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1.
Synapse ; 78(1): e22284, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37996987

RESUMO

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system, which is composed of DA and non-DA cells, and divided into specific subregions. Although CRF inputs to the midline A10 nuclei ("classic VTA") are known, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregions. We characterized CRF-labeled synaptic terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions using immunoreactive electron microscopy (EM) in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted TH-negative dendrites in both subregions. Most CRF-positive terminals had symmetric profiles. In both PBP and A8, CRF symmetric (putative inhibitory) synapses onto TH-negative dendrites were significantly greater than asymmetric (putative excitatory) profiles. This overall pattern was similar in males and females, despite shifts in the size of these effects between regions depending on sex. Because stress and gonadal hormone shifts can influence CRF expression, we also did hormonal assays over a 6-month time period and found little variability in basal cortisol across similarly housed animals at the same age. Together our findings suggest that at baseline, CRF-positive synaptic terminals in the primate PBP and A8 are poised to regulate DA indirectly through synaptic contacts onto non-DA neurons.


Assuntos
Benzenoacetamidas , Hormônio Liberador da Corticotropina , Dopamina , Piperidonas , Humanos , Animais , Masculino , Feminino , Dopamina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Macaca/metabolismo , Terminações Pré-Sinápticas/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Support Care Cancer ; 32(1): 68, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38153568

RESUMO

BACKGROUND: In the field of exercise oncology, there is a need to quantify the potential benefits of moderate, self-directed physical activity during active treatment. In a pooled analysis of three identical single-arm intervention studies, we investigate the association of activity tracker steps with patient-reported toxicities during chemotherapy. METHODS: Women with early breast cancer who were enrolled in the intervention studies reported their symptom severity every 2-3 weeks throughout chemotherapy, and daily steps were documented through a Fitbit activity tracker. Relative risks (RR) and 95% confidence intervals (CI) were calculated using Poisson regression models with robust variance. For outcomes significant in unadjusted models, adjusted RRs were calculated controlling for race, age, and education level. Tracker step cut point (high step, low step) was determined by the means. Cumulative incidence functions of moderate, severe, and very severe (MSVS) symptoms were estimated using the Kaplan-Meier method and compared using a Cox proportional hazard model. RESULTS: In a sample of 283 women, mean age was 56 years and 76% were White. Mean tracker-documented steps/week were 29,625, with 55% walking below the mean (low step) and 45% above (high step). In multivariable analysis, high step patients had lower risk for fatigue [RR 0.83 (0.70, 0.99)] (p = 0.04), anxiety [RR 0.59 (0.42, 0.84)] (p = 0.003), nausea [RR 0.66 (0.46, 0.96)] (p = 0.03), depression [RR 0.59 (0.37, 0.03)] (p = 0.02), and ≥ 6 MSVS symptoms [RR 0.73 (0.54, 1.00)] (p = 0.05) and had 36% lower risk for dose reductions [RR 0.64 (95% CI 0.43, 0.97)] (p = 0.03). CONCLUSION: Self-directed walking at a rate of at least 30,000 steps/week may moderate the severity of treatment side effects during chemotherapy for early breast cancer. TRIAL NUMBERS: NCT02167932, NCT02328313, NCT03761706.


Assuntos
Neoplasias da Mama , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Ansiedade , Neoplasias da Mama/tratamento farmacológico , Exercício Físico , Caminhada
3.
Cereb Cortex ; 30(2): 550-562, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-31219571

RESUMO

Rodent fear-learning models posit that amygdala-infralimbic connections facilitate extinction while amygdala-prelimbic prefrontal connections mediate fear expression. Analogous amygdala-prefrontal circuitry between rodents and primates is not established. Using paired small volumes of neural tracers injected into the perigenual anterior cingulate cortex (pgACC; areas 24b and 32; a potential homologue to rodent prelimbic cortex) and subgenual anterior cingulate cortex (sgACC, areas 25 and 14c; a potential homologue to rodent infralimbic cortex) in a single hemisphere, we mapped amygdala projections to the pgACC and sgACC within single subjects. All injections resulted in dense retrograde labeling specifically within the intermediate division of the basal nucleus (Bi) and the magnocellular division of the accessory basal nucleus (ABmc). Areal analysis revealed a bias for connectivity with the sgACC, with the ABmc showing a greater bias than the Bi. Double fluorescence analysis revealed that sgACC and pgACC projections were intermingled within the Bi and ABmc, where a proportion were double labeled. We conclude that amygdala inputs to the ACC largely originate from the Bi and ABmc, preferentially connect to the sgACC, and that a subset collaterally project to both sgACC and pgACC. These findings advance our understanding of fear extinction and fear expression circuitry across species.


