Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
1.
J Nutr Health Aging ; 22(3): 328-334, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29484345

RESUMO

OBJECTIVES: To evaluate the overall rate of adherence by general practitioners (GPs) to treatment modifications suggested at discharge from hospital and to assess the way communication between secondary and primary care could be improved. DESIGN: Observational prospective cohort study. SETTING: Patients hospitalized from the emergency department to the acute geriatric care unit of a university hospital. PARTICIPANTS: 206 subjects with a mean age of 85 years. MEASUREMENTS: Changes in drug regimen undertaken during hospitalization were collected with the associated justifications. Adherence at one month by GPs to treatment modifications was assessed as well as modifications implemented in primary care with their rationale in case of non-adherence. Community pharmacists' and GPs' opinions about quality of communication and information transfer at hospital-general practice interface were investigated. RESULTS: 5.5 ± 2.8 drug regimen changes were done per patient during hospitalization. The rate of adherence by GPs to treatment modifications suggested at discharge from hospital was 83%. In most cases, non-adherence by GPs to treatment modifications done during hospitalization was due to dosage adjustments, symptoms resolution but also worsening of symptoms. The last of which was particularly true for psychotropic drugs. All GPs received their patients' discharge letters but the timely dissemination still needs to be improved. Only 6.6% of community pharmacists were informed of treatment modifications done during their patients' hospitalization. CONCLUSION: Our findings showed a successful rate of adherence by GPs to treatment modifications suggested at discharge from hospital, due to the fact that optimization was done in a collaborative way between geriatricians and hospital pharmacists and that justifications for drug regimen changes were systematically provided in discharge letters. Communication processes at the interface between secondary and primary care, particularly with community pharmacists, must be strengthened to improve seamless care.


Assuntos
Assistência Ambulatorial/estatística & dados numéricos , Atitude do Pessoal de Saúde , Protocolos Clínicos , Clínicos Gerais/estatística & dados numéricos , Erros de Medicação/estatística & dados numéricos , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Comunicação , Prescrições de Medicamentos , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Alta do Paciente , Farmacêuticos , Atenção Primária à Saúde , Estudos Prospectivos
2.
J Nutr Health Aging ; 21(8): 849-854, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28972235

RESUMO

BACKGROUND: Consequences of inappropriate prescriptions and polymedication in patients suffering from cancer are beginning to be well documented. However, the methods used to evaluate these consequences are often discussed. Few studies evaluate the risk of interaction with anticancer drugs in elderly patients suffering from cancer. OBJECTIVES: To describe the prevalence (i) of polypharmacy, (ii) of potentially inappropriate drug prescriptions and (iii) of drug interactions involving anticancer treatments, using a multiple reference tools. DESIGN: A retrospective, cross-sectional, multicenter study performed from January to December 2012. PARTICIPANTS: Patients aged 65 years or older suffering from cancer presented at the oncogeriatric multidisciplinary meeting. MEASUREMENTS: Polymedication (>6 drugs), potentially inappropriate prescriptions and drug interactions involving anticancer treatment were analyzed in combination with explicit and implicit criteria within a global approach. RESULTS: Among the 106 patients included in this study, polypharmacy was present in 60.4% of cases, potentially inappropriate drug prescription in 63.1% and drug interactions in 16% of case, of which 47% involved anti-cancer treatments. Twenty-seven major drug interactions were identified and eight interactions involved chemotherapy. CONCLUSION: Polymedication, inappropriate prescribing and drug interactions involving anti-cancer drugs are common and largely underestimated in elderly cancer patients.


Assuntos
Antineoplásicos/efeitos adversos , Prescrições de Medicamentos/normas , Prescrição Inadequada/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Interações Medicamentosas , Feminino , Humanos , Masculino , Estudos Retrospectivos
4.
Oncogene ; 34(42): 5317-28, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25728679

RESUMO

Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of ß-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.


Assuntos
Senescência Celular , Neoplasias Pulmonares/patologia , Proteínas Supressoras de Tumor/fisiologia , Proteínas Wnt/fisiologia , beta Catenina/fisiologia , Animais , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Humanos , Iloprosta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Associadas a Fase S/fisiologia , Transdução de Sinais
5.
Eur Respir J ; 37(4): 775-83, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20562128

RESUMO

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1α in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n = 6; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n = 13; stage III and IV). We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1α and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1α and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1α protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1α protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry. In conclusion, reduced expression of HIF-1α protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.


