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1.
Cancer Res Commun ; 4(6): 1410-1429, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38717140

RESUMO

Encouraged by the observations of significant B7-H3 protein overexpression in many human solid tumors compared to healthy tissues, we directed our focus towards targeting B7-H3 using chimeric antigen receptor (CAR) T cells. We utilized a nanobody as the B7-H3-targeting domain in our CAR construct to circumvent the stability issues associated with single-chain variable fragment-based domains. In efforts to expand patient access to CAR T-cell therapy, we engineered our nanobody-based CAR into human Epstein-Barr virus-specific T cells (EBVST), offering a readily available off-the-shelf treatment. B7H3.CAR-armored EBVSTs demonstrated potent in vitro and in vivo activities against multiple B7-H3-positive human tumor cell lines and patient-derived xenograft models. Murine T cells expressing a murine equivalent of our B7H3.CAR exhibited no life-threatening toxicities in immunocompetent mice bearing syngeneic tumors. Further in vitro evaluation revealed that while human T, B, and natural killer cells were unaffected by B7H3.CAR EBVSTs, monocytes were targeted because of upregulation of B7-H3. Such targeting of myeloid cells, which are key mediators of cytokine release syndrome (CRS), contributed to a low incidence of CRS in humanized mice after B7H3.CAR EBVST treatment. Notably, we showed that B7H3.CAR EBVSTs can target B7-H3-expressing myeloid-derived suppressor cells (MDSC), thereby mitigating MDSC-driven immune suppression. In summary, our data demonstrate that our nanobody-based B7H3.CAR EBVSTs are effective as an off-the-shelf therapy for B7-H3-positive solid tumors. These cells also offer an avenue to modulate the immunosuppressive tumor microenvironment, highlighting their promising clinical potential in targeting solid tumors. SIGNIFICANCE: Clinical application of EBVSTs armored with B7-H3-targeting CARs offer an attractive solution to translate off-the-shelf CAR T cells as therapy for solid tumors.


Assuntos
Antígenos B7 , Herpesvirus Humano 4 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Antígenos B7/imunologia , Antígenos B7/metabolismo , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Herpesvirus Humano 4/imunologia , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Neoplasias/terapia , Neoplasias/imunologia , Feminino , Anticorpos de Domínio Único/imunologia
2.
J Mol Cell Cardiol ; 186: 125-137, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38008210

RESUMO

N-terminal cardiac myosin-binding protein C (cMyBP-C) domains (C0-C2) bind to thick (myosin) and thin (actin) filaments to coordinate contraction and relaxation of the heart. These interactions are regulated by phosphorylation of the M-domain situated between domains C1 and C2. In cardiomyopathies and heart failure, phosphorylation of cMyBP-C is significantly altered. We aimed to investigate how cMyBP-C interacts with myosin and actin. We developed complementary, high-throughput, C0-C2 FRET-based binding assays for myosin and actin to characterize the effects due to 5 HCM-linked variants or functional mutations in unphosphorylated and phosphorylated C0-C2. The assays indicated that phosphorylation decreases binding to both myosin and actin, whereas the HCM mutations in M-domain generally increase binding. The effects of mutations were greatest in phosphorylated C0-C2, and some mutations had a larger effect on actin than myosin binding. Phosphorylation also altered the spatial relationship of the probes on C0-C2 and actin. The magnitude of these structural changes was dependent on C0-C2 probe location (C0, C1, or M-domain). We conclude that binding can differ between myosin and actin due to phosphorylation or mutations. Additionally, these variables can change the mode of binding, affecting which of the interactions in cMyBP-C N-terminal domains with myosin or actin take place. The opposite effects of phosphorylation and M-domain mutations is consistent with the idea that cMyBP-C phosphorylation is critical for normal cardiac function. The precision of these assays is indicative of their usefulness in high-throughput screening of drug libraries for targeting cMyBP-C as therapy.