Assuntos
Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Animais , Extinção Psicológica/fisiologia , Macaca fascicularis , Masculino , Camundongos , Vias Neurais/citologia , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Ratos , Especificidade da Espécie
4.
Clin Exp Allergy ; 47(4): 488-498, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28000949

RESUMO

BACKGROUND: Eosinophils contribute to the pathogenesis of multiple diseases, including asthma. Treatment with antibodies targeting IL-5 or IL-5 receptor α reduces the frequency of asthma exacerbations. Eosinophil receptors for IL-5 share a common ß-chain with IL-3 and GM-CSF receptors. We recently reported that IL-3 is more potent than IL-5 or GM-CSF in maintaining the ERK/p90S6K/RPS6 ribosome-directed signaling pathway, leading to increased protein translation. OBJECTIVE: We aimed to determine disease-relevant consequences of prolonged eosinophil stimulation with IL-3. RESULTS: Human blood eosinophils were used to establish the impact of activation with IL-3 on IgG-driven eosinophil degranulation. When compared to IL-5, continuing exposure to IL-3 further induced degranulation of eosinophils on aggregated IgG via increased production and activation of both CD32 (low affinity IgG receptor) and αMß2 integrin. In addition, unlike IL-5 or GM-CSF, IL-3 induced expression of CD32B/C (FCGRIIB/C) subtype proteins, without changing CD32A (FCGRIIA) protein and CD32B/C mRNA expression levels. Importantly, these in vitro IL-3-induced modifications were recapitulated in vivo on airway eosinophils. CONCLUSIONS AND CLINICAL RELEVANCE: We observed for the first time upregulation of CD32B/C on eosinophils, and identified IL-3 as a potent inducer of CD32- and αMß2-mediated eosinophil degranulation.


Assuntos
Degranulação Celular/imunologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Interleucina-3/metabolismo , Antígeno de Macrófago 1/metabolismo , Receptores de IgG/metabolismo , Anticorpos Monoclonais/farmacologia , Biomarcadores , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Humanos , Interleucina-3/farmacologia , Receptores de IgG/antagonistas & inibidores
5.
Clin Exp Allergy ; 44(12): 1484-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25109477

RESUMO

BACKGROUND: Asthma exacerbations contribute to significant morbidity, mortality and healthcare utilization. Furthermore, viral infections are associated with asthma exacerbations by mechanisms that are not fully understood. OBJECTIVE: The aim of this analysis was to determine whether cytokine patterns in patients with colds could identify risks for subsequent asthma exacerbations. METHODS: We analysed cytokine levels in nasal lavage fluid (NLF) in 59 subjects (46 with asthma) with acute upper respiratory symptoms and after symptomatic resolution. Analyte choice was based on potential relevance to asthma exacerbations: antiviral (IFN-α, IFN-ß, IFN-γ, IFN-λ1, IP-10, TRAIL), cell recruiting (G-CSF, IL-1ß, IL-8, MCP-1, MCP-3, TNF-α), polarizing (CXCL13, IL-10, IL-13, IL-17, TSLP), and injury remodelling (fibronectin, IL-33, MMP-9, VEGF). RESULTS: The overall cytokine response induced during viral infections was not different between asthmatic and non-asthmatic individuals for a wide array of cytokines. However, mean levels of VEGF, TNF-α and IL-1ß were 1.7-, 5.1- and 4.7-fold higher in samples from asthma subjects who exacerbated in the first 3 weeks of the cold compared with those who did not exacerbate (P = 0.006, 0.01, 0.048, respectively). Using receiver operating characteristic curve-defined thresholds, high VEGF and TNF-α levels predicted a shorter time-to-exacerbation after NLF sampling (25% exacerbation rate: 3 vs. 45 days, and 3 vs. 26 days; P = 0.03, 0.04, respectively). CONCLUSION AND CLINICAL RELEVANCE: Although they produce similar cytokine responses to viral infection as non-asthmatics, asthmatics with higher levels of VEGF and TNF-α in NLF obtained during acute cold phases predicted subsequent asthma exacerbations in this cohort of patients with mild-to-moderate disease. In the future, stratifying the risk of an asthma exacerbation by cytokine profile may aid the targeting of personalized treatment and intervention strategies.