Assuntos
Enfisema/metabolismo , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Núcleo Celular/metabolismo , Estudos de Coortes , Citoplasma/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Histopathology ; 50(2): 258-65, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17222255

RESUMO

AIMS: To identify individual histopathological features within usual interstitial pneumonia pattern that predict responsiveness to immunosuppressive therapy. METHODS AND RESULTS: Fifty-six retrospectively confirmed usual interstitial pneumonia pattern surgical lung biopsy specimens from subjects with idiopathic pulmonary fibrosis treated with corticosteroid and cytotoxic therapy were included. Eleven prospectively defined histopathological features were evaluated by two expert pulmonary pathologists. Regression analysis identified predictors of response to therapy, as defined by the change in percent predicted forced vital capacity over 6 months. Additional end-points were change in dyspnoea score over 6 months, and survival time. Improvement in percent predicted forced vital capacity was associated with lymphoplasmacytic inflammation, while worsening of percent predicted forced vital capacity was associated with the presence of organizing pneumonia and fibroblast foci. Worsening dyspnoea was associated with fibroblast foci. Survival time was associated with age and baseline percent predicted forced vital capacity, but not with any individual histopathological feature. CONCLUSIONS: In pathological usual interstitial pneumonia pattern, the presence of lymphoplasmacytic inflammation predicts responsiveness to immunomodulatory therapy, while airspace organization predicts lack of response.


Assuntos
Linfócitos/patologia , Pneumonia/patologia , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
7.
Eur Respir J ; 28(2): 364-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16571614

RESUMO

Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.


Assuntos
Doenças Autoimunes , Doenças do Sistema Imunitário , Doenças Pulmonares Intersticiais , Linfocitose , Adolescente , Adulto , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/mortalidade , Doenças Autoimunes/patologia , Feminino , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/patologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/patologia , Linfocitose/complicações , Linfocitose/tratamento farmacológico , Linfocitose/mortalidade , Linfocitose/patologia , Masculino , Pessoa de Meia-Idade , Doenças Raras/tratamento farmacológico , Doenças Raras/mortalidade , Doenças Raras/patologia
8.
Am J Physiol Lung Cell Mol Physiol ; 289(6): L1083-93, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16085670

RESUMO

Loss of PKC-epsilon limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-epsilon would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-epsilon wild-type (PKC-epsilon(+/+)), heterozygous null, and homozygous null (PKC-epsilon(-/-)) mice were exposed to normoxia or Hx for 5 wk. PKC-epsilon(-/-) mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-epsilon(+/+) mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-epsilon(+/+) mice) in both the proximal and distal PKC-epsilon(-/-) pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-epsilon(-/-) mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-epsilon(-/-) than PKC-epsilon(+/+) mice. In contrast, expression of nNOS in PKC-epsilon(+/+) mice decreased in response to chronic Hx, while lung levels in PKC-epsilon(-/-) mice remained unchanged. In summary, loss of PKC-epsilon results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-epsilon appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.


Assuntos
Hipóxia/enzimologia , Pulmão/irrigação sanguínea , Pulmão/enzimologia , Proteína Quinase C-épsilon/metabolismo , Circulação Pulmonar , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/genética , Hipóxia/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/administração & dosagem , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo III , Proteína Quinase C-épsilon/deficiência , Proteína Quinase C-épsilon/genética , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
9.
Nucl Instrum Methods Phys Res A ; 548(1-2): 30-37, 2005 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-17369874

RESUMO

Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology.

