RESUMO
BACKGROUND/OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS's independent contribution to macrovascular CVD risk measures in obese adolescents. SUBJECTS/METHODS: This cross-sectional observational study was conducted at Children's Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. Thirty-one obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-à-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. RESULTS: The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. body mass index (BMI) associated positively with cIMTmax (r=0.52, P=0.006) and CFPWV (r=0.45, P=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=-0.63, P<0.0005). Insulin levels were negatively associated with AIx (r=-0.53, P=0.02). CONCLUSIONS: OSAS did not predict carotid structural changes or arterial stiffness independently of BMI in obese adolescents. Higher insulin levels associated with lower central pressure wave augmentation. Finally, long-term hypercapnia may predispose to carotid narrowing.
Assuntos
Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Obesidade Infantil/complicações , Apneia Obstrutiva do Sono/complicações , Adolescente , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Feminino , Humanos , Resistência à Insulina , Lipoproteínas/metabolismo , Masculino , Obesidade Infantil/epidemiologia , Obesidade Infantil/fisiopatologia , Philadelphia/epidemiologia , Polissonografia , Valor Preditivo dos Testes , Análise de Onda de Pulso , Fatores de Risco , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologia , Rigidez VascularRESUMO
An injection of viable thymus or thoracic duct lymphocytes was absolutely essential to enable a normal or near-normal 19S liemolysin-forming cell response in the spleens of neonatally thymectomized mice challenged with sheep erythrocytes. Syngeneic thymus lymphocytes were as effective as thoracic duct lymphocytes in this system and allogeneic or semiallogeneic cells could also reconstitute their hosts. No significant elevation of the response was achieved by giving either bone marrow cells, irradiated thymus or thoracic duct cells, thymus extracts or yeast. Spleen cells from reconstituted mice were exposed to anti-H2 sera directed against either the donor of the thymus or thoracic duct cells, or against the neonatally thymectomized host. Only isoantisera directed against the host could significantly reduce the number of hemolysin-forming cells present in the spleen cell suspensions. It is concluded that these antibody-forming cells are derived, not from the inoculated thymus or thoracic duct lymphocytes, but from the host. Thoracic duct cells from donors specifically immunologically tolerant of sheep erythrocytes had a markedly reduced restorative capacity in neonatally thymectomized recipients challenged with sheep erythrocytes. These results have suggested that there are cell types, in thymus or thoracic duct lymph, with capacities to react specifically with antigen and to induce the differentiation, to antibody-forming cells, of hemolysin-forming cell precursors derived from a separate cell line present in the neonatally thymectomized hosts.
Assuntos
Formação de Anticorpos/fisiologia , Proteínas Hemolisinas/biossíntese , Linfócitos , Baço/citologia , Ducto Torácico , Timo , Animais , Animais Recém-Nascidos , Eritrócitos , Feminino , Tolerância Imunológica , Injeções Intravenosas , Masculino , Camundongos , Ovinos , Baço/imunologia , Ducto Torácico/efeitos da radiação , Timectomia , Timo/efeitos da radiação , Extratos de Tecidos/farmacologiaRESUMO
The number of discrete hemolytic foci and of hemolysin-forming cells arising in the spleens of heavily irradiated mice given sheep erythrocytes and either syngeneic thymus or bone marrow was not significantly greater than that detected in controls given antigen alone. Thoracic duct cells injected with sheep erythrocytes significantly increased the number of hemolytic foci and 10 million cells gave rise to over 1000 hemolysin-forming cells per spleen. A synergistic effect was observed when syngeneic thoracic duct cells were mixed with syngeneic marrow cells: the number of hemolysin-forming cells produced in this case was far greater than could be accounted for by summating the activities of either cell population given alone. The number of hemolytic foci produced by the mixed population was not however greater than that produced by an equivalent number of thoracic duct cells given without bone marrow. Thymus cells given together with syngeneic bone marrow enabled irradiated mice to produce hemolysin-forming cells but were much less effective than the same number of thoracic duct cells. Likewise syngeneic thymus cells were not as effective as thoracic duct cells in enabling thymectomized irradiated bone marrow-protected hosts to produce hemolysin-forming cells in response to sheep erythrocytes. Irradiated recipients of semiallogeneic thoracic duct cells produced hemolysin-forming cells of donor-type as shown by the use of anti-H2 sera. The identity of the hemolysin-forming cells in the spleens of irradiated mice receiving a mixed inoculum