Assuntos
Asma/diagnóstico , Asma/etiologia , Resfriado Comum/complicações , Resfriado Comum/metabolismo , Líquido da Lavagem Nasal , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Líquido da Lavagem Nasal/imunologia , Curva ROC
6.
bioRxiv ; 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38293165

RESUMO

The central nucleus (CeN) of the amygdala is an important afferent to the DA system that mediates motivated learning. We previously found that CeN terminals in nonhuman primates primarily overlap the elongated lateral VTA (parabrachial pigmented nucleus, PBP, A10), and retrorubral field(A8) subregion. Here, we examined CeN afferent contacts on cell somata and proximal dendrites of DA and GABA neurons, and distal dendrites of each, using confocal and electron microscopy (EM) methods, respectively. At the soma/proximal dendrites, the proportion of TH+ and GAD1+ cells receiving at least one CeN afferent contact was surprisingly similar (TH = 0.55: GAD1=0.55 in PBP; TH = 0.56; GAD1 =0.51 in A8), with the vast majority of contacted TH+ and GAD1+ soma/proximal dendrites received 1-2 contacts. Similar numbers of tracer-labeled terminals also contacted TH-positive and GAD1-positive small dendrites and/or spines (39% of all contacted dendrites were either TH- or GAD1-labeled). Overall, axon terminals had more symmetric (putative inhibitory) axonal contacts with no difference in the relative distribution in the PBP versus A8, or onto TH+ versus GAD1+ dendrites/spines in either region. The striking uniformity in the amygdalonigral projection across the PBP-A8 terminal field suggests that neither neurotransmitter phenotype nor midbrain location dictates likelihood of a terminal contact. We discuss how this afferent uniformity can play out in recently discovered differences in DA:GABA cell densities between the PBP and A8, and affect specific outputs. Significance statement: The amygdala's central nucleus (CeN) channels salient cues to influence both appetitive and aversive responses via DA outputs. In higher species, the broad CeN terminal field overlaps the parabrachial pigmented nucleus ('lateral A10') and the retrorubral field (A8). We quantified terminal contacts in each region on DA and GABAergic soma/proximal dendrites and small distal dendrites. There was striking uniformity in contacts on DA and GABAergic cells, regardless of soma and dendritic compartment, in both regions. Most contacts were symmetric (putative inhibitory) with little change in the ratio of inhibitory to excitatory contacts by region.We conclude that post-synaptic shifts in DA-GABA ratios are key to understanding how these relatively uniform inputs can produce diverse effects on outputs.