10.
Eur Respir J Suppl ; 46: 28s-32s, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14621104

RESUMO

Chronic obstructive lung disease affects the entire lung, not just the airways. Although pulmonary hypertension (PH) has long been recognised in a subset of patients with COLD, the important pathophysiological questions remain unanswered. Oxygen supplementation, however, has been shown to blunt the exercise-induced PH in these patients. Hypercoagulability has also been described in patients with COLD. This may, in part, be due to the inflammatory aspects of COLD exacerbation events. In addition to perivascular inflammation, the pathology of vessels in COLD includes intimal thickening, muscularisation of arterioles, in situ thrombosis, loss of capillaries and precapillary arterioles, and vascular congestion and stasis. Recent work describes apoptosis of septal endothelial cells and decreased expression of vascular endothelial growth factor (VEGF) and one of its receptors, VEGFRII, in lungs from patients with emphysema. Based on this work, a rat model was developed that shows chronic blockade of VEGF receptors leads to septal cell apoptosis and results in emphysema and PH. This animal model has led to prevention trials using 1) a broad-spectrum caspase inhibitor, 2) a superoxide dismutase mimetic, and 3) alpha1-antitrypsin. These findings highlight the importance of vascular endothelial growth factor, apoptosis, oxidative stress and protease activity in the pathogenesis of emphysema. They also underscore the importance of the vasculature in what is traditionally thought of as an airways disease. Future treatment strategies need to address the vascular components of chronic obstructive lung disease.


Assuntos
Artéria Pulmonar/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Animais , Coagulação Sanguínea , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Inflamação , Artéria Pulmonar/patologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologia , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Trombose/etiologia , Trombose/fisiopatologia
11.
Eur Respir J ; 22(3): 403-7, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14516126

RESUMO

Primary pulmonary hypertension (PPH) and Castleman's disease (CD) are rare conditions infrequently encountered in clinical practice. In this paper, two patients diagnosed with both of these diseases are reported. The authors speculate that rather than being a chance occurrence, these conditions are linked by a common angio-proliferative mechanism. Therefore, an association between infection with the human herpesvirus-8 and the diseases of PPH and CD was sought. Evidence of human herpesvirus-8 infection was found in the lung tissue and, specifically, in the plexiform lesions from one of the patients.


Assuntos
Hiperplasia do Linfonodo Gigante/virologia , Infecções por Herpesviridae/complicações , Herpesvirus Humano 8/isolamento & purificação , Hipertensão Pulmonar/virologia , Adulto , Cateterismo Cardíaco , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Infecções por Herpesviridae/patologia , Humanos , Hipertensão Pulmonar/patologia , Imuno-Histoquímica , Pulmão/patologia , Linfonodos/patologia , Masculino , Reação em Cadeia da Polimerase
12.
Bone Marrow Transplant ; 31(10): 939-41, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12748674

RESUMO

Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-gamma.


Assuntos
Corticosteroides/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carmustina/efeitos adversos , Interferon gama/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Fibrose Pulmonar/induzido quimicamente , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/radioterapia , Feminino , Humanos , Pessoa de Meia-Idade , Fibrose Pulmonar/radioterapia , Testes de Função Respiratória , Síndrome , Fatores de Tempo , Resultado do Tratamento
13.
Eur Respir J ; 19(1): 20-30, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11843321

RESUMO

In obliterative bronchiolitis, inflammation and fibrosis lead to narrowing or occlusion of bronchiolar lumina. To determine how bronchiolar structural alterations relate to lung physiology, 19 patients with a pathological diagnosis of obliterative bronchiolitis were studied. The bronchiolar inflammatory and fibrotic features were correlated to the clinical presentation, and lung function tests. Eleven patients demonstrated airflow limitation, one had a restrictive pattern and one had a mixed pattern, two had isolated gas trapping, but four had normal spirometry. Mild-to-moderate bronchiolar inflammation was invariably present. It involved 60% of bronchioles subepithelially and 54% in the adventitia. Subepithelial fibrosis was observed in 15 patients and adventitial in 12. Adventitial bronchiolar inflammation correlated with forced expiratory volume in one second and forced vital capacity and inversely correlated with residual volume. Subepithelial fibrosis inversely correlated with subepithelial and adventitial inflammation. High-resolution computed tomography in 10 patients revealed inspiratory (five out of 10) and expiratory air trapping (five out of five), ground glass opacities (seven out of 10), bronchial wall thickening (five out of 10), bronchiectasis (two out of 10) and centrilobular nodules (two out of 10). The present study suggests that inflammation and fibrosis occurs in bronchioles at different time points in the disease process, or that there is no transition between these types of pathology in the same patient. No correlation was observed between the degree of bronchiolar fibrosis and the degree of airflow limitation.


