde Pública/economia , Educação Profissional em Saúde Pública/economia , Educação Profissional em Saúde Pública/organização & administração , Educação Profissional em Saúde Pública/estatística & dados numéricos , Docentes/estatística & dados numéricos , Feminino , Financiamento Governamental , Humanos , Masculino , New York , Objetivos Organizacionais , Política Pública , Faculdades de Saúde Pública/organização & administração , Faculdades de Saúde Pública/estatística & dados numéricos , Estudantes/estatística & dados numéricos , Estados Unidos
4.
J Health Commun ; 16 Suppl 3: 103-18, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21951246

RESUMO

Health literacy research has concentrated on adults; there has been inadequate research on youth health literacy and the effect it may have on health outcomes. Low-income, minority populations have low levels of health literacy and are at higher risk of illness and disease. Building Wellness™ is a youth health literacy curriculum targeting low-income youth from 3rd grade to 8th grade in order to prepare the youth to be active, educated participants in their healthcare. Lessons focus on asthma, obesity and overweight, accidental injury, and drug and alcohol use. Curriculum development was based on qualitative and quantitative assessment of the target population. The preliminary findings from the pilot project show an increase in knowledge, improved healthy behaviors, and enthusiasm from participants and facilitators. The development of the pilot project is described, with a suggestion for future development of youth health literacy assessment tools.


Assuntos
Currículo , Letramento em Saúde , Educação de Pacientes como Assunto/organização & administração , Desenvolvimento de Programas/métodos , Adolescente , Criança , Escolaridade , Humanos , Grupos Minoritários , Avaliação das Necessidades , Projetos Piloto , Pobreza , Avaliação de Programas e Projetos de Saúde
5.
Psychooncology ; 19(6): 583-93, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19484714

RESUMO

OBJECTIVE: The objective of this paper is to report the implementation and assessment of the Comskil Training Curriculum at Memorial Sloan-Kettering Cancer Center. METHOD: Twenty-eight attending physicians and surgeons participated in communication skills training modules as part of a train-the-trainer program. Doctors were video recorded in clinical consultations with patients two times before training and two times after training, resulting in 112 video recordings for analysis. Recordings were coded using the Comskil Coding System. RESULTS: Communication skills related to two of the six major skill sets, Establishing the Consultation Framework and Checking, increased following training. Limited changes emerged in three skill sets, while one skill set, Shared Decision Making, did not change. Doctors who attended more training modules had higher levels of change. Female participants demonstrated three skills more frequently than males post-training. CONCLUSIONS: The intervention produced significant communication skills uptake in a group of experienced attending clinicians, mediated by the amount of training. Future research should focus on the dose of training necessary to achieve skills uptake and the effect of skills training on patient outcomes.


Assuntos
Comunicação , Oncologia/educação , Competência Clínica/normas , Currículo , Feminino , Humanos , Masculino , Oncologia/normas , Relações Médico-Paciente , Avaliação de Programas e Projetos de Saúde , Fatores Sexuais , Resultado do Tratamento , Gravação em Vídeo
6.
Qual Life Res ; 19(2): 149-55, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20058087

RESUMO

PURPOSE: We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection. METHODS: Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002-2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls. RESULTS: HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients. CONCLUSION: HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected.


Assuntos
Infecções por HIV/psicologia , Linfoma não Hodgkin/psicologia , Qualidade de Vida/psicologia , Perfil de Impacto da Doença , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , California , Estudos de Casos e Controles , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Psicometria , Sistema de Registros , Adulto Jovem
7.
Med Educ ; 43(4): 342-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19335576

RESUMO

OBJECTIVES: Evidence suggests that the most important component of communication skills training (CST) is experiential learning through role-play sessions that rely on facilitators to guide learners. However, there is little published evidence about processes of assessing facilitator competence in CST. This paper reports on the development and application of procedures to assess facilitator competence in a large-scale CST programme. METHODS: Thirty-two novice facilitators in a large CST programme were audio-recorded while facilitating small-group CST training sessions in order to explore whether the training they had received had prepared them to competently facilitate. Audio-recordings were assessed using the Comskil facilitator assessment coding system. Facilitators were rated as having achieved basic competence, advanced competence or expert competence. RESULTS: Facilitation tasks that were most frequently coded as being used always included inviting the learner to give feedback first and inviting all group members to give feedback. The facilitation task coded least frequently as being used always was involving group members in solving problems. Of the 32 facilitators, 18 reached at least a basic level of competence. Psychosocially trained facilitators and MD facilitators differed in their use of five facilitation tasks. CONCLUSIONS: Modest training and minimal practice does not result in complete facilitator competence. Some facilitation skills appear to be more easily acquired than others. These findings highlight which skills should be prioritised in the further training of novice facilitators. A long-term project currently underway will study whether facilitator competence improves with practice and regular feedback.