7.
Clin Exp Allergy ; 43(3): 292-303, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23414537

RESUMO

BACKGROUND: IL-5 activates α(M) ß(2) integrin on blood eosinophils in vitro. Eosinophils in bronchoalveolar lavage (BAL) following segmental antigen challenge have activated ß(2) -integrins. OBJECTIVE: To identify roles for IL-5 in regulating human eosinophil integrins in vivo. METHODS: Blood and BAL eosinophils were analysed by flow cytometry in ten subjects with allergic asthma who underwent a segmental antigen challenge protocol before and after anti-IL-5 administration. RESULTS: Blood eosinophil reactivity with monoclonal antibody (mAb) KIM-127, which recognizes partially activated ß(2) -integrins, was decreased after anti-IL-5. Before anti-IL-5, surface densities of blood eosinophil ß(2) , α(M) and α(L) integrin subunits increased modestly post challenge. After anti-IL-5, such increases did not occur. Before or after anti-IL-5, surface densities of ß(2) , α(M) , α(L) and α(D) and reactivity with KIM-127 and mAb CBRM1/5, which recognizes high-activity α(M) ß(2) , were similarly high on BAL eosinophils 48 h post-challenge. Density and activation state of ß(1) -integrins on blood and BAL eosinophils were not impacted by anti-IL-5, even though anti-IL-5 ablated a modest post-challenge increase on blood or BAL eosinophils of P-selectin glycoprotein ligand-1 (PSGL-1), a receptor for P-selectin that causes activation of ß(1) -integrins. Forward scatter of blood eosinophils post-challenge was less heterogeneous and on the average decreased after anti-IL-5; however, anti-IL-5 had no effect on the decreased forward scatter of eosinophils in post-challenge BAL compared with eosinophils in blood. Blood eosinophil KIM-127 reactivity at the time of challenge correlated with the percentage of eosinophils in BAL post-challenge. CONCLUSION AND CLINICAL RELEVANCE: IL-5 supports a heterogeneous population of circulating eosinophils with partially activated ß(2) -integrins and is responsible for up-regulation of ß(2) -integrins and PSGL-1 on circulating eosinophils following segmental antigen challenge but has minimal effects on properties of eosinophils in BAL. Dampening of ß(2) -integrin function of eosinophils in transit to inflamed airway may contribute to the decrease in lung inflammation caused by anti-IL-5.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos/imunologia , Antígenos CD18/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Interleucina-5/imunologia , Adulto , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Asma/imunologia , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Antígenos CD18/imunologia , Eosinófilos/efeitos dos fármacos , Epitopos/imunologia , Feminino , Humanos , Interleucina-5/antagonistas & inibidores , Contagem de Leucócitos , Masculino , Glicoproteínas de Membrana/metabolismo , Adulto Jovem
8.
Clin Exp Allergy ; 43(2): 187-97, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23331560

RESUMO

BACKGROUND: Allergic airway inflammation contributes to the airway remodelling that has been linked to increased obstruction and morbidity in asthma. However, the mechanisms by which allergens contribute to airway remodelling in humans are not fully established. CCL18, chitotriosidase (CHIT1) and YKL-40 are readily detectable in the lungs and contribute to remodelling in other fibrotic diseases, but their involvement in allergic asthma is unclear. OBJECTIVE: We hypothesized that CCL18, YKL-40 and CHIT1 bioactivity are enhanced in allergic asthma subjects after segmental allergen challenge and are related to increased pro-fibrotic and Th2-associated mediators in the lungs. METHODS: Levels of CCL18 and YKL-40 protein and chitotriosidase (CHIT1) bioactivity in bronchoalveolar lavage (BAL) fluid, as well as CCL18, YKL-40 and CHIT1 mRNA levels in BAL cells were evaluated in patients with asthma at baseline and 48 h after segmental allergen challenge. We also examined the correlation between CCL18 and YKL-40 levels and CHIT1 activity with the levels of other pro-fibrotic factors and chemokines previously shown to be up-regulated after allergen challenge. RESULTS: Chitotriosidase activity and YKL-40 and CCL18 levels were elevated after segmental allergen challenge and these levels correlated with those of other pro-fibrotic factors, T cell chemokines, and inflammatory cells after allergen challenge. CCL18 and YKL-40 mRNA levels also increased in BAL cells after allergen challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that CCL18 and YKL-40 levels and CHIT1 activity are enhanced in allergic airway inflammation and thus may contribute to airway remodelling in asthma.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Asma/metabolismo , Quimiocinas CC/metabolismo , Quitinases/metabolismo , Adipocinas/metabolismo , Adulto , Remodelação das Vias Aéreas , Alérgenos/administração & dosagem , Asma/genética , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proteína 1 Semelhante à Quitinase-3 , Citocinas/metabolismo , Ativação Enzimática , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Lectinas/metabolismo , Masculino , Fatores de Tempo , Adulto Jovem
9.
Clin Exp Allergy ; 42(12): 1756-64, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23181791