of semiallogeneic thoracic duct cells and syngeneic marrow was not determined because no synergistic effect was obtained in these recipients in contrast to the results in the syngeneic situation. Thymectomized irradiated mice protected with bone marrow for a period of 2 wk and injected with semiallogeneic thoracic duct cells together with sheep erythrocytes did however produce a far greater number of hemolysin-forming cells than irradiated mice receiving the same number of thoracic duct cells without bone marrow. Anti-H2 sera revealed that the antibody-forming cells arising in the spleens of these thymectomized irradiated hosts were derived, not from the injected thoracic duct cells, but from bone marrow. It is concluded that thoracic duct lymph contains a mixture of cell types: some are hemolysin-forming cell precursors and others are antigen-reactive cells which can interact with antigen and initiate the differentiation of hemolysin-forming cell precursors to antibody-forming cells. Bone marrow contains only precursors of hemolysin-forming cells and thymus contains only antigen-reactive cells but in a proportion that is far less than in thoracic duct lymph.
Assuntos
Formação de Anticorpos/fisiologia , Células da Medula Óssea , Medula Óssea/efeitos da radiação , Proteínas Hemolisinas/biossíntese , Linfócitos , Efeitos da Radiação , Baço/citologia , Ducto Torácico/efeitos da radiação , Timo/efeitos da radiação , Animais , Eritrócitos , Camundongos , Ovinos , Baço/imunologia , TimectomiaRESUMO
Collaboration between thymus-derived lymphocytes, and nonthymus-derived antibody-forming cell precursors occurs during the immune response of mice to sheep erythrocytes (SRBC). The aim of the experiments reported here was to attempt to induce tolerance in each of the two cell populations to determine which cell type dictates the specificity of the response. Adult mice were rendered specifically tolerant to SRBC by treatment with one large dose of SRBC followed by cyclophosphamide. Attempts to restore to normal their anti-SRBC response by injecting lymphoid cells from various sources were unsuccessful. A slight increase in the response was, however, obtained in recipients of thymus or thoracic duct lymphocytes and a more substantial increase in recipients of spleen cells or of a mixture of thymus or thoracic duct cells and normal marrow or spleen cells from thymectomized donors. Thymus cells from tolerant mice were as effective as thymus cells from normal or cyclophosphamide-treated controls in enabling neonatally thymectomized recipients to respond to SRBC and in collaborating with normal marrow cells to allow a response to SRBC in irradiated mice. Tolerance was thus not achieved at the level of thelymphocyte population within the thymus, perhaps because of insufficient penetration of the thymus by the antigens concerned. By contrast, thoracic duct lymphocytes from tolerant mice failed to restore to normal the response of neonatally thymectomized recipients to SRBC. Tolerance is thus a property that can be linked specifically to thymus-derived cells as they exist in the mobile pool of recirculating lymphocytes outside the thymus. Thymus-derived cells are thus considered capable of recognizing and specifically reacting with antigenic determinants. Marrow cells from tolerant mice were as effective as marrow cells from cyclophosphamide-treated or normal controls in collaborating with normal thymus cells to allow a response to SRBC in irradiated recipients. When a mixture of thymus or thoracic duct cells and lymph node cells was given to irradiated mice, the response to SRBC was essentially the same whether the lymph node cells were derived from tolerant donors or from thymectomized irradiated, marrow-protected donors. Attempts to induce tolerance to SRBC in adult thymectomized, irradiated mice 3-4 wk after marrow protection, by treatment with SRBC and cyclophosphamide, were unsuccessful: after injection of thoracic duct cells, a vigorous response to SRBC occurred. The magnitude of the response was the same whether or not thymus cells had been given prior to the tolerization regime. The various experimental designs have thus failed to demonstrate specific tolerance in the nonthymus-derived lymphocyte population. Several alternative possibilities were discussed. Perhaps such a population does not contain cells capable of dictating the specificity of the response. This was considered unlikely. Alternatively, tolerance may have been achieved but soon masked by a rapid, thymus-independent, differentiation of marrow-derived lymphoid stem cells. On the other hand, tolerance may not have occurred simply because the induction of tolerance, like the induction of antibody formation, requires the collaboration of thymus-derived cells. Finally, tolerance in the nonthymus-derived cell population may never be achieved because the SRBC-cyclophosphamide regime specifically eliminates thymus-derived cells leaving the antibody-forming cell precursors intact but unable to react with antigen as there are no thymus-derived cells with which to interact.