Assuntos
Comunicação , Educação Médica/métodos , Competência Profissional/normas , Avaliação Educacional/métodos , Humanos , New York , Relações Médico-Paciente
8.
Int Health ; 10(5): 401-403, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29897586

RESUMO

Background: Young people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (PLWA) are at risk for HIV stigma. Methods: The HIV/AIDS Stigma Instrument for PLWA was administered to 36 young PLWA across six clinics in Bandung, Indonesia, to assess the fear of contagion (FC), verbal abuse (VA), social isolation (SI), workplace stigma (WS), health care neglect (HCN) and negative self-perception (NSP). Results: The median scores for FC, VA, SI, WS and HCN were all 0 while the median score for NSP was 4. In the last 3 months approximately 45% of surveyed PLWA felt they did not deserve to live and 64% felt completely worthless. Conclusions: While these results are preliminary, access to mental health services should be a priority in the clinics that provide antiretroviral therapies.


Assuntos
Infecções por HIV/psicologia , Autoimagem , Estigma Social , Estereotipagem , Adulto , Feminino , Humanos , Indonésia , Masculino , Preconceito , Autorrevelação , Adulto Jovem
9.
Antivir Ther ; 12(1): 55-62, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17503748

RESUMO

OBJECTIVES: To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM). METHODS: Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system. RESULTS: A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the Al estimates and modelled values (r > 0.79 for all comparisons; P < 0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 microg/ml versus 3.89 microg/ml; P = 0.02) and LPV (7.99 microg/ml versus 8.79 microg/ml; P < 0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (kappa) = 0.53; P < 0.001] and 47 out of 49 EFV cases (kappa = 0.91; P < 0.001). CONCLUSION: The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.


Assuntos
Antirretrovirais/farmacocinética , Inteligência Artificial , Sistemas Computacionais , Monitoramento de Medicamentos/métodos , Infecções por HIV/metabolismo , Adulto , Algoritmos , Alcinos , Antirretrovirais/sangue , Antirretrovirais/uso terapêutico , Teorema de Bayes , Benzoxazinas/farmacocinética , California , Ciclopropanos , Quimioterapia Combinada , Sistemas Inteligentes , Feminino , Lógica Fuzzy , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Lopinavir , Masculino , Modelos Biológicos , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Pirimidinonas/farmacocinética , Reprodutibilidade dos Testes
10.
Sci Rep ; 7(1): 6861, 2017 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-28761045

RESUMO

Large molecular complexes known as inflammasomes regulate the release of IL-1ß from immune cells in response to infection and injury. Salmonella typhimurium infection is reported to activate NLRP3 and NLRC4 inflammasomes which are subsequently involved in pyroptosis of the cell and pathogen clearance. However, the response to S. typhimurium in primary human monocytes has not been studied in detail. The aim of this study was to investigate the effect of S. typhimurium on inflammasomes in primary human monocytes. Much of the previous research in the field has been conducted in murine models and human THP-1 cells, which may not reflect the responses of primary human monocytes. Here, we report that inhibiting NLRP3 with the selective inhibitor MCC950, blocked release of IL-1ß and the related cytokine IL-1α from primary human monocytes in response to S. typhimurium. Additionally, under these conditions S. typhimurium-induced IL-1 release occurred independently of pyroptosis. We propose that IL-1ß release without pyroptosis may occur in early-recruited monocytes to regulate a maximal innate immune response to Salmonella infection, allowing a sustained inflammatory signal. This insight into the mechanisms involved in IL-1 release from primary human monocytes highlights major differences between immune cell types, and the defences they employ during bacterial infection.


Assuntos
Interleucina-1/metabolismo , Monócitos/microbiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Salmonella typhimurium/patogenicidade , Células Cultivadas , Humanos , Inflamassomos/metabolismo , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores
11.
AIDS Patient Care STDS ; 31(2): 87-95, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28099036