RESUMO

BACKGROUND: Differentiation and activation of CD4(+) T cells is controlled by various cytokines produced by innate immune cells. We have shown that eosinophils (EOS) have the potential to influence Th1 and Th2 cytokine generation by CD4(+) cells, but their influence on IL-17A (IL-17) has not been established. OBJECTIVE: The purpose of this study is to determine the effect of EOS on IL-17 production by lymphocytes. METHODS: Pre-activated CD4(+) T cells were cultured in the presence of either autologous EOS or EOS culture supernatants. Expression of IL-17 was determined by real-time quantitative PCR (qPCR) after 5 h and protein level was measured after 48 h. To determine the effect of allergen-induced airway EOS on IL-17, subjects with mild allergic asthma underwent bronchoscopic segmental bronchoprovocation with allergen (SBP-Ag) after a treatment with an anti-IL-5 neutralizing antibody (mepolizumab) to reduce airway eosinophilia. IL-17 mRNA was measured in bronchoalveolar lavage (BAL) cells by qPCR. RESULTS: In vitro, EOS significantly increased IL-17 production by CD4(+) T cells. Addition of exogenous IL-1ß increased expression of IL-17 mRNA by CD4(+) T cells. EOS expressed and released IL-1ß. Furthermore, levels of IL-1ß in EOS supernatants highly correlated with their ability to increase IL-17 expression by CD4(+) T cells, and neutralizing antibody to IL-1ß reduced expression of IL-17 mRNA. In vivo, reduction of EOS in the airway using mepolizumab was associated with diminished IL-17 expression after SBP-Ag. CONCLUSIONS AND CLINICAL RELEVANCE: Our data demonstrate that EOS can promote IL-17 production through the release of IL-1ß. Enhanced IL-17 cytokine production is another mechanism by which EOS may participate in pathogenesis of allergic airway inflammation in asthma.


Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Eosinófilos/metabolismo , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Ativação Linfocitária/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/terapia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Eosinófilos/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Hipersensibilidade , Interleucina-17/genética , Interleucina-1beta/genética , Resultado do Tratamento , Regulação para Cima
10.
Neurosci Biobehav Rev ; 90: 247-259, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29704516

RESUMO

Corticotropin-releasing factor (CRF) is a neuropeptide that mediates the stress response. Long known to contribute to regulation of the adrenal stress response initiated in the hypothalamic-pituitary axis (HPA), a complex pattern of extrahypothalamic CRF expression is also described in rodents and primates. Cross-talk between the CRF and midbrain dopamine (DA) systems links the stress response to DA regulation. Classically CRF + cells in the extended amygdala and paraventricular nucleus (PVN) are considered the main source of this input, principally targeting the ventral tegmental area (VTA). However, the anatomic complexity of both the DA and CRF system has been increasingly elaborated in the last decade. The DA neurons are now recognized as having diverse molecular, connectional and physiologic properties, predicted by their anatomic location. At the same time, the broad distribution of CRF cells in the brain has been increasingly delineated using different species and techniques. Here, we review updated information on both CRF localization and newer conceptualizations of the DA system to reconsider the CRF-DA interface.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Dopamina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Área Tegmentar Ventral/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Neurônios Dopaminérgicos/patologia , Humanos
11.
Nat Commun ; 7: 10905, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26948129

RESUMO

Microglia are the resident immune cells of the brain. Increasingly, they are recognized as important mediators of normal neurophysiology, particularly during early development. Here we demonstrate that microglia are critical for ocular dominance plasticity. During the visual critical period, closure of one eye elicits changes in the structure and function of connections underlying binocular responses of neurons in the visual cortex. We find that microglia respond to monocular deprivation during the critical period, altering their morphology, motility and phagocytic behaviour as well as interactions with synapses. To explore the underlying mechanism, we focused on the P2Y12 purinergic receptor, which is selectively expressed in non-activated microglia and mediates process motility during early injury responses. We find that disrupting this receptor alters the microglial response to monocular deprivation and abrogates ocular dominance plasticity. These results suggest that microglia actively contribute to experience-dependent plasticity in the adolescent brain.


Assuntos
Microglia/metabolismo , Plasticidade Neuronal , Receptores Purinérgicos P2Y12/metabolismo , Córtex Visual/fisiologia , Animais , Dominância Ocular , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Receptores Purinérgicos P2Y12/genética , Sinapses/genética , Sinapses/metabolismo
12.
J Interferon Cytokine Res ; 17(8): 481-7, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9282829

RESUMO

T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-gamma (IFN-gamma), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-gamma:IL-4 and IFN-gamma:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation.