Assuntos
Formação de Anticorpos , Eritrócitos/imunologia , Tolerância Imunológica , Linfócitos/imunologia , Timo/imunologia , Animais , Células Produtoras de Anticorpos , Reações Antígeno-Anticorpo , Imunoensaio , Camundongos , Efeitos da Radiação , Ovinos , Ducto Torácico/imunologia , Ducto Torácico/efeitos da radiação , Timectomia , Timo/efeitos da radiaçãoRESUMO
The effect of thymectomy on the genetically controlled murine immune response-1 (Ir-1) to the synthetic polypeptide poly-L(Tyr, Glu)-poly-D, L-Ala--poly-L-Lys [(T, G)-A--L] was studied with both aqueous and adjuvant immunization regimens. Adult thymectomy (combined with irradiation and bone marrow transfusion) did not affect the aqueous antigen-induced (IgM) primary response of either high or low responder mice, but did ablate the (IgG) secondary or tertiary response, a response which is restricted to the high responder strains. Adult thymectomy also blocked the normal high response to (T,G)-A--L in Freund's adjuvant in high responder mice and the high response to methylated bovine serum albumin (MBSA)-(T,G)-A--L in low responder mice. Neonatal thymectomy was also effective in blocking the response to (T, G)-A--L in Freund's adjuvant in high responder mice. These data are consistent with the concept that the Ir-1 gene effect is mediated via thymus cell interaction with antigen and with "B"-cells during the time of induction of IgG antibody formation.
Assuntos
Aminoácidos , Formação de Anticorpos , Imunogenética , Peptídeos/farmacologia , Timectomia , Timo/imunologia , Adjuvantes Imunológicos , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Anticorpos Anti-Idiotípicos , Transplante de Medula Óssea , Feminino , Adjuvante de Freund , Imunização , Imunização Secundária , Imunoglobulina G , Imunoglobulina M , Imunoglobulinas/farmacologia , Memória Imunológica , Camundongos , Camundongos Endogâmicos , Coelhos , Efeitos da Radiação , Transplante HomólogoRESUMO
Two new methods are described for making chromosomal spreads of single antibody-forming cells. The first depends on the controlled rupture of cells in small microdroplets through the use of a mild detergent and application of a mechanical stress on the cell. The second is a microadaptation of the conventional Ford technique. Both methods have a success rate of over 50%, though the quality of chromosomal spreads obtained is generally not as good as with conventional methods. These techniques have been applied to an analysis of cell to cell interaction in adoptive immune responses, using the full syngeneic transfer system provided by the use of CBA and CBA/T6T6 donor-recipient combinations. When neonatally thymectomized mice were restored to adequate immune responsiveness to sheep erythrocytes by injections of either thymus cells or thoracic duct lymphocytes, it was shown that all the actual dividing antibody-forming cells were not of donor but of host origin. When lethally irradiated mice were injected with chromosomally marked but syngeneic mixtures of thymus and bone marrow cells, a rather feeble adoptive immune response ensued; all the antibody-forming cells identified were of bone marrow origin. When mixtures of bone marrow cells and thoracic duct lymphocytes were used, immune restoration was much more effective, and over three-quarters of the antibody-forming mitotic figures carried the bone marrow donor chromosomal marker. The results were deemed to be consistent with the conclusions derived in the previous paper of this series, namely that thymus contains some, but a small number only of antigen-reactive cells (ARC), bone marrow contains antibody-forming cell precursors (AFCP) but no ARC, and thoracic duct lymph contains both ARC and AFCP with a probable predominance of the former. A vigorous immune response to sheep erythrocytes probably requires a collaboration between the two cell lineages, involving proliferation first of the ARC and then of the AFCP. The results stressed that the use of large numbers of pure thoracic duct lymphocytes in adoptive transfer work could lead to good adoptive immune responses, but that such results should not be construed as evidence against cell collaboration hypotheses. Some possible further uses of single cell chromosome techniques were briefly discussed.