Assuntos
Citoesqueleto de Actina , Actinas , Proteínas de Transporte , Actinas/metabolismo , Fosforilação , Citoesqueleto de Actina/metabolismo , Miosinas/genética , Miosinas/metabolismo , Mutação
4.
Cancer Nurs ; 43(4): E186-E196, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30543568

RESUMO

BACKGROUND: Nurse-patient communication is of the utmost importance to oncology patients. OBJECTIVE: The aim of this study was to investigate the factors influencing the level of satisfaction with nurse-patient communication among oncology patients during their daily routine procedures. METHODS: In this observational study, 25 registered nurses and 94 patients were recruited from an oncology unit. The patients were asked to complete a concern checklist before and after each admission, administration of medication, and wound-dressing procedure. Nonverbal cues expressed by the nurses and patients were noted on the checklist during these nursing procedures. RESULTS: The results showed that patients at stage 3 cancer and patients receiving admission procedures were significantly more satisfied with their communication with nurses compared with those who were more concerned about the impact of the disease on self-care. CONCLUSIONS: Cancer stage, time of admission, and psychological concern related to self-care ability are the potential factors affecting the satisfaction level of nurse-patient communication. IMPLICATIONS FOR NURSING: Emphasis could be placed on utilizing the time of admission to interact with patients in a busy environment to strive for better communication with oncology patients. The results underscore the importance of applying the self-care enhancement approach for hospitalized cancer patients.


Assuntos
Comunicação , Neoplasias/enfermagem , Relações Enfermeiro-Paciente , Satisfação do Paciente/estatística & dados numéricos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Admissão do Paciente/estatística & dados numéricos , Autocuidado/psicologia , Fatores de Tempo
6.
BMC Public Health ; 18(1): 1113, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208869

RESUMO

BACKGROUND: Quality of life (QOL) is an important component in assessing people's health. Environmental quality can influence people's QOL in the physical health, psychological, social relationships and environment domains. QOL in the four domains, overall QOL and general heath of residents living in the Kowloon Peninsula of Hong Kong were assessed. The association between satisfaction with the neighborhood environment and QOL, and health-related behaviors which mediated the effect were investigated. METHODS: A sample of 317 residents completed a questionnaire which comprised the WHOQOL-BREF (Hong Kong version) to assess QOL, the International Physical Activity Questionnaire (IPAQ) to study physical activities, and questions on satisfaction with the neighborhood environment, health-related behaviors and socio-demographics. One-way ANOVA and linear regression were used to study the associations between environmental satisfaction and QOL in the four domains, overall QOL and general health, followed by assessing the relationships between environmental satisfaction and the potential health-related behavior mediators with regression tests. Mediation analysis was conducted using multiple linear regressions to study the effects of environmental satisfaction on QOL in the four domains, overall QOL and general health, as well as the potential mediating roles played by various health-related behaviors. A P-value of < 0.05 was considered as statistically significant. RESULTS: The residents had a relatively higher physical health mean score of 70.83 ± 12.69, and a lower environmental mean score of 61.98 ± 13.76. Moderate satisfaction with the neighborhood environment had a significant relationship with QOL in the psychological domain (ß = 0.170, P = 0.006), however, this effect was partially mediated by the non-smoking behavior of the residents (ß = 0.143, P = 0.022). CONCLUSIONS: Our residents had lower QOL in the physical health and psychological domains but similar QOL in the social relationships and environmental domains compared to other countries. Only QOL in the psychological domain could be predicted by the satisfaction with the neighborhood environment, and non-smoking status was a partial mediator of the effect of moderate environmental satisfaction on QOL in the psychological domain. Refrain from smoking seems to be able to lower the influence of neighborhood environment on people's QOL in the psychological domain to a certain extent.


Assuntos
Comportamentos Relacionados com a Saúde , Satisfação Pessoal , Qualidade de Vida , Características de Residência , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/psicologia , Inquéritos e Questionários , Adulto Jovem
7.
PLoS One ; 13(6): e0199183, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29912967

