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We present what we believe is the first report on a polarization-insensitive 3 × 3 silicon star-crossing utilizing a composite subwavelength metamaterial waveguide structure. Two different types of subwavelength grating metamaterials (nanohole grating and fan-shaped bent subwavelength grating) are respectively used to address diffraction issues in the crossing region and mode interference issues caused by a compact non-adiabatic design. This approach results in a device with an ultra-compact footprint of 12.68 × 10.98â µm2 on a standard 220â nm silicon-on-insulator (SOI) platform. Simulation results show low insertion loss (IL) values of <0.2â dB/0.3â dB and suppressed cross talk (CT) levels of <-27.2â dB/-23.6â dB for TE/TM polarizations across a wavelength range of 100â nm (1500-1600â nm). Experimental measurements of the fabricated devices confirm outstanding performance, with IL values of <0.35â dB/0.4â dB and CT levels of <-31.5â dB/-28.6â dB for TE/TM polarization in the C-band.
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Objectives: This study aimed to analyze the psychological status and quality of life (QoL) of patients with advanced lung cancer and assess the impact of continuous nursing intervention on these parameters. Methods: A total of 160 advanced lung cancer patients were randomly assigned to a control group or a study group, with 80 patients in each. The control group received the routine nursing intervention, while the study group received the continuous nursing intervention, including health record establishment, regular follow-ups, diet guidance, health knowledge education, psychological counseling, and work and rest guidance. Inflammatory markers (IL-6, TNF-α, PGE2, and SP), Spitzer Quality of Life Index (SQLI), anxiety and depression self-evaluation scales, Visual Analogue Scale (VAS) for pain, and patient satisfaction were measured before and after 4 weeks of intervention. Results: Post-intervention, the study group showed a significant reduction in serum IL-6 and TNF-α levels (P < .001), improved SQLI scores (P = .002), and lower anxiety and depression scores (P < .001) compared to the control group. A significant negative correlation between psychological status and QoL was observed (P < .001). The study group also reported lower VAS pain scores (P < .001) and higher patient satisfaction (P = .000) after the intervention. Conclusions: Continuous nursing intervention has significantly improved psychological well-being, alleviated pain, and enhanced the overall quality of life for patients facing advanced lung cancer. These results indicate that a comprehensive and sustained nursing intervention strategy can serve as an effective approach to improve the well-being of individuals navigating advanced lung cancer during chemotherapy.
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We report an observation of a dynamical super Efimovian expansion in a strongly interacting Fermi gas by engineering time dependent external harmonic trap frequencies. When the trap frequency is tailored as [1/4t^{2}+1/t^{2}λlog^{2}(t/t_{*})]^{1/2}, where t_{*} and λ are two controllable parameters, and the change is faster than a critical value, the expansion of such a quantum gas shows novel dynamics that share the same characteristics as the super Efimov effect. A clear double-log periodicity with discrete geometric scaling emerges for the cloud size in the expansion. The universality of such scaling dynamics is verified both in the noninteracting and in the unitarity limit of Fermi gas. Moreover, the measured energy scaling reveals that the potential and internal energy also show double-log periodicity with a π/2 phase difference, but the total energy is monotonically decreased. Observing super Efimovian evolution represents a paradigm in probing universal properties and allows us in a new way to study many-body nonequilibrium dynamics with experiments.
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RATIONALE: The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region. OBJECTIVE: The purpose of this study was to investigate the contribution of titin's proline-glutamate-valine-lysine (PEVK) region to biomechanics and growth of the heart. METHODS AND RESULTS: We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element. CONCLUSIONS: Titin's PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.
Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Ventrículos do Coração/metabolismo , Proteínas Musculares/metabolismo , Proteínas Quinases/metabolismo , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Sequência de Aminoácidos/genética , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Conectina , Elasticidade , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/ultraestrutura , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Quinases/genética , Estrutura Terciária de Proteína/genética , Sarcômeros/genética , Sarcômeros/metabolismo , Sarcômeros/ultraestrutura , Deleção de Sequência/genéticaRESUMO
Colloidal PbS nanoplatelets (NPLs) are highly interesting materials for near-infrared optoelectronic applications. We use ultrafast transient optical absorption spectroscopy to study the characteristics and dynamics of photoexcited excitons in ultrathin PbS NPLs with a cubic crystal structure. NPLs are synthesized at near room temperature from lead oleate and thiourea precursors; they show an optical absorption onset at 680 nm (1.8 eV) and photoluminescence at 720 nm (1.7 eV). By postsynthetically treating PbS NPLs with CdCl2, their photoluminescence quantum yield is strongly enhanced from 1.4% to 19.4%. The surface treatment leads to an increased lead to sulfur ratio in the structures and associated reduced nonradiative recombination. Additionally, exciton-phonon interactions in pristine and CdCl2 treated NPLs at frequencies of 1.96 and 2.04 THz are apparent from coherent oscillations in the transient absorption spectra. This study is an important step forward in unraveling and controlling the optical properties of IV-VI semiconductor NPLs.