Assuntos
Formação de Anticorpos , Antígenos , Cromossomos , Efeitos da Radiação , Baço/citologia , Timectomia , Animais , Animais Recém-Nascidos , Células da Medula Óssea , Imunidade , Injeções , Métodos , Camundongos , Ducto Torácico , TimoRESUMO
Acute necrotizing inflammatory disease after intracerebral injection of LCM virus is largely dependent on the host immune response to the virus and is controlled, in part, by a dominant gene which is closely linked to the H-2 locus. The F(1) hybrid (H-2(q/k)) from mating a susceptible SWR/J mouse (H-2(q/q)) to a resistant C3H/HeJ mouse (H-2(k/k)) is susceptible to LCM virus disease. When such hybrids (H-2(q/k)) are backcrossed to susceptible parents (H-2(q/q)), all F(2) offspring (H-2(q/q), H-2(q/k)) are highly susceptible. In contrast, hybrid (H-2(q/k)) backcross to resistant parents (H-2(k/k)) results in half of the F(2) offspring being susceptible (H-2(q/k)) while the other half are resistant (H-2(k/k)). Similarly, in congenic H-2(q/q) and H-2(k/k) mice, H-2(q/q) mice are relatively susceptible to acute LCM disease, whereas H-2(k/k) are resistant.
Assuntos
Histocompatibilidade , Coriomeningite Linfocítica/imunologia , Adsorção , Alelos , Animais , Encéfalo/patologia , Células Cultivadas , Cruzamentos Genéticos , Embrião de Mamíferos , Feminino , Genes Dominantes , Injeções , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/crescimento & desenvolvimento , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
Using anti-allotype sera and AKR anti thetaC3H sera, a requirement for two cell types has been demonstrated in the adoptive secondary response of mice to heterologous erythrocytes. The cell types have been designated B cells [precursors of plaque-forming cells (PFC)] and T cells (thymus-influenced cells, not providing precursors of detectable PFC). The in vivo indirect PFC response of spleen cells from primed mice is markedly reduced by in vitro treatment of the cells with a mixture of anti-theta serum and guinea pig serum (Anti theta + GPS). This B cell response is fully restored to control levels by thymus cells from normal mice which do not themselves provide precursors of indirect PFC. Thus memory is carried by the B cell lineage but the expression of this memory is dependent on the presence of a cell population which is sensitive to Anti theta + GPS and which is replaced functionally by unprimed T cells. When assayed for T cell activity, thoracic duct cells from specifically primed mice are better than cells from nonspecifically primed mice in restoring the B cell response of spleen cells from immunized mice. Moreover, the T cell activity of a reconstitutive cell population from primed mice is reduced by incubation with Anti theta + GPS. We conclude that memory to heterologous erythrocyte antigens is carried by the T cell lineage as well as the B cell lineage even though unprimed T cells are sufficient for expression of B cell memory.