RESUMO

BACKGROUND: The nursing shortage and its impact on patient care are well-documented global issues. Patients living with cancer as a chronic illness have many psychosocial problems and often lack adequate support as a result of ineffective nurse-patient communication. A review of the literature on factors influencing the delivery of psychosocial care to cancer patients indicates that the delivery of psychosocial care in routine cancer nursing within a biomedical healthcare system has not been widely explored. OBJECTIVE: To explore patients' perceptions of their experiences with nurse-patient communication in an oncological clinical environment. METHOD: A focused ethnographic study was undertaken in two oncology wards of a hospital in Hong Kong. Data were collected through observations of the ward environment, the activities and instances of nurse-patient communication, semi-structured interviews with patients, and a review of nursing documents. RESULTS: Two main themes were identified: 1. Nurses' workload and the environment and 2. Nurse-patient partnership and role expectations. Within these two themes were related subthemes on: Sympathy for the busy nurses; Prioritizing calls to the nurses; Partnership through relationship; Nurses' role in psychosocial care; and Reduction of psychosocial concerns through physical care. CONCLUSIONS: Many cancer patients do not expect to receive psychosocial care in the form of emotional talks or counseling from busy nurses, but appreciate the attention paid by nurses to their physiological and physical needs. Nurse-patient partnerships in cancer care may reduce the potential workload of nurses. The psychosocial needs of cancer patients could be optimized by providing good physical care through effective communication within a time-constrained oncology setting.


Assuntos
Comunicação , Relações Enfermeiro-Paciente , Enfermagem Oncológica , Adulto , Feminino , Humanos , Entrevistas como Assunto , Masculino , Neoplasias/enfermagem , Neoplasias/psicologia
8.
Chemosphere ; 168: 1248-1256, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27814953

RESUMO

The concentrations of organic flame retardants (FRs) and dioxin-like activities in dust collected from five countries were investigated. The correlations between the concentrations of the different groups of FRs and dioxin-like activities were examined. Chlorinated paraffins (CPs, C9 to C31) were found in the highest concentration (median ∑CP 700 µg/g, range 280-4750 µg/g), followed by organophosphate esters (median ∑13OPEs 56 µg/g, range 21-110 µg/g), halogenated flame retardants (median ∑17HFRs 3.3 µg/g, range 0.87-14 µg/g) and polybrominated diphenyl ethers (median ∑17PBDEs 2.8 µg/g, range 0.46-11 µg/g). There were no significant differences in concentrations of the FRs among the countries but differences in PBDE and CP congener profiles were found. BDE209 predominated in dust from Australia, the UK, Sweden and China, ranging from 50 to 70% of total PBDEs. The lowest percentage of BDE209 was found in the dust from Canada, representing only 20% of total PBDEs. For CPs in dust from Sweden, the long-chain CPs (especially C18 congeners) predominated, while for other countries, medium-chain CPs (especially C14 congeners) predominated. The dioxin-activities of the dusts ranged from 58 to 590 pg CALUX-TEQ/g, and had a median of 200 pg CALUX-TEQ/g. There were significant positive correlations between concentrations of PBDEs and CPs with dioxin-like activities. The dioxin-like activity may be due to the presence of polychlorinated or polybrominated dioxin/furans (PBDD/DFs) or polychlorinated naphthalenes (PCNs) in the dust. The PBDD/DFs are known impurities and degradation product of the penta-BDE mixture, and PCNs are known impurities of CPs which exhibit dioxin-like activities.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Poeira/análise , Poluentes Atmosféricos/farmacologia , Animais , Austrália , Canadá , Linhagem Celular Tumoral , China , Dioxinas/análise , Dioxinas/farmacologia , Monitoramento Ambiental , Ésteres , Retardadores de Chama/análise , Retardadores de Chama/farmacologia , Éteres Difenil Halogenados/análise , Éteres Difenil Halogenados/farmacologia , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/farmacologia , Luciferases/genética , Luciferases/metabolismo , Organofosfatos/análise , Organofosfatos/farmacologia , Parafina/análise , Parafina/farmacologia , Ratos , Receptores de Hidrocarboneto Arílico/metabolismo , Suécia , Reino Unido
9.
Environ Sci Technol ; 49(23): 13844-52, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26196214