Assuntos
Bronquiolite Obliterante/patologia , Bronquiolite Obliterante/fisiopatologia , Adulto , Bronquiolite Obliterante/diagnóstico por imagem , Feminino , Humanos , Inflamação/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/patologia , Espirometria , Tomografia Computadorizada por Raios X
14.
J Pathol ; 195(3): 367-74, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11673836

RESUMO

Pulmonary arteries of patients with severe pulmonary hypertension (SPH) presenting in an idiopathic form (primary PH-PPH) or associated with congenital heart malformations or collagen vascular diseases show plexiform lesions. It is postulated that in lungs with SPH, endothelial cells in plexiform lesions express genes encoding for proteins involved in angiogenesis, in particular, vascular endothelial growth factor (VEGF) and those involved in VEGF receptor-2 (VEGFR-2) signalling. On immunohistochemistry and in situ hybridization, endothelial cells in the plexiform lesions expressed VEGF mRNA and protein and overexpressed the mRNA and protein of VEGFR-2, and the transcription factor subunits HIF-1alpha and HIF-1beta of hypoxia inducible factor, which are responsible for the hypoxia-dependent induction of VEGF. When compared with normal lungs, SPH lungs showed decreased expression of the kinases PI3 kinase and src, which, together with Akt, relay the signal transduction downstream of VEGFR-2. Because markers of angiogenesis are expressed in plexiform lesions in SPH, it is proposed that these lesions may form by a process of disordered angiogenesis.


Assuntos
Proteínas de Ligação a DNA , Fatores de Crescimento Endotelial/análise , Hipertensão Pulmonar/metabolismo , Linfocinas/análise , Artéria Pulmonar/metabolismo , Receptores Proteína Tirosina Quinases/análise , Receptores de Hidrocarboneto Arílico , Receptores de Fatores de Crescimento/análise , Translocador Nuclear Receptor Aril Hidrocarboneto , Biomarcadores/análise , Estudos de Casos e Controles , Fatores de Crescimento Endotelial/genética , Humanos , Hipertensão Pulmonar/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Hibridização In Situ/métodos , Linfocinas/genética , Neovascularização Patológica , Oligopeptídeos/análise , Fosfatidilinositol 3-Quinases/análise , Artéria Pulmonar/patologia , RNA Mensageiro/análise , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento do Endotélio Vascular , Fatores de Transcrição/análise , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
15.
Clin Chest Med ; 22(3): 405-18, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11590837

RESUMO

Dysfunctional endothelial cells have a central and critical role in the initiation and progression of severe pulmonary hypertension. The elucidation of the mechanisms involved in the control of endothelial cell proliferation and cell death in the pulmonary vasculature, therefore, is fundamentally important in the pathogenesis of severe pulmonary hypertension and of great interest for a better understanding of endothelial cell biology. Because the intravascular growth of endothelial cells resulting in tumorlets is unique to severe pulmonary hypertension, this phenomenon can teach researchers about the factors involved in the formation and maintenance of the normal endothelial cell monolayer. Clearly, in severe pulmonary hypertension, the "law of the endothelial cell monolayer" has been broken. The ultimate level of such a control is at the altered gene expression pattern that is conducive to endothelial cell growth and disruption of pulmonary blood flow. Secondary pulmonary hypertension certainly also is associated with proliferated pulmonary endothelial cells and plexiform lesions that are histologically indistinguishable from those in PPH. What is then the difference in the mechanisms of endothelial cell proliferation between primary and secondary pulmonary hypertension? The authors believe that PPH is a disease caused by somatic mutations in key angiogenesis- or apoptosis-related genes such as the TGF-beta receptor-2 and Bax. The loss of these important cell growth control mechanisms allows for the clonal expansion of endothelial cells from a single cell that has acquired a selective growth advantage. On the other hand, the proliferated endothelial cells in secondary pulmonary hypertension are polyclonal. It follows from this finding that local (vascular) factor(s) (such as increased shear stress), rather than mutations, play a major role in triggering endothelial cell proliferation. In PPH and secondary pulmonary hypertension, the researcher can postulate that the pulmonary vascular bed contains progenitor-like cells with the capacity of dysregulated growth. The main difference in the pathogenesis of primary and secondary pulmonary endothelial cell proliferation therefore may be the initial mechanism involved in the recruitment of an endothelial progenitor-like cell. In PPH, anorexigen-associated, and familial PPH, the proliferation of endothelial cells occurs from a mutated single cell, whereas in secondary pulmonary hypertension, several progenitor-like cells would be activated to grow. The abnormal endothelial cells in both forms of severe pulmonary hypertension expand because of the expression of angiogenesis-related molecules such as VEGF, VEGFR-2, HIF-1 alpha, and HIF-beta. Also important for the expansion of these cells is the down-regulation of expression of apoptosis-related mediators such as TGF-beta receptor-2 or Bax. The success of any therapy for severe pulmonary hypertension requires that the underlying process of endothelial cell proliferation could be controlled or reversed.


Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Animais , Coagulação Sanguínea/fisiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Endotélio Vascular/patologia , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Oxirredutases Intramoleculares/metabolismo , Linfocinas/metabolismo , Repetições de Microssatélites , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Mutação , Óxido Nítrico/metabolismo , Isoformas de Proteínas/metabolismo , Artéria Pulmonar/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Vasoconstrição
16.
Am J Respir Crit Care Med ; 163(3 Pt 1): 737-44, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11254533

RESUMO

Emphysema due to cigarette smoking is characterized by a loss of alveolar structures. We hypothesize that the disappearance of alveoli involves apoptosis of septal endothelial cells and a decreased expression of lung vascular endothelial growth factor (VEGF) and its receptor 2 (VEGF R2). By terminal transferase dUTP nick end labeling (TUNEL) in combination with immunohistochemistry, we found that the number of TUNEL+ septal epithelial and endothelial cells/lung tissue nucleic acid (microg) was increased in the alveolar septa of emphysema lungs (14.2 +/- 2.0/microg, n = 6) when compared with normal lungs (6.8 +/- 1.3/microg, n = 7) (p < 0.01) and with primary pulmonary hypertensive lungs (2.3 +/- 0.8/microg, n = 5) (p < 0.001). The cell death events were not significantly different between healthy nonsmoker (7.4 +/- 1.9/microg) and smoker (5.7 +/- 0.7/microg) control subjects. The TUNEL results were confirmed by single-stranded DNA and active caspase-3 immunohistochemistry, and by DNA ligation assay. Emphysema lungs (n = 12) had increased levels of oligonucleosomal-length DNA fragmentation when compared with normal lungs (n = 11). VEGF, VEGF R2 protein, and mRNA expression were significantly reduced in emphysema. We propose that epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.


Assuntos
Apoptose , Enfisema/metabolismo , Enfisema/patologia , Fatores de Crescimento Endotelial/biossíntese , Receptores ErbB/biossíntese , Linfocinas/biossíntese , Adolescente , Adulto , Idoso , Enfisema/genética , Fatores de Crescimento Endotelial/análise , Receptores ErbB/análise , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Linfocinas/análise , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
17.
Am J Physiol Lung Cell Mol Physiol ; 280(1): L39-49, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11133493

RESUMO

Tumor necrosis factor (TNF)-alpha is a key proinflammatory cytokine that is thought to be important in the development of pulmonary fibrosis, whereas its role in pulmonary emphysema has not been as thoroughly documented. In the present study, TNF-alpha was overexpressed in alveolar type II cells under the control of the human surfactant protein C promoter. In this report, we further characterized the pulmonary abnormalities and provided a physiological assessment of these mice. Histopathology of the lungs revealed chronic inflammation, severe alveolar air space enlargement and septal destruction, and bronchiolitis. However, pulmonary fibrosis was very limited and only seen in the subpleural, peribronchiolar, and perivascular regions. Physiological assessment showed an increase in lung volumes and a decrease in elastic recoil characteristic of emphysema; there was no evidence of restrictive lung disease characteristic of pulmonary fibrosis. In addition, the mice raised in ambient conditions in Denver developed pulmonary hypertension. Gelatinase activity was increased in the lavage fluid from these lungs. These results suggest that in these mice TNF-alpha contributed to the development of pulmonary emphysema through chronic lung inflammation and activation of the elastolytic enzymes but by itself was unable to produce significant pulmonary fibrosis.