Assuntos
Formação de Anticorpos , Imunidade Celular , Animais , Antígenos Heterófilos/farmacologia , Medula Óssea/imunologia , Células da Medula Óssea , Linhagem Celular , Células/imunologia , Eritrócitos/imunologia , Feminino , Cavalos , Soros Imunes/farmacologia , Imunoglobulina A/análise , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos , Ovinos , Baço/citologia , Ducto Torácico/citologia , Timo/citologia , gama-Globulinas/análiseRESUMO
Cytotoxic antiserum to theta antigen reduces the capacity of mouse spleen cells to generate direct and indirect plaque-forming cells to sheep erythrocytes in vitro but does not affect plaque-forming cells, their precursors, or hemopoietic stem cells. The response of spleen cells treated with antiserum to theta antigen is restored by thymus cells incubated in vivo with sheep erythrocytes.
Assuntos
Reações Antígeno-Anticorpo , Eritrócitos/imunologia , Baço/imunologia , Animais , Medula Óssea/imunologia , Células da Medula Óssea , Técnica de Placa Hemolítica , Soros Imunes , Imunidade , Técnicas In Vitro , Camundongos , Ovinos , Timo/imunologiaRESUMO
BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP (WASL) locus is associated with carotid-femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.
Assuntos
Envelhecimento , Aorta Torácica/fisiopatologia , Proteínas do Citoesqueleto/genética , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Rigidez Vascular/fisiologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Pressão Sanguínea , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , DNA/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Hipertensão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia , Análise de Onda de PulsoRESUMO
We show that the subcellular location of foreign antigens expressed in recombinant vaccinia viruses influences their effectiveness as immunogens. Live recombinant viruses induced very poor antibody responses to a secreted repetitive plasmodial antigen (the S-antigen) in rabbits and mice. The poor response accords with epidemiological data suggesting that S-antigens are poorly immunogenic. Appending the transmembrane domain of a membrane immunoglobulin (immunoglobulin G1) to its carboxy terminus produced a hybrid S-antigen that was no longer secreted but was located on the surface of virus-infected cells. This recombinant virus elicited high antibody titers to the S-antigen. This approach will facilitate the use of live virus delivery systems to immunize against a wide range of foreign nonsurface antigens.
Assuntos
Antígenos de Protozoários/imunologia , Transformação Celular Viral , Plasmodium falciparum/imunologia , Vaccinia virus/imunologia , Sequência de Aminoácidos , Animais , Formação de Anticorpos , Antígenos de Protozoários/genética , Sequência de Bases , Linhagem Celular , DNA Recombinante/metabolismo , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Genes , Camundongos , Plasmodium falciparum/genética , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Transfecção , Vaccinia virus/genéticaRESUMO
Infarct expansion after myocardial infarction results in early ventricular enlargement and distortion of ventricular geometry. To characterize the components of late volume enlargement, biplane left ventriculography was performed in 52 patients 3 weeks and 1 year after a first anterior myocardial infarction. Biplane diastolic circumference and contractile and noncontractile segment lengths were measured. Global geometry was evaluated by using a sphericity index (angiographic volume of the ventricle divided by the volume of a sphere with the same circumference). Regional geometry was assessed by measurement of endocardial curvature, an important determinant of wall tension. End-diastolic volume was enlarged at baseline and increased at 1 year (230 +/- 42 to 244 +/- 55 ml, p = 0.01) as a result of increases in contractile segment length (34 +/- 5 to 37 +/- 5 cm, p less than 0.001) and sphericity index (0.74 +/- 0.07 to 0.76 +/- 0.08, p less than 0.001), whereas the noncontractile segment length decreased (15 +/- 6 to 12 +/- 6 cm, p less than 0.005). Curvature analysis revealed a flattening of presumably high tension concavity at the anterobasal (-6.0 +/- 4.0 to -4.5 +/- 3.7, p less than 0.01) and inferior (-4.5 +/- 2.0 to -3.6 +/- 2.1, p less than 0.005) margins of the infarct and less bulging of the anterior wall (9.4 +/- 2.5 to 8.2 +/- 2.3, p less than 0.001). Patients selected for late enlargement (diastolic volume increase greater than 20 ml, n = 19) had an increase in sphericity (0.75 +/- 0.05 to 0.80 +/- 0.08, p less than 0.005) and in diastolic circumference (54 +/- 3 to 56 +/- 4 cm, p less than 0.001) secondary to elongation of the contractile segment (32 +/- 4 to 36 +/- 4 cm, p = 0.001) at 1 year. Thus, late ventricular enlargement after anterior infarction results from an increase in contractile segment length and a change in ventricular geometry and is not a result of progressive infarct expansion. In the group of patients at high risk for late ventricular enlargement because of persistent occlusion of the infarct-related vessel, captopril therapy attenuated late volume enlargement by preventing these changes in contractile segment length and chamber geometry.