RESUMO

The Arctic has been contaminated by legacy organochlorine pesticides (OCPs) and currently used pesticides (CUPs) through atmospheric transport and oceanic currents. Here we report the time trends and air-water exchange of OCPs and CUPs from research expeditions conducted between 1993 and 2013. Compounds determined in both air and water were trans- and cis-chlordanes (TC, CC), trans- and cis-nonachlors (TN, CN), heptachlor exo-epoxide (HEPX), dieldrin (DIEL), chlorobornanes (ΣCHBs and toxaphene), dacthal (DAC), endosulfans and metabolite endosulfan sulfate (ENDO-I, ENDO-II, and ENDO SUL), chlorothalonil (CHT), chlorpyrifos (CPF), and trifluralin (TFN). Pentachloronitrobenzene (PCNB and quintozene) and its soil metabolite pentachlorothianisole (PCTA) were also found in air. Concentrations of most OCPs declined in surface water, whereas some CUPs increased (ENDO-I, CHT, and TFN) or showed no significant change (CPF and DAC), and most compounds declined in air. Chlordane compound fractions TC/(TC + CC) and TC/(TC + CC + TN) decreased in water and air, while CC/(TC + CC + TN) increased. TN/(TC + CC + TN) also increased in air and slightly, but not significantly, in water. These changes suggest selective removal of more labile TC and/or a shift in chlordane sources. Water-air fugacity ratios indicated net volatilization (FR > 1.0) or near equilibrium (FR not significantly different from 1.0) for most OCPs but net deposition (FR < 1.0) for ΣCHBs. Net deposition was shown for ENDO-I on all expeditions, while the net exchange direction of other CUPs varied. Understanding the processes and current state of air-surface exchange helps to interpret environmental exposure and evaluate the effectiveness of international protocols and provides insights for the environmental fate of new and emerging chemicals.


Assuntos
Poluentes Atmosféricos/análise , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Poluentes Químicos da Água/análise , Regiões Árticas , Clordano/análise , Clordano/química , Endossulfano/análogos & derivados , Endossulfano/análise , Endossulfano/química , Monitoramento Ambiental/métodos , Gases/análise , Gases/química , Hidrocarbonetos Clorados/química , Oceanos e Mares , Praguicidas/química , Água do Mar/análise , Água do Mar/química , Poluentes do Solo/análise , Volatilização
10.
Environ Int ; 74: 82-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25454223

RESUMO

Quantifying the competing rates of intake and elimination of persistent organic pollutants (POPs) in the human body is necessary to understand the levels and trends of POPs at a population level. In this paper we reconstruct the historical intake and elimination of ten polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) from Australian biomonitoring data by fitting a population-level pharmacokinetic (PK) model. Our analysis exploits two sets of cross-sectional biomonitoring data for PCBs and OCPs in pooled blood serum samples from the Australian population that were collected in 2003 and 2009. The modeled adult reference intakes in 1975 for PCB congeners ranged from 0.89 to 24.5ng/kgbw/day, lower than the daily intakes of OCPs ranging from 73 to 970ng/kgbw/day. Modeled intake rates are declining with half-times from 1.1 to 1.3years for PCB congeners and 0.83 to 0.97years for OCPs. The shortest modeled intrinsic human elimination half-life among the compounds studied here is 6.4years for hexachlorobenzene, and the longest is 30years for PCB-74. Our results indicate that it is feasible to reconstruct intakes and to estimate intrinsic human elimination half-lives using the population-level PK model and biomonitoring data only. Our modeled intrinsic human elimination half-lives are in good agreement with values from a similar study carried out for the population of the United Kingdom, and are generally longer than reported values from other industrialized countries in the Northern Hemisphere.


Assuntos
Poluentes Ambientais/análise , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Bifenilos Policlorados/análise , Adolescente , Adulto , Austrália , Criança , Pré-Escolar , Estudos Transversais , Monitoramento Ambiental , Poluentes Ambientais/história , Poluentes Ambientais/farmacocinética , Feminino , Meia-Vida , Hexaclorobenzeno/análise , Hexaclorobenzeno/farmacocinética , História do Século XX , Humanos , Hidrocarbonetos Clorados/história , Hidrocarbonetos Clorados/farmacocinética , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Praguicidas/história , Praguicidas/farmacocinética , Bifenilos Policlorados/história , Bifenilos Policlorados/farmacocinética , Adulto Jovem
11.
J Comput Aided Mol Des ; 28(11): 1143-51, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25168706