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Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.
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Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Insuficiência Cardíaca Diastólica/induzido quimicamente , Insuficiência Cardíaca Diastólica/patologia , Interleucina-18/farmacologia , Miocárdio/patologia , Osteopontina/biossíntese , Animais , Pressão Sanguínea/fisiologia , Volume Sanguíneo/fisiologia , Separação Celular , Colágeno/química , Colágeno/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrose , Hidroxiprolina/química , Hidroxiprolina/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação/fisiologia , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/efeitos dos fármacosRESUMO
Aged individuals have impaired diastolic relaxation-lusitropic function. Dobutamine, a selective B1-adrenergic agonist, is used to augment systolic cardiac function at the termination of cardiopulmonary bypass (CPB). However, our question is whether dobutamine will also enhance the lusitropic function in the aged individual. The myocyte mechanism for the rate of ventricular relaxation is dependent on the velocity of calcium removal from the myocyte contractile elements by sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), which is regulated by an inhibitory protein, phospholamban (PLB). Ventricular tissues harvested from young (4 month) and aged (20 months) mice were analyzed to compare the protein levels of SERCA2a and PLB with immunoblot and gene expression for PLB with reverse-transcriptase-polymerase chain reaction. The molecular analyses were compared with in vivo left ventricular function in the young and old mice before and during an intravenous infusion of dobutamine (5 microg/kg/min). The SERCA2a levels were not different between the groups; however, there was a 2-fold increase in PLB in the aged group compared with the young group (p < .05). The gene expression for PLB was increased by 5-fold in the aged group compared with the young group (p < .01). There were significant differences between the young and aged groups related to the lusitropic parameters, tau and dP/dt(min), and dobutamine infusion increased these parameters in the aged group to that of the young group. This report supports the concept that altered PLB levels correspond with the respective lusitropic function and that dobutamine administration in the aged group increased lusitropic function that was comparable with the young group. Because the patient population requiring CPB is aging, these data suggest that the use of dobutamine at the terminal phase of CPB is warranted to increase systolic and diastolic function.
Assuntos
Agonistas Adrenérgicos beta , Dobutamina/farmacologia , Fosforilação/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Retículo Sarcoplasmático/efeitos dos fármacos , Fatores Etários , Envelhecimento , Animais , ATPases Transportadoras de Cálcio/efeitos dos fármacos , Diástole/efeitos dos fármacos , Feminino , Ventrículos do Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Camundongos , Células Musculares/efeitos dos fármacos , Contração MiocárdicaRESUMO
Cardiac remodeling is a determinant of the clinical progression of heart failure and now slowing or reversing remodeling is considered as a potential therapeutic target in heart failure. Pycnogenol has been reported to mediate a number of beneficial effects in the cardiovascular system but its effects on hemodynamic and functional cardiovascular changes following cardiac remodeling have not been elucidated. Therefore, we investigated the influence of Pycnogenol supplementation (30 mg/kg) on left ventricular function and myocardial extracellular matrix composition in old C57BL/6N mice following induction of cardiac remodeling by chronic nitric oxide synthase blockade by NG-nitro-L-arginine methyl ester (L-NAME) administration. L-NAME-treated mice demonstrated dilated cardiomyopathy at compensated state, associated with a significant increase of pro-matrix metalloproteinase (MMP)-9 gene expression and activity, a marked decrease in pro-collagen IIIalpha1 gene expression, and a subsequent reduction in cardiac total and cross-linked collagen content. Upon supplementation with Pycnogenol in L-NAME-exposed mice, cardiac gene expression patterns for pro-MMP-2, -9, and -13, and MMP-9 activity were significantly decreased, associated with a significant increase in cardiac tissue inhibitor of metalloproteinase (TIMP)-4 expression. These findings were coincided with a marked increase in myocardial total and cross-linked collagen content, compared with L-NAME-only-treated mice. Moreover, Pycnogenol treatment was associated with reversal of L-NAME-induced alternations in hemodynamic parameters. These data indicate that Pycnogenol can prevent adverse myocardial remodeling induced by L-NAME, through modulating TIMP and MMPs gene expression, MMPs activity, and further reduction in myocardial collagen degradation rate.