Assuntos
Asma/sangue , Citocinas/sangue , Estresse Fisiológico/sangue , Adolescente , Estudos de Casos e Controles , Eosinófilos/fisiologia , Feminino , Humanos , Imunoglobulina E/sangue , Interferon gama/sangue , Interleucina-2/sangue , Interleucina-4/sangue , Interleucina-5/sangue , Masculino , Pico do Fluxo Expiratório , Valores de Referência , Estimulação Química
13.
Pediatrics ; 90(5): 744-9, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1408548

RESUMO

The aim of this study was to assess all relevant aspects of auditory function, including acuity and perception, of a cohort of extremely low birth weight (< 1000 g) children who survived to 8 years of age; 42 of the 59 consecutive survivors born over a 4-year period from January 1, 1977, had a full auditory assessment. Of the 42 children, 4 (9.5%) had a sensorineural hearing impairment, 5 (11.9%) had a conductive hearing impairment, 24 (57.1%) had figure/ground differentiation problems, and 20 (47.6%) had a short-term auditory memory problem. The 4 children with sensorineural hearing impairments had had significantly higher maximum concentrations of bilirubin in the newborn period (median 167 mumol/L vs 138 mumol/L and had required more intensive care; at 8 years of age they were significantly disadvantaged in verbal ability. The 5 children with conductive hearing impairments were not significantly different on any perinatal or other 8-year outcome variables. The proportion with figure/ground differentiation problems (57.1%) was significantly higher than in a normative population (11.7%, chi 2 = 24.2). Extremely low birth weight children with figure/ground differentiation problems were more likely to be restless in the classroom (45.0% [9/20]) than those without these problems (16.7% [2/12]), but the difference was not statistically significant (chi 2 = 2.7). Children with short-term auditory memory problems had significantly higher maximum bilirubin concentrations in the newborn period (median 152 mumol/L vs 137.5 mumol/L). At 8 years of age they had significantly reduced intelligence and reading ability.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Percepção Auditiva , Transtornos da Audição/etiologia , Audição , Recém-Nascido de Baixo Peso , Audiometria , Criança , Feminino , Seguimentos , Transtornos da Audição/diagnóstico , Perda Auditiva Condutiva/etiologia , Perda Auditiva Neurossensorial/etiologia , Humanos , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Masculino
14.
Obstet Gynecol ; 90(4 Pt 2): 672-4, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11770591

RESUMO

BACKGROUND: Brodifacoum is a potent warfarin-like anticoagulant used in many rat-poisoning products. Its availability has led to several reported human ingestions, none previously reported in pregnancy. CASE: A woman presented at 22 weeks' gestation in hemorrhagic diathesis, attributed to the ingestion of rat poison containing brodifacoum several days earlier. Aggressive vitamin K therapy controlled the maternal coagulopathy, and no fetal hemorrhage was observed by sonography. Her subsequent prenatal course and delivery were unremarkable, and she was delivered of a healthy infant, who has remained well for at least 1 year. CONCLUSION: In this patient, brodifacoum ingestion in pregnancy caused substantial maternal hemorrhage, but no fetal hemorrhage or teratogenic effects were observed.


Assuntos
4-Hidroxicumarinas/intoxicação , Complicações Cardiovasculares na Gravidez/induzido quimicamente , Resultado da Gravidez , Rodenticidas/intoxicação , Tentativa de Suicídio , 4-Hidroxicumarinas/administração & dosagem , Adulto , Feminino , Humanos , Gravidez , Rodenticidas/administração & dosagem
15.
Obstet Gynecol ; 81(6): 931-5, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7684516

RESUMO

OBJECTIVE: To determine the sensorineural outcome at 2 years of age in a complete cohort of survivors of fetal intravascular transfusions. METHODS: From March 1984 to May 1990, 38 of 52 consecutive fetuses (73%) suffering from severe erythroblastosis survived attempted intravascular transfusions at the Royal Women's Hospital, Melbourne. At 2 years of age, corrected for prematurity where appropriate, the survivors had a psychological assessment, including the mental developmental index of the Bayley scales, and a standardized neurodevelopmental examination. RESULTS: Only one transfused child had a severe sensorineural disability, with severe developmental delay and multiple minor motor seizures. Another child was moderately disabled with spastic hemiplegia. In neither case were complications of an intravascular transfusion the likely explanation for the disability. Only one other child had a mental developmental index in the suspect range. The remaining 35 children (92.1%) had no sensorineural disability. The overall rate of sensorineural impairments and disabilities was lower in the group transfused than in previous reports of survivors of intraperitoneal transfusions. The mean mental developmental index was significantly higher in the transfused group than in a control group of normal birth weight children. CONCLUSION: Children who survive fetal intravascular transfusions compare favorably not only with other high-risk survivors, but also with low-risk children.