RESUMO

Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 µM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , PPAR gama/agonistas , Tiazolidinedionas/administração & dosagem , Sítios de Ligação , Diabetes Mellitus Tipo 2/patologia , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , PPAR gama/química , Receptores Ativados por Proliferador de Peroxissomo/química , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
12.
J Immunol ; 193(2): 496-509, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24943219

RESUMO

The Blomia tropicalis dust mite is prevalent in tropical and subtropical regions of the world. Although it is a leading cause of asthma, little is known how it induces allergy. Using a novel murine asthma model induced by intranasal exposure to B. tropicalis, we observed that a single intranasal sensitization to B. tropicalis extract induces strong Th2 priming in the lung draining lymph node. Resident CD11b(+) dendritic cells (DCs) preferentially transport Ag from the lung to the draining lymph node and are crucial for the initiation of Th2 CD4(+) T cell responses. As a consequence, mice selectively deficient in CD11b(+) DCs exhibited attenuated Th2 responses and more importantly did not develop any allergic inflammation. Conversely, mice deficient in CD103(+) DCs and CCR2-dependent monocyte-derived DCs exhibited similar allergic inflammation compared with their wild-type counterparts. We also show that CD11b(+) DCs constitutively express higher levels of GM-CSF receptor compared with CD103(+) DCs and are thus selectively licensed by lung epithelial-derived GM-CSF to induce Th2 immunity. Taken together, our study identifies GM-CSF-licensed CD11b(+) lung DCs as a key component for induction of Th2 responses and represents a potential target for therapeutic intervention in allergy.


Assuntos
Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Pulmão/imunologia , Ácaros/imunologia , Células Th2/imunologia , Administração Intranasal , Transferência Adotiva , Animais , Asma/imunologia , Asma/metabolismo , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Feminino , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunização/métodos , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ácaros/metabolismo , Ovalbumina/imunologia , Células Th2/metabolismo , Extratos de Tecidos/administração & dosagem , Extratos de Tecidos/imunologia
13.
J Invest Dermatol ; 134(3): 666-676, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24061165

RESUMO

Monocytes and their derived cells have critical roles in inflammation and immune defense. However, their function in skin diseases such as allergic contact dermatitis remains poorly defined. Using a model of contact hypersensitivity (CHS) toward 2,4-dinitrochlorobenzene, we show that Ly6C+ CD11b+ monocytic cells participate in the pathophysiology of CHS and their accumulation is regulated by effector CD8 T cells. These Ly6C+ CD11b+ monocytic cells are the primary contributors of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) and derive from Ly6C(hi)CCR2+ monocytes, as they were absent in non-inflamed skin and accumulate as a consequence of inflammation in a C-C chemokine receptor type 2 (CCR2)-dependent manner. Importantly, CCR2(-/-) mice, or wild-type mice depleted of monocytes via clodronate liposomes, display a marked decrease in TNF-α and iNOS expression accompanied by attenuated skin inflammation. Using transgenic mice and antibody depletion, we show that effector CD8 T cells regulate the accumulation of Ly6C+ CD11b+ monocytic cells through IL-17 and activate them for TNF-α and iNOS through IFN-γ. CD8 T cell-derived IFN-γ was also critical for the accumulation of the major histocompatibility complex II-expressing Ly6C+ CD11b+ subset, which expressed intermediate levels of CD11c and costimulatory molecules. Taken together, our findings provide further insight into the pathophysiology of allergic contact dermatitis by showing that CD8 T cells regulate the inflammatory cascade through TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Dermatite Alérgica de Contato/imunologia , Monócitos/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Receptores CCR2/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Dermatite Alérgica de Contato/metabolismo , Feminino , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores CCR2/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
14.
Blood ; 122(22): 3666-77, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24113869