Assuntos
Envelhecimento/fisiologia , Inibidores Enzimáticos/toxicidade , Matriz Extracelular/efeitos dos fármacos , Flavonoides/farmacologia , Coração/efeitos dos fármacos , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Reagentes de Ligações Cruzadas , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/citologia , Extratos Vegetais , RNA/biossíntese , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Scale invariance plays an important role in unitary Fermi gases. Discrete scaling symmetry manifests itself in quantum few-body systems such as the Efimov effect. Here, we report on the theoretical prediction and experimental observation of a distinct type of expansion dynamics for scale-invariant quantum gases. When the frequency of the harmonic trap holding the gas decreases continuously as the inverse of time t, the expansion of the cloud size exhibits a sequence of plateaus. The locations of these plateaus obey a discrete geometric scaling law with a controllable scale factor, and the expansion dynamics is governed by a log-periodic function. This marked expansion shares the same scaling law and mathematical description as the Efimov effect.
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Methamphetamine (MA) abuse represents a growing problem in the USA with an increase of sudden death. To evaluate the immune function alterations due to chronic methamphetamine use, we examined C57BL/C mice with LP-BM5 retrovirus infection plus methamphetamine exposure. Mice were randomly assigned to the following groups: placebo, placebo retrovirus-infected, uninfected MA treated and retrovirus-infected MA treated. Placebo, MA-treated groups were intraperitoneally injected with saline, MA, respectively, with a gradually increasing dose from 15 to 40 mg/kg for 12 weeks (5 days/week). Con A- and LPS-induced mitogenesis of splenocytes, cytokine production by splenocytes culture and lipid peroxides in the liver were measured. Heart tissue histopathology was analyzed in all the groups with murine cytomegalovirus (CMV) superinfection. Our data showed that MA treatment significantly decreased production of IL-2 and interferon gamma (IFN-gamma) in uninfected mice but did not further suppress the reduced Th1 cytokines in retrovirus-infected mice. There were no significant effects on cytokines IL-4 and IL-6. However, tumor necrosis factor (TNF-alpha) was significantly increased in both uninfected and infected mice due to MA treatment. Lipid peroxides in liver were significantly increased both in uninfected and retrovirus-infected mice due to MA exposure. Vitamin E levels in liver were significantly decreased in uninfected mice due to MA treatment. CMV superinfection greatly increased the cardiac lesions in retrovirus-infected mice while no significant histopathology changes were detected due to MA treatment. Our data suggest that MA has immunomodulation activity, suppressing Th1 cytokine production and enhancing some Th2 cytokine secretion, as well as increasing lipid peroxides in uninfected mice. The interaction between LP-BM5 and MA remains unclear.
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Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Metanfetamina/administração & dosagem , Infecções por Retroviridae/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Citomegalovirus/imunologia , Esquema de Medicação , Feminino , Sistema Imunitário/metabolismo , Sistema Imunitário/virologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Retroviridae/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Cocaethylene is an active cocaine metabolite believed to play a causative role in the increased incidence of sudden cardiac death in individuals who co-administer alcohol and cocaine. Prolonged and excessive abuse of cocaine and alcohol will result in marked alteration of host immunity to increased susceptibility to infection. To test the chronic direct effect of cocaethylene on the heart function, a conductance catheter system (CCS) was used in vivo in this study. To test whether cocaethylene injection exacerbates coxsackievirus B3 (CVB3) or cytomegalovirus (CMV) cardiomyopathy during murine AIDS, female C57BL/6 mice were infected with LP-BM5 retrovirus and superinfected with CVB3 or CMV. Daily, mice were injected intraperitoneally with cocaethylene in 0.9% saline solution (concentration increased gradually from 15 to 25 mg/ml). Histopathology of heart tissue was analyzed in all groups, and cytokines of spleen were measured in the CMV-infected groups. Results showed there was little effect on the cardiovascular system after cocaethylene injection. Cocaethylene injection during murine retrovirus infection greatly exacerbated the pathogenesis of CVB3 or CMV infection, whereas CMV-infected mice showed relatively moderate cardiac pathology compared with CVB3 infection. Both CMV and retrovirus infection suppressed the Th1 response. Our data suggest that cocaethylene treatment shifts the cytokine balance and suppresses Th1 response particularly, facilitating increased CVB3- or CMV-induced myocarditis.