Assuntos
Transfusão de Sangue Intrauterina , Paralisia Cerebral/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Eritroblastose Fetal/terapia , Transfusão de Sangue Intrauterina/efeitos adversos , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Recém-Nascido , Testes de Inteligência , Masculino , Fatores de Risco
16.
Obstet Gynecol ; 73(5 Pt 1): 743-6, 1989 May.
Artigo em Inglês | MEDLINE | ID: mdl-2704500

RESUMO

Over a 63-month period beginning January 1, 1977, 258 infants with birth weights of 500-999 g were born alive at one tertiary perinatal center; 170 were offered full intensive care. The mothers of 67 (39.4%) of these 170 infants had been given betamethasone antenatally to accelerate fetal lung maturation. Of the 67 infants exposed to steroids antenatally, 46 (68.7%) survived their primary hospitalization, compared with 43 (41.7%) of the 103 infants who had not been exposed to steroids. This difference is highly significant (chi 2 = 10.7; P less than .005) but is biased because infants in the steroid group had a better prognosis. After adjustment for discrepancies in birth weight and gestational age and other confounding obstetric variables, survival in the steroid group remained substantially higher (relative odds of survival 1.85, 95% confidence intervals 1.16-2.86; P = .006). The improvements in survival were not at the expense of increased rates of chronic ill health or impairments of growth neurodevelopment up to at least 5 years of age. For extremely immature and extremely low birth weight infants, steroids are rarely contraindicated on fetal grounds.


Assuntos
Betametasona/efeitos adversos , Recém-Nascido de Baixo Peso/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Betametasona/uso terapêutico , Paralisia Cerebral/epidemiologia , Estudos de Coortes , Feminino , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Nível de Saúde , Hospitalização , Humanos , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Pulmão/embriologia , Oxigenoterapia , Gravidez , Morte Súbita do Lactente/epidemiologia
17.
Obstet Gynecol ; 79(2): 268-75, 1992 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-1731298

RESUMO

The aim of this study was to assess the outcome up to 2 years of age for the fetus of birth weight 500-999 g, over time and in association with changes in obstetric care. Two consecutive cohorts of infants of birth weight 500-999 g were compared from two eras, 1977-1982 and 1985-1987, and their outcome up to 2 years of age was determined with particular emphasis on the effect of various obstetric interventions at the time of birth, such as cesarean delivery, electronic fetal monitoring, antenatal steroid therapy, and tocolytic therapy. The outcome to 2 years was analyzed by logistic function regression to adjust for imbalances in confounding perinatal variables. In the latter era, the survival rate to 2 years increased significantly by almost 50%, and only 7% of the survivors were severely disabled. The rates of delivery by cesarean and of electronic fetal monitoring both increased significantly in the latter era, but neither was associated with the improved outcome. The only variable associated with an improved outcome that was amenable to obstetric intervention at the time of birth was antenatal steroid therapy, which was used equally in both eras. The obstetrician may aid the fetus of birth weight 500-999 g by giving the mother steroids to accelerate fetal lung maturity, but cesarean cannot be recommended as the routine mode of delivery unless there are recognized maternal or fetal indications.


Assuntos
Recém-Nascido de Baixo Peso , Obstetrícia/tendências , Parto Obstétrico , Feminino , Seguimentos , Humanos , Recém-Nascido , Razão de Chances , Gravidez , Complicações na Gravidez/epidemiologia , Análise de Sobrevida
18.
J Appl Physiol (1985) ; 67(1): 174-80, 1989 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2759942