RESUMO

Lymphangiogenesis is an important physiological response to inflammatory insult, acting to limit inflammation. Macrophages, dendritic cells, and lymphocytes are known to drive lymphangiogenesis. In this study, we show that neutrophils recruited to sites of inflammation can also coordinate lymphangiogenesis. In the absence of B cells, intranodal lymphangiogenesis induced during prolonged inflammation as a consequence of immunization is dependent on the accumulation of neutrophils. When neutrophils are depleted in wild-type mice developing skin inflammation in response to immunization or contact hypersensitization, lymphangiogenesis is decreased and local inflammation is increased. We demonstrate that neutrophils contribute to lymphangiogenesis primarily by modulating vascular endothelial growth factor (VEGF)-A bioavailability and bioactivity and, to a lesser extent, secreting VEGF-D. We further show that neutrophils increased VEGF-A bioavailability and bioactivity via the secretion of matrix metalloproteinases 9 and heparanase. Together, these findings uncover a novel function for neutrophils as organizers of lymphangiogenesis during inflammation.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Linfangiogênese/fisiologia , Neutrófilos/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismo , Animais , Linfócitos B/imunologia , Dermatite/etiologia , Dermatite/metabolismo , Dermatite/patologia , Feminino , Glucuronidase/metabolismo , Inflamação/patologia , Linfangiogênese/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/imunologia , Neutrófilos/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Eur J Neurosci ; 36(10): 3314-21, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22845723

RESUMO

Somatic sensory neuron somata are located within the dorsal root ganglia (DRG) and are mostly ensheathed by individual satellite glial cell sheets. It has been noted, however, that a subpopulation of these DRG somata are intimately associated, separated only by a single thin satellite glial cell membrane septum. We set out to test whether such neuron-glial cell-neuron trimers (NGlNs) are also linked functionally. The presence of NGlNs in chick DRGs was confirmed by electron microscopy. Selective satellite glial cell immunostains were identified and were used to image the inter-neuron septa in DRG frozen sections. We used a gentle, dispase-based enzymatic method to isolate chick and rat NGlNs in vitro for double patch clamp recordings. In the majority of pairs tested, an action potential-like stimulus train delivered to one soma resulted in a delayed, noisy and long-duration response in its idle partner. The response to a second stimulus train given minutes later was markedly facilitated. Both bidirectional and unidirectional transmission was observed between the paired neurons. Transmission was chemical and block by the general purinergic blocker suramin implicated ATP as a neurotransmitter. We conclude that the two neuronal somata in the NGlN can communicate by chemical transmission, which may involve a transglial, bi-synaptic pathway. This novel soma-to-soma transmission reflects a novel form of processing that may play a role in sensory disorders in the DRG and interneuron communication in the central nervous system.


Assuntos
Gânglios Espinais/fisiologia , Células Receptoras Sensoriais/fisiologia , Transmissão Sináptica/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Embrião de Galinha , Neuroglia/citologia , Neuroglia/fisiologia , Antagonistas Purinérgicos/farmacologia , Ratos , Células Receptoras Sensoriais/citologia , Suramina/farmacologia , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos
16.
Environ Sci Pollut Res Int ; 19(6): 1908-14, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22767288

RESUMO

The air-sea gas exchange of alpha-hexachlorocyclohexane (α-HCH) in the Canadian Arctic was estimated using a micrometeorological approach and the commonly used Whitman two-film model. Concurrent shipboard measurements of α-HCH in air at two heights (1 and 15 m) and in surface seawater were conducted during the Circumpolar Flaw Lead study in 2008. Sampling was carried out during eight events in the early summer time when open water was encountered. The micrometeorological technique employed the vertical gradient in air concentration and the wind speed to estimate the flux; results were corrected for atmospheric stability using the Monin-Obukhov stability parameter. The Whitman two-film model used the concentrations of α-HCH in surface seawater, in bulk air at 1 and 15 m above the surface, and the Henry's law constant adjusted for temperature and salinity to derive the flux. Both approaches showed that the overall net flux of α-HCH was from water to air. Mean fluxes calculated using the micrometeorological technique ranged from -3.5 to 18 ng m(-2) day(-1) (mean 7.4), compared to 3.5 to 14 ng m(-2) day(-1) (mean 7.5) using the Whitman two-film model. Flux estimates for individual events agreed in direction and within a factor of two in magnitude for six of eight events. For two events, fluxes estimated by micrometeorology were zero or negative, while fluxes estimated with the two-film model were positive, and the reasons for these discrepancies are unclear. Improvements are needed to shorten air sampling times to ensure that stationarity of meteorological conditions is not compromised over the measurement periods. The micrometeorological technique could be particularly useful to estimate fluxes of organic chemicals over water in situations where no water samples are available.