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Cocaína/análogos & derivados , Cocaína/toxicidade , Inibidores da Captação de Dopamina/toxicidade , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Síndrome de Imunodeficiência Adquirida Murina/patologia , Animais , Cateterismo Cardíaco , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/patologia , Citocinas/biossíntese , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Coração/fisiopatologia , Coração/virologia , Hemodinâmica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/complicações , Miocárdio/patologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
This study compared two established dietary formulations, high salt and high fat-high carbohydrate, separately or in combination on the induction cardiovascular dysfunction. One-month-old C57BL/6J mice were fed one of the following diets for 3 mo: (1) control diet consisting of a high fat-high sim-ple carbohydrate (HFHSC); (2) 8% NaCl diet (HS); or (3) HFHSC diet supplemented with 1% NaCl (HFHS). After 3 mo, the HFHSC mice demonstrated significantly increased end-diastolic volume and end-systolic volume, specifically increases of 35% and 78%, respectively (p < 0.01) and a reduction of ventricular stiffness by 27% (p = 0.015). The HS mice exhibited arterial hyper-tension with an increase of 33% in maximum end-systolic pressure (p =.024) and a decrease of 44% in arterial elastance (p = 0.020), corroborated by an increase in the heart weight to body weight ratios (p = 0.002) and vascular types I and III collagen (p = 0.03 and p = 0.0008, respectively). The HFHS group revealed a striking response of 230% to the alpha1-adrenergic challenge (p = 0.00034). These data suggest that the HFHSC diet causes dilated cardio-myopathy, whereas the HS diet produces arterial hypertension and the HFHS diet causes a vascular dysfunctional state that was highly responsive to alpha-adrenergic stimulation.
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Gorduras na Dieta/farmacologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Animais , Artérias/efeitos dos fármacos , Colágeno/biossíntese , Colágeno/genética , Dieta , Carboidratos da Dieta/farmacologia , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Dilated cardiomyopathy (DCM) is a clinically relevant disease that can occur independently or secondary to other diseases such as HIV infection and AIDS. To study this latter process, we used a model in which mice are infected with the LP-BM5 murine AIDS (MAIDS) retrovirus. Cardiac function of control and infected mice was determined through the in vivo analysis of left ventricular pressure-volume loops. Furthermore, the role of myocarditis was investigated through immunohistochemistry for T-cell, B-cell, and macrophage cardiac infiltrates and Northern blot analysis for tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS). End-systolic and end-diastolic volumes were significantly increased and ventricular stiffness was significantly decreased in infected mice, consistent with DCM; however, no staining for inflammatory cellular infiltrates or TNF-alpha and iNOS was seen. These data support the conclusion that the LP-BM5 HIV model virus causes DCM in the absence of chronic cardiac inflammation. These findings support MAIDS retroviral infection as a new model of idiopathic DCM in which myo-carditis does not occur.
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Cardiomiopatia Dilatada/virologia , Modelos Animais de Doenças , Síndrome de Imunodeficiência Adquirida Murina/complicações , Miocardite/virologia , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , DNA Viral/análise , Feminino , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/metabolismo , Síndrome de Imunodeficiência Adquirida Murina/fisiopatologia , Miocardite/imunologia , Miocardite/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Retroviridae/genética , Retroviridae/isolamento & purificação , Volume Sistólico , Fator de Necrose Tumoral alfa/metabolismo , Disfunção Ventricular EsquerdaRESUMO
Methamphetamine (MA) not only affects the nervous system but also has cardiac toxicity and immunosuppressive properties. This manuscript will provide support that there is a relationship between MA use and heart disease as well as immune dysfunction. The cardiovascular manifestations of acute MA use include tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA causes cardiomyopathy including cellular infiltration, myocardial hypertrophy, myocardium rupture and fibrosis. The increased catecholamine levels are responsible for the cardiac lesions induced by MA. The additional problem with MA use is its potential to disrupt the immune system function leading to suppression of mitogen-stimulated lymphocyte, a reduction in circulating lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B cell proinflammatory cytokine secretion. Concomitant MA use and Human Immunodeficiency Virus (HIV) infection not only enhances immunosuppression associated with HIV but also increases the heart disease occurrence with a coincidentally complication of AIDS or AIDS medications.