Assuntos
Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Medidas de Volume Pulmonar , Fator de Necrose Tumoral alfa/genética , Fatores Etários , Altitude , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Citocinas/imunologia , Enfisema/imunologia , Enfisema/patologia , Enfisema/fisiopatologia , Expressão Gênica/imunologia , Hipertensão Pulmonar/imunologia , Hipertrofia Ventricular Direita/imunologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Metaloproteinase 12 da Matriz , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Proteolipídeos/genética , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Surfactantes Pulmonares/genética , RNA Mensageiro/análise , Mucosa Respiratória/enzimologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Células Th1/imunologia , Transgenes/fisiologia , Fator de Necrose Tumoral alfa/imunologia
18.
Am J Respir Crit Care Med ; 161(6): 2026-34, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10852784

RESUMO

To investigate the role of mast cells (MC) and their fibrogenic growth factors in silicosis, we performed quantitative immunohistochemistry for MC tryptase and for basic fibroblast growth factor (bFGF) in lung tissue from silicotic and control subjects. Anti-bFGF antibody was bound to lung MC, basement membrane, endothelial cells, and smooth-muscle cells. Morphometric analysis revealed that the volume density (V(v)) of MC was increased in silicotic lung and that the V(v) of bFGF-positive (bFGF(+)) cells was significantly higher than normal in silicotic lung. Most MC contained bFGF (rho = 0.88, p < 0.001). The V(v) of collagen/reticulin fibers was increased in silicosis and correlated with the V(v) of bFGF(+) cells (rho = 0.81, p < 0.001). Immature silicotic nodules contained bFGF(+) MC throughout the loose array of collagen/reticulin fibers. In large, mature nodules, the density of collagen/reticulin fibers was higher, and bFGF(+) MC were found only in the nodule periphery. Because of this circumferential MC alignment in silicotic nodules, we observed a negative correlation between the V(v) of bFGF(+) MC and the density of collagen/reticulin fibers in silicotic nodules (rho = -0.80, p < 0.001) and between the V(v) of all other nodule-associated cells and the density of collagen/reticulin fibers in the hypocellular nodule centers (rho = -0.84, p < 0.001). We conclude that MC that produce bFGF may play an important role in the development of silicosis.


Assuntos
Fator 2 de Crescimento de Fibroblastos/análise , Mastócitos/patologia , Silicose/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Valores de Referência
19.
J Nucl Med ; 41(1): 57-64, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10647605

RESUMO

UNLABELLED: To determine the relationship between cerebral cortical blood flow loss and the temporal development of the dementia in Alzheimer's disease (AD), SPECT was studied in a cross section of AD patients with a broad range of impairment. METHODS: Thirty patients with a diagnosis of probable AD had their mini-mental state examination scores transformed into time-index values to give an estimation of dementia severity relative to the developmental time course. SPECT images were obtained using 99mTc-ethyl cysteinate dimer and a 3-head camera. Cortical surface perfusion was analyzed, including modified Talairach standardization, to obtain cortical elements from the convexity (each representing about 0.25 cm2 at the surface, 6.6-mm cortical depth) referenced to the mean perfusion of the full greater cerebellar hemisphere. These element ratios were analyzed (individually and by averages of estimated Brodmann's areas and brain regions) using linear regression with the time-index value. RESULTS: For individual posterotemporal and inferoparietal Brodmann's areas (21, 22 and 39, 40, respectively) the correlation coefficients between cortical perfusion ratios and dementia severity ranged between -0.67 and -0.78 (P < 0.001). Perfusion ratios from these regions declined 2.5%-4.2% for each estimated year of progression. Prefrontal area perfusion showed less association with severity. Perfusion in primary cortical regions had no significant association with dementia severity. CONCLUSION: Cerebral cortical perfusion loss is temporally related to development of dementia. The spatial pattern of high, significant correlations between cortical perfusion and dementia severity shows a regional distribution that corresponds closely to the distribution of AD pathology described in autopsy studies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Doença de Alzheimer/fisiopatologia , Circulação Cerebrovascular/fisiologia , Cisteína/análogos & derivados , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Entrevista Psiquiátrica Padronizada , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Índice de Gravidade de Doença , Fatores de Tempo
20.
Medicine (Baltimore) ; 79(6): 369-78, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11144035

RESUMO

Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.


Assuntos
Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/mortalidade , Doença Aguda , Adulto , Idoso , Biópsia , Causas de Morte , Tosse/etiologia , Cianose/etiologia , Progressão da Doença , Dispneia/etiologia , Feminino , Febre/etiologia , Seguimentos , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Respiração Artificial , Análise de Sobrevida , Tomografia Computadorizada por Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...