Assuntos
Poluentes Atmosféricos/análise , Hexaclorocicloexano/análise , Poluentes Químicos da Água/análise , Regiões Árticas , Atmosfera/análise , Canadá , Monitoramento Ambiental/métodos , Conceitos Meteorológicos , Microtecnologia/métodos
17.
J Immunol ; 188(8): 4065-80, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22430738

RESUMO

During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention. This restoration in lymphocyte egress was supported by a preferential expansion of cortical and medullary sinuses during late inflammation. Cortical and medullary sinus remodeling during late inflammation was dependent on temporal and spatial changes in vascular endothelial growth factor-A distribution. Specifically, its expression was restricted to the subcapsular space of the LN during early inflammation, whereas its expression was concentrated in the paracortical and medullary regions of the LN at later stages. We next showed that this process was mostly driven by the synergistic cross-talk between fibroblastic reticular cells and interstitial flow. Our data shed new light on the biological significance of LN lymphangiogenesis during prolonged inflammation and further underscore the collaborative roles of stromal cells, immune cells, and interstitial flow in modulating LN plasticity and function.


Assuntos
Linfonodos/imunologia , Linfócitos/imunologia , Transferência Adotiva , Animais , Anticorpos Neutralizantes/farmacologia , Comunicação Celular , Movimento Celular , Proliferação de Células , Células Endoteliais/imunologia , Células Endoteliais/patologia , Feminino , Hipertrofia , Inflamação/imunologia , Inflamação/patologia , Injeções Intraperitoneais , Linfonodos/patologia , Linfangiogênese , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Estromais/imunologia , Células Estromais/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Environ Sci Technol ; 46(5): 2668-74, 2012 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-22243402

RESUMO

As the uses of polybrominated diphenyl ethers (BDEs) are being phased out in many countries, soils could become a secondary emission source to the atmosphere. It is also anticipated that the demand for alternative brominated flame retardants (BFRs) will grow, but little is known about their environmental fate in soils. In this study, the volatility and degradation of BFRs and organochlorine pesticides (OCPs) in soil was investigated. A low organic carbon (5.6%) urban soil was spiked with a suite of BFRs and OCPs, followed by incubation under laboratory condition for 360 days. These included BDE- 17, -28, -47, -99; α- and ß-1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH), ß-1,2,5,6-tetrabromocyclooctane (TBCO), and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE), OCPs: α-hexachlorocyclohexane (α-HCH) and (13)C(6)-α-HCH, trans-chlordane (TC), and (13)C(10)-TC. The volatility of spiked chemicals was investigated using a fugacity meter to measure the soil-air partition coefficient (K(SA)). K(SA) of some spiked BFRs and OCPs increased from Day 10 to 60 or 90 and leveled off afterward. This suggests that the volatility of BFRs and OCPs decreases over time as the chemicals become more strongly bound to the soil. Degradation of alternative BFRs (α- and ß-TBECH, ß-TBCO, DPTE), BDE-17, and α-HCH ((13)C-labeled and nonlabeled) was evident in soils over 360 days, but no degradation was observed for the BDE-28, -47, -99, and TC ((13)C-labeled and nonlabeled). A method to separate the enantiomers of α-TBECH and ß-TBCO was developed and their degradation, along with α-HCH ((13)C-labeled and nonlabeled) was enantioselective. This is the first study which reports the enantioselective degradation of chiral BFRs in soils. Discrepancies between the enantiomer fraction (EF) of chemicals extracted from the soil by dichloromethane (DCM) and air were found. It is suggested that DCM removes both the sequestered and loosely bound fractions of chemicals in soil, whereas air accesses only the loosely bound fraction, and these two pools are subject to different degrees of enantioselective degradation. This calls for caution when interpreting EFs obtained from DCM extraction of soil with EFs in ambient air.