RESUMO

We studied the effect of maturation on contractile properties of tracheal smooth muscle from seventeen 2-wk-old swine (2ws) and fifteen 10-wk-old swine (10ws) in situ and in vitro. The response to parasympathetic stimulation was studied in situ in isometrically fixed segments. Contraction was elicited at lower frequencies [half-maximal response to electrical stimulation (ES50) = 6.7 +/- 0.05 Hz] in 2ws than in 10ws (ES50 = 9.1 +/- 0.4 Hz; P less than 0.01). Despite substantial differences in morphometrically normalized cross-sectional area in 2ws (0.012 +/- 0.003 cm2) and 10ws (0.028 +/- 0.001 cm2; P less than 0.01), maximal active tension elicited by parasympathetic stimulation was similar (12.4 +/- 3.2 g/cm in 2ws vs. 13.3 +/- 2.3 g/cm in 10ws; P = NS). In separate in vitro studies in 25 tracheal smooth muscle strips from 10 swine, concentration-response curves generated with potassium-substituted Krebs solution (KCl) were similar in 2ws and 10ws. In 58 other strips (10 swine), maximal active force elicited with acetylcholine (ACh) in 2ws was significantly greater than for 10ws (P less than 0.001). Removal of the epithelium had no effect. However, cholinesterase inhibition with 10(-7) M physostigmine augmented the response to ACh in 10ws (P less than 0.02) but not 2ws. We demonstrate increased force generation and sensitivity to vagal stimulation in 2ws vs. 10ws, which corresponds to increased reactivity to ACh in vitro. The relative hyperresponsiveness in 2ws is specific for cholinergic response and is attenuated at least in part by maturation of the activity of acetylcholinesterase enzyme.


Assuntos
Acetilcolinesterase/metabolismo , Envelhecimento/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Suínos/fisiologia , Traqueia/fisiologia , Animais , Masculino , Músculo Liso/enzimologia , Traqueia/enzimologia
19.
Am J Trop Med Hyg ; 35(4): 803-11, 1986 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2942048

RESUMO

Mice sensitized with radiation-attenuated Schistosoma mansoni cercariae were treated by a variety of procedures known to interrupt immunoregulatory circuitries in attempts to alter the resistance induced by irradiated cercarial sensitization. Both highly resistant C57BL/6 and the often poorly resistant CBA/J strains were examined. Immunomanipulations included adult thymectomy, or administration of different drugs in relation to the time of challenge infection (day 0). Adult thymectomy was performed 3 weeks prior to sensitization or 3 weeks prior to challenge. Drug treatment included cyclophosphamide given at a dose of 20 mg/kg on alternate days, day -11 through day +11, cimetidine at 50 mg/kg/day, day -7 through day +21, or indomethacin at 2.5 mg/kg/day, day 0 through day +10. In most experiments, irradiated cercarial sensitized C57BL/6 mice developed significant resistance which was not altered by the immunomanipulative regimens used. If however, as fortuitously occurred in two adult thymectomy experiments, irradiated cercarial sensitization did not induce significant resistance, immunomanipulation by adult thymectomy allowed the development of a significant protected state. Similarly, adult thymectomy or cimetidine treatment in concert with immunization of CBA/J mice conferred moderate, statistically significant levels of stable resistance in this normally "less resistant" strain.


Assuntos
Imunização , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Animais , Cimetidina/farmacologia , Ciclofosfamida/farmacologia , Feminino , Imunidade Inata , Indometacina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Monócitos/imunologia , Linfócitos T Reguladores/imunologia , Timectomia
20.
Acad Med ; 69(1): 20-4, 1994 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8285991

RESUMO

The ease with which individuals can access the Internet and with which institutions can make information available on the Internet explains the exponential growth of this national resource. Once one accomplishes the difficult task of installing network services and establishing an ongoing mechanism for their support, it is relatively simple to use software systems such as those described in this article to gainfully traverse the Internet for a wide range of professional activities. But, as we have discussed, every step of the process, from simple naming conventions to organizations and ongoing maintenance of network-based information services, should proceed only after careful consideration of a network growing hourly in complexity. Despite the power of the technology available on one's desktop, one can often be frustrated by the small decisions: what is my colleague's email address? How can I most effectively find relevant information on home health care software? How should I organize a gopher server? When is WAIS preferable to Gopher or W3? Who will help me learn more? The process comes full circle back to academic medical institutions. The usefulness of the Internet hinges upon the policies these institutions create to aid the organization and dissemination of medical information, and in the means they use to make their constituents aware of the pitfalls and potentials of various technologies.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Redes de Comunicação de Computadores
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