Assuntos
Cardiomegalia/fisiopatologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Captopril/uso terapêutico , Cateterismo Cardíaco , Volume Cardíaco/efeitos dos fármacos , Volume Cardíaco/fisiologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/tratamento farmacológico , Cardiomegalia/epidemiologia , Método Duplo-Cego , Ventrículos do Coração/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Variações Dependentes do Observador , Radiografia , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
OBJECTIVES: This study sought to delineate salvage-dependent from salvage-independent coronary reperfusion in acute myocardial infarction and the effects on spontaneously occurring arrhythmias and arrhythmic death in rats. BACKGROUND: Reperfusion of the infarct-related artery might increase electrical stability independently of salvage of ischemic myocardium. METHODS: In 98 conscious rats the electrocardiogram was monitored by telemetry for 48 h after MI, and all episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analyzed. Reperfusion at 45 min (RP45) (n = 15), 90 min (RP90) (n = 18) and 180 min (RP180) (n = 30) min was compared with permanent coronary artery occlusion (CAO) (n = 35) with respect to the post-reperfusion periods. RESULTS: RP45, RP90 and RP180 reduced the incidence of VT by 93%, 98% and 88% and VF by 89%, 97% and 92%, respectively (all p < 0.01 vs. CAO). The all-cause mortality rate was reduced from 47% (CAO) to 8% (RP45, p < 0.05) and 0% (RP90, p < 0.01); after RP180 it was 17% (CAO 42%, p = 0.08). All reperfusion regimens reduced arrhythmic deaths: 47% to 8% (RP45, p < 0.05), 47% to 0% (RP90, p < 0.01) and 42% to 8% (RP180, p < 0.05). Infarct size was identical to that during CAO (49 +/- 10% [mean +/- SD]) and RP180 (49 +/- 10%), whereas preferentially epicardial salvage occurred at RP45 (36 +/- 8%, p < 0.001) and RP90 (38 < 10%, p < 0.001). CONCLUSIONS: Early and late reperfusion reduce the incidence and duration of VT and VF in conscious rats with acute MI. Thereby, arrhythmia-related mortality is improved through the prevention of fatal VF episodes. Thus, reperfusion increases the electrical stability of the heart independently of myocyte salvage, as proposed by the open artery hypothesis.