Assuntos
Cidades , Recuperação e Remediação Ambiental , Retardadores de Chama/análise , Hidrocarbonetos Bromados/análise , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Poluentes do Solo/análise , Ar , Meia-Vida , Hidrocarbonetos Bromados/química , Hidrocarbonetos Clorados/química , Estereoisomerismo , Fatores de Tempo , Volatilização
19.
BMC Health Serv Res ; 11: 149, 2011 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-21679471

RESUMO

BACKGROUND: Studies on readmissions attributed to particular medical conditions, especially heart failure, have generally not addressed the factors associated with readmissions and the implications for health outcomes and costs. This study aimed to investigate the factors associated with 30-day unplanned readmission for 10 common conditions and to determine the cost implications. METHODS: This population-based retrospective cohort study included patients admitted to all public hospitals in Hong Kong in 2007. The sample consisted of 337,694 hospitalizations in Internal Medicine. The disease-specific risk-adjusted odd ratio (OR), length of stay (LOS), mortality and attributable medical costs for the year were examined for unplanned readmissions for 10 medical conditions, namely malignant neoplasms, heart diseases, cerebrovascular diseases, pneumonia, injury and poisoning, nephritis and nephrosis, diabetes mellitus, chronic liver disease and cirrhosis, septicaemia, and aortic aneurysm. RESULTS: The overall unplanned readmission rate was 16.7%. Chronic liver disease and cirrhosis had the highest OR (1.62, 95% confidence interval (CI) 1.39-1.87). Patients with cerebrovascular disease had the longest LOS, with mean acute and rehabilitation stays of 6.9 and 3.0 days, respectively. Malignant neoplasms had the highest mortality rate (30.8%) followed by aortic aneurysm and pneumonia. The attributed medical cost of readmission was highest for heart disease (US$3 199 418, 95% CI US$2 579 443-803 393). CONCLUSIONS: Our findings showed variations in readmission rates and mortality for different medical conditions which may suggest differences in the quality of care provided for various medical conditions. In-hospital care, comprehensive discharge planning, and post-discharge community support for patients need to be reviewed to improve the quality of care and patient health outcomes.


Assuntos
Custos de Cuidados de Saúde/tendências , Tempo de Internação/tendências , Mortalidade/tendências , Readmissão do Paciente/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Glob Health Action ; 4: 5276, 2011 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-21394246

RESUMO

BACKGROUND: Novel efforts and accompanying tools are needed to tackle the global burden of chronic disease. This paper presents an approach to describe the environments in which people live, work, and play. Community Health Environment Scan Survey (CHESS) is an empirical assessment tool that measures the availability and accessibility, of healthy lifestyle options lifestyle options. CHESS reveals existing community assets as well as opportunities for change, shaping community intervention planning efforts by focusing on community-relevant opportunities to address the three key risk factors for chronic disease (i.e. unhealthy diet, physical inactivity, and tobacco use). METHODS: The CHESS tool was developed following a review of existing auditing tools and in consultation with experts. It is based on the social-ecological model and is adaptable to diverse settings in developed and developing countries throughout the world. RESULTS: For illustrative purposes, baseline results from the Community Interventions for Health (CIH) Mexico site are used, where the CHESS tool assessed 583 food stores and 168 restaurants. Comparisons between individual-level survey data from schools and community-level CHESS data are made to demonstrate the utility of the tool in strategically guiding intervention activities. CONCLUSION: The environments where people live, work, and play are key factors in determining their diet, levels of physical activity, and tobacco use. CHESS is the first tool of its kind that systematically and simultaneously examines how built environments encourage/discourage healthy eating, physical activity, and tobacco use. CHESS can help to design community interventions to prevent chronic disease and guide healthy urban planning.


Assuntos
Ingestão de Alimentos , Meio Ambiente , Exercício Físico , Inquéritos Epidemiológicos , Estilo de Vida , Fumar , Doença Crônica/prevenção & controle , Comportamentos Relacionados com a Saúde , Humanos , Fatores de Risco , Instituições Acadêmicas
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