RESUMO

HIV-related stigma remains a persistent global health concern among people living with HIV/AIDS (PLWA) in developing nations. The literature is lacking in studies about healthcare students' perceptions of PLWA. This study is the first effort to understand stigmatizing attitudes toward HIV-positive patients by healthcare students in Mwanza, Tanzania, not just those who will be directly treating patients but also those who will be indirectly involved through nonclinical roles, such as handling patient specimens and private health information. A total of 208 students were drawn from Clinical Medicine, Laboratory Sciences, Health Records and Information Management, and Community Health classes at the Tandabui Institute of Health Sciences and Technology for a voluntary survey that assessed stigmatizing beliefs toward PLWA. Students generally obtained high scores on the overall survey instrument, pointing to low stigmatizing beliefs toward PLWA and an overall willingness to treat PLWA with the same standard of care as other patients. However, there are gaps in knowledge that exist among students, such as a comprehensive understanding of all routes of HIV infection. The study also suggests that students who interact with patients as part of their training are less likely to exhibit stigmatizing beliefs toward PLWA. A comprehensive course in HIV infection, one that includes classroom sessions focused on the epidemiology and routes of transmission as well as clinical opportunities to directly interact with PLWA-perhaps through teaching sessions led by PLWA-may allow for significant reductions in stigma toward such patients and improve clinical outcomes for PLWA around the world.


Assuntos
Infecções por HIV/diagnóstico , Conhecimentos, Atitudes e Prática em Saúde , Estigma Social , Estereotipagem , Estudantes de Ciências da Saúde/psicologia , Adulto , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Humanos , Percepção , Estudantes de Ciências da Saúde/estatística & dados numéricos , Estudantes de Medicina/psicologia , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e Questionários , Tanzânia/epidemiologia
12.
AIDS ; 20(9): 1295-302, 2006 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-16816559

RESUMO

OBJECTIVE: We conducted a randomized, multi-site, controlled trial of a cognitive-behavioral adherence intervention for patients initiating or changing an antiretroviral (ART) regimen. DESIGN: A 3 x 2 factorial design was used with the primary randomization assigning patients (1: 1: 1) to one of two adherence interventions or usual care. METHODS: The five-session adherence interventions consisted of cognitive-behavioral and motivational components, with or without a 2-week pre-treatment placebo practice trial. Intent-to-treat analysis used probability weights and regression tree analysis to account for missing data. RESULTS: A total of 230 patients were randomized; 199 started ART, of whom 74% completed the 48-week study. Electronic monitored adherence outcomes between the two intervention groups did not differ significantly and were thus pooled in analyses. At week 4, 82% of intervention patients had taken at least 90% of their prescribed ART doses, compared with 65% of controls (P < 0.01); this group difference dropped to 12% at week 12 (72 versus 60%; P = 0.15) and 11% at week 24 (66 versus 55%; P = 0.28). Mean adherence in the intervention group was significantly higher than the control group at week 24 (89 versus 81%; P < 0.05) only. There were no group differences with respect to HIV-1 RNA throughout the study. CONCLUSIONS: The effects of the cognitive-behavioral intervention on adherence were modest and transient, and no effects were observed on viral load or CD4 cell count. More robust effects may require a more intense intervention that combines ongoing adherence monitoring and individualized intervention "dosage" that matches the need and performance of each patient.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Cognitivo-Comportamental/métodos , Infecções por HIV/terapia , HIV-1 , Cooperação do Paciente , Adulto , Idoso , Análise de Variância , Contagem de Linfócito CD4 , Distribuição de Qui-Quadrado , Feminino , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos , Carga Viral
13.
Curr HIV Res ; 4(3): 375-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16842088

RESUMO

Highly active retroviral therapy (HAART) has been in widespread use in the United States since 1996. We sought to determine how the use of HAART influenced survival among patients with acquired immunodeficiency syndrome (AIDS) and primary central nervous system (CNS) non-Hodgkin's lymphoma (NHL). We used the population-based San Diego and Orange County cancer registry to identify 94 patients with both AIDS and CNS NHL diagnosed 1994-1999, of whom 31 were diagnosed 1996-1999. We performed Kaplan-Meier analyses to compare survival between patients who received HAART at NHL diagnosis or thereafter versus untreated patients and Cox proportional hazard models for adjusted survival. Among the patients diagnosed with NHL in 1996-1999, seven (23%) were taking HAART at the time of NHL diagnosis. Median survival was eight months for those who received HAART at the time of lymphoma diagnosis or after, versus one month for untreated patients. HAART, radiation therapy, and better performance status were associated with improved survival. We conclude that HAART prolongs survival in AIDS-related CNS NHL.