Assuntos
Arritmias Cardíacas/fisiopatologia , Morte Súbita Cardíaca/etiologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Sobrevivência de Tecidos/fisiologia , Animais , Arritmias Cardíacas/patologia , Morte Súbita Cardíaca/patologia , Eletrocardiografia Ambulatorial , Feminino , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Necrose , Ratos , Ratos Wistar , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/patologia , Fibrilação Ventricular/fisiopatologiaRESUMO
OBJECTIVES: The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction. BACKGROUND: Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction. METHODS: Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials. RESULTS: Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001). CONCLUSIONS: One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Esfigmomanômetros , Disfunção Ventricular Esquerda/diagnóstico , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Método Duplo-Cego , Enalapril/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Prognóstico , Fluxo Pulsátil/efeitos dos fármacos , Taxa de Sobrevida , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/mortalidade , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Eosinophilic polymorphonuclear leukocytes were isolated from the peritoneal cavity of BALB/c mice infected with the parasite Mesocestoides corti. Approximately 4 X 10(7) eosinophils (purity, 50%) could be harvested from each mouse. A high yield and purity of eosinophils was obtained from the peritoneal cells of infected male BALB/c mice using density centrifugation on a gradient of slightly hypotonic colloidal silica sol (Percoll). After initial irradiation of the mice to lower the lymphocyte contamination, subsequent density gradient (and where necessary sedimentation velocity) centrifugation yielded 10(8) eosinophils (purity > 95%) from six to eight mice. It was also possible to isolate small numbers of eosinophils (2 X 10(4) cells/minute, purity > 99%) without irradiating the mice. This could be achieved by separating the density gradient purified peritoneal cells by light-scatter on a Becton-Dickinson cell sorter (FACS II). Analysis of proteins extracted from eosinophils using polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate revealed a group of high molecular weight proteins (bwtween 250K and 160K) which were not as distinctive in the neutrophil profile. Surface labeling was performed, before the cell separation by using 125I and 1,3,4,6-tetrachloro-3 alpha, 6 alpha-diphenylglycoluril. Only five 125I-labeled proteins were detected initially (all with apparent molecular weights > 50,000). No 125I appeared to be associated with actin under the conditions used for surface labeling. Four of the eosinophil surface labeled proteins corresponded to surface labeled proteins on neutrophils, but the major surface component of the eosinophils (MW 79,000) appeared to be smaller than the major neutrophil protein (MW 90,000).
Assuntos
Eosinófilos/citologia , Proteínas de Membrana/sangue , Animais , Líquido Ascítico/citologia , Diferenciação Celular , Centrifugação com Gradiente de Concentração , Infecções por Cestoides/sangue , Eletroforese em Gel de Poliacrilamida , Eosinófilos/análise , Feminino , Radioisótopos do Iodo , Marcação por Isótopo , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Neutrófilos/análise , Neutrófilos/citologiaRESUMO
Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension.
Assuntos
Pressão Sanguínea , Transtornos Cerebrovasculares/diagnóstico , Hipertensão/diagnóstico , Pulso Arterial , Idoso , Análise de Variância , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/fisiopatologia , Complacência (Medida de Distensibilidade) , Feminino , Humanos , Hipertensão/complicações , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Masculino , Prognóstico , SístoleRESUMO
Portions of nitrocellulose filters containing blotted electrophoresed antigens of Schistosoma japonicum adult worms were reacted with polyclonal rabbit antisera raised to this human parasite. Eluted antibodies were used as probes for detection of antigen-positive clones in an Escherichia coli lambda gt11 amp3 expression library of adult worm cDNA. Several cloned antigens corresponding to a S. japonicum antigen of Mr 26 000, being sought as a candidate vaccine molecule in a mouse model of schistosomiasis japonica, were identified using this approach. The method provides an antibody reagent that is an attractive alternative to other more tedious means of producing oligospecific antibodies, including monoclonal antibodies, for screening of expression libraries.
Assuntos
Antígenos de Helmintos/genética , Schistosoma japonicum/imunologia , Animais , Anticorpos/imunologia , Antígenos de Helmintos/imunologia , Precipitação Química , Clonagem Molecular , DNA/genética , Técnicas de Imunoadsorção , Schistosoma japonicum/genéticaRESUMO
Surface labeling studies using two populations of Onchocerca gibsoni microfilariae revealed important differences in major radioiodinated proteins. Small numbers of microfilariae harvested from the skin of cattle or the uteri of adult worms from skin nodules were purified, radioiodinated, solubilized and the proteins analysed by two dimensional gel electrophoresis and autoradiography. As reported previously, uterine microfilariae showed a complex profile of radioiodinated proteins, none of which appeared to be bovine albumin or immunoglobulin. In contrast, application of the same techniques to skin microfilariae demonstrated only one major labeled protein complex of approximate Mr 67 000. This protein complex was immunoprecipitated with an antiserum to bovine serum albumin. Surprisingly, fluorescence techniques failed to show bovine serum albumin on the surface of living microfilariae. Although the evidence is circumstantial at present, acquisition of host albumin (perhaps oriented in a particular way) may be a means whereby skin microfilariae evade immune effector mechanisms and, when living, generally fail to elicit inflammatory reactions in the skin of the host.
Assuntos
Antígenos , Onchocerca/imunologia , Proteínas/análise , Útero/parasitologia , Animais , Autorradiografia , Bovinos , Doenças dos Bovinos/parasitologia , Feminino , Radioisótopos do Iodo , Lectinas , Microfilárias/imunologia , Oncocercose/parasitologia , Pele/parasitologia , Ureia/análogos & derivadosRESUMO
A 43-kDa putative lipoprotein receptor from Schistosoma japonicum adult worms (Sj43) has been purified by reverse-phase high-performance liquid chromatography (HPLC) using a Waters Delta-pak C4 300 A 15 mu 3.9 mm x 300 mm column. A linear acetonitrile gradient from 10-95%, spanning 40 min and at a flow rate of 0.9 ml min-1 was employed for the elution of bound material. Sj43 had a retention time of approximately 13 min on the column, whereas other main components from the parasite extract had a much longer retention time. Sj43 purified as a doublet which could be cleaved with Staphylococcus aureus V8 protease but was unaffected by treatment with a mixture of endoglycosidase F and glycopeptidase F. Human low-density lipoprotein exhibited typical saturation kinetics on the HPLC-purified Sj43 with a calculated stoichiometry of 2 mol LDL mol-1 of the putative receptor. No evidence of high-density lipoprotein (HDL3) saturation was observed on purified Sj43, this being of some interest since it parallels observations made with mammalian HDL3-binding proteins.
Assuntos
Lipoproteínas/metabolismo , Receptores de Superfície Celular/isolamento & purificação , Schistosoma japonicum/análise , Animais , Cromatografia Líquida de Alta Pressão , Detergentes , Eletroforese em Gel de Poliacrilamida , Cinética , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Octoxinol , Polietilenoglicóis , Receptores de Superfície Celular/metabolismo , Receptores de LipoproteínasRESUMO
Cloning by limit dilution of an isolate of Leishmania tropica (LRC-L137) that is infective for mice resulted in 7 stable clones, only one of which was infective in BALB/c mice. Three of the non-infective clones that were examined for survival in BALB/c macrophages in vitro seemed to be killed more readily, suggesting failure to establish in macrophages as the basis for non-infectivity in vivo. Promastigotes from three non-infective clones and one infective clone were biosynthetically labelled or surface radioiodinated, and the detergent lysates were analyzed by 2-dimensional gel electrophoresis. The pattern of the radiolabelled cytoplasmic and membrane proteins of promastigotes from all L. tropica clones was similar, with minor differences. All clones as well as the uncloned population bound to the same extent to a series of lectins with galactose and N-acetylgalactosamine as specificities. They also bound in a solid-phase radioimmunoassay to 9 monoclonal antibodies raised against the uncloned L. tropica (LRC-L137). The genetic characterization of four L. tropica clones was attempted by analysis of their isolated kinetoplast DNA. The clones from two schizodemes since they possess kinetoplast DNAs which exhibit similar restriction endonuclease fingerprints and show extensive DNA sequence homology, suggesting that the four clones are closely related and that the non-infective variants may be derived from the infective presumptive parental clone L137-7-121. Further characterization of the clones of L. tropica should allow a better understanding of the genetic basis of parasite virulence in cutaneous leishmaniasis.