Assuntos
Terapia Antirretroviral de Alta Atividade , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma Relacionado a AIDS/mortalidade , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Feminino , Humanos , Linfoma Relacionado a AIDS/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
14.
Leuk Lymphoma ; 47(9): 1822-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17064995

RESUMO

We used the San Diego/Orange County cancer registry to identify 64 cases of systemic non-Hodgkin's lymphoma (NHL) with AIDS who received highly active antiretroviral therapy (HAART) at the time of NHL diagnosis or thereafter and 64 NHL controls without AIDS, matched on age, sex, race, time of NHL diagnosis (1994-1995 and 1996-1999), and hospital type (academic, large community, and small community). We compared cases and controls by chi-squared tests and Kaplan-Meier methods. Thirty-three percent of cases had high grade histology versus 11% of controls (p < 0.01); 69% had baseline hemoglobin <13 g/dL versus 35% controls (p < 0.001) and 21% had baseline neutrophils <2,000/mcl versus 4% of controls (p < 0.001). Overall median survival was 16 months for cases versus 99 months for controls (p < 0.01). Among 40 matched pairs of cases and controls who received chemotherapy, 32% of cases received reduced-dose chemotherapy versus 5% of controls (p < 0.01) and median survival was 33 months for cases and 99 months for controls (p < 0.44). Patients with AIDS-related NHL who received HAART had high grade histology and baseline cytopenia and received reduced-dose chemotherapy more often than patients without AIDS. However, AIDS patients who received HAART and chemotherapy had survival similar to NHL patients without AIDS, an improvement from the pre-HAART era. Appropriate hematologic support, through growth factors, transfusions, and avoidance of drugs with hematologic toxicity, might allow full dosing of chemotherapy, and perhaps would further improve outcomes among patients with AIDS and NHL.


Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Infecções por HIV/complicações , Humanos , Linfoma Relacionado a AIDS/complicações , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
15.
Methods Mol Biol ; 1417: 75-88, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27221482

RESUMO

The pro-inflammatory cytokine interleukin (IL)-1ß is an important mediator of the inflammatory response. In order to perform its role in the inflammatory cascade, IL-1ß must be secreted from the cell, yet it lacks a signal peptide that is required for conventional secretion, and the exact mechanism of release remains undefined. Conventional biochemical methods have limited the investigation into the processes involved in IL-1ß secretion to population dynamics, yet heterogeneity between cells has been observed at a single-cell level. Here, greater sensitivity is achieved with the use of a newly developed vector that codes for a fluorescently labelled version of IL-1ß. Combining this with real-time single-cell confocal microscopy using the methods described here, we have developed an effective protocol for investigating the mechanisms of IL-1ß secretion and the testing of the hypothesis that IL-1ß secretion requires membrane permeabilisation.


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/citologia , Análise de Célula Única/métodos , Animais , Células Cultivadas , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Transdução de Sinais
17.
AIDS Patient Care STDS ; 19(3): 150-6, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15798382

RESUMO

HIV infection and its treatment can have significant effects on physical appearance and functioning, which can affect self-perceived body image. We assessed the psychometric properties of a newly developed Body Image Scale (BIS), a subjective measure of body image perception in persons with HIV infection, as well as the scale's relationship to disease progression, symptoms, and demographic factors. HIV-positive men (n = 129) and women (n = 21) attending two outpatient HIV clinics were administered the BIS survey along with a one-page questionnaire. A subset (n = 38) were administered the survey on two occasions to assess test-retest reliability. Nearly half of the sample (46%) had AIDS and 25% had a CD4 count below 200 cells/mm(3) within the prior 3 months. The BIS had unidimensional factor structure, good internal consistency reliability (Chronbach alpha = 0.91), and good test-retest reliability (r = 0.71, p < 0.001) after controlling for the length of interval between assessments. Patients' current perception of their body image was worse then what they perceived it to be prior to HIV infection (p < 0.001), but better than their perception of how others view people with HIV (p < 0.001). The presence of symptomatic disease (p < 0.001) and a diagnosis of AIDS (p = 0.02) were associated with a less favorable body image, although laboratory markers of disease progression (CD4 count and plasma HIV viral load) were not. We conclude that the BIS has good construct validity and is a highly reproducible measure of self-perceptive of body image in HIV-infected patients. Further exploration of its relationship to psychological well being, medication adherence and other aspects of medical care is indicated.


Assuntos
Síndrome da Imunodeficiência Adquirida/psicologia , Imagem Corporal , Infecções por HIV/psicologia , Inquéritos e Questionários , Análise de Variância , Contagem de Linfócito CD4 , Progressão da Doença , Análise Fatorial , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes
18.
Immunotargets Ther ; 4: 131-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27471719

RESUMO

Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1ß and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well-characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1ß and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS.

19.
Nat Commun ; 6: 8761, 2015 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-26508369

RESUMO

Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1ß. The biologically inactive IL-1ß precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1α and IL-1ß release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca(2+) flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock.


Assuntos
Caspases Iniciadoras/imunologia , Caspases/imunologia , Inflamassomos/imunologia , Monócitos/enzimologia , Caspases/genética , Caspases Iniciadoras/genética , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/imunologia , Monócitos/imunologia , Transdução de Sinais
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