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Síndrome da Imunodeficiência Adquirida/etiologia , Cardiopatias/induzido quimicamente , Metanfetamina/toxicidade , Transtornos Relacionados ao Uso de Substâncias/complicações , Animais , Humanos , Sistema Imunitário/efeitos dos fármacos , Metanfetamina/metabolismoRESUMO
Methamphetamine (MA) increases catecholamine levels, which have detrimental effects on heart function through vasoconstriction, myocardial hypertrophy, and fibrosis. Murine retrovirus infection induces dilated cardiomyopathy (DCM). The present study investigated the cardiovascular effects of chronic MA treatment on uninfected and retrovirus-infected mice. C57BL/6 mice were studied after 12 weeks treatment. The four study groups were (group I) uninfected, MA placebo; (group II) infected, MA placebo; (group III) uninfected, MA treatment; and (group IV) infected and MA treatment. MA injections were given i.p. once a day for 5 days/week with a increasing dose from 15 mg/kg to 40 mg/kg. Left ventricular mechanics were measured in situ a using Millar conductance catheter system for pressure-volume loop analysis. Cardiac pathology was determined with histological analysis. In the uninfected mice, the load independent contractile parameters, pre-load recruitable stroke work (PRSW) and dP/dt(max) vs. Ved, significantly decreased by 32% and 35% in MA treated mice when compared to the saline injected mice. In retrovirus-infected mice, although there were no significant difference in Ees, PRSW, and dP/dt(max) vs. Ved due to MA treatment, they were increased 45%, 15% and 42% respectively when compared to saline treated mice. No further lowered heart function during murine AIDS may be due to the counteraction of the retroviral DCM and the MA induced myocardial fibrosis and hypertrophy (thickening of the ventricular walls). This is supported by increases in the End-diastolic volume (Ved, 38%) and End-systolic volume (Ves, 84%) in the retrovirus-infected saline injected mice, the decreases of 33% and 17% in the uninfected MA-treated mice, but no significant changes in the retrovirus-infected MA treated mice when compared to uninfected saline injected mice. These data suggest that MA induced myocardial cellular changes compensate for retrovirus induced DCM.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Vírus da Leucemia Murina , Leucemia Experimental/fisiopatologia , Metanfetamina/farmacologia , Infecções por Retroviridae/fisiopatologia , Infecções Tumorais por Vírus/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cateterismo Cardíaco , Débito Cardíaco/efeitos dos fármacos , Débito Cardíaco/fisiologia , Feminino , Testes de Função Cardíaca , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologiaRESUMO
Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers - T-cell receptor Vß peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.
Assuntos
Cardiomiopatias/patologia , Diástole/imunologia , Matriz Extracelular/metabolismo , Colágenos Fibrilares/metabolismo , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T/metabolismo , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Débito Cardíaco/fisiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Técnicas de Cocultura , Feminino , Fibroblastos/metabolismo , Fibrose , Expressão Gênica , Coração/fisiologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Phenylephrine (PE) is a alpha-adrenergic agent commonly administered by perfusion and anesthesia. It is important to identify the effect of PE, especially on cardiac function. This study was intended to show the effects of PE on cardiac function in the murine model via pressure-volume loops. METHODS: Six C57BL/6J twelve-week-old female mice were studied prior to and following PE administration at 50 microg/kg IV. In vivo pressure-volume loops were recorded at both time points. RESULTS: There was an expected increase in maximum arterial pressure by 30% (p < 0.001) and end-systolic pressure by 34% (p < 0.001). However, there was a decrease in cardiac output by 30% (p = 0.0006), ejection fraction by 36% (p = 0.0003) and stroke volume by 25% (p < 0.004). CONCLUSIONS: This study demonstrates that PE has an effect on cardiac function beyond increasing vascular resistance. The data suggest the negative effects of PE on cardiac function may be related to stimulation of cardiac alpha-adrenergic receptors.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Fenilefrina/farmacologia , Agonistas alfa-Adrenérgicos/administração & dosagem , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fenilefrina/administração & dosagem , Receptores Adrenérgicos/metabolismo , Volume Sistólico/efeitos dos fármacosRESUMO
Left ventricular dysfunction is associated with reperfusion injury occurring during open-heart surgery. There is an increased secretion of angiotensin II (Ang II) and increased matrix metalloproteinases (MMPs) activities associated with open-heart surgery that may affect the cardiac extracellular matrix (ECM). The goal of this study was to determine the effects of Ang II and selective angiotensin II receptor (AT1-R and AT2-R) blockers on the enzymatic activities of MMPs in primary adult murine cardiac fibroblasts (CF). Our hypothesis is that Aug II, with and without a selective receptor blocker, differentially affects CF MMPs activities. The CF were treated with Ang II (10(-6) M) and doses of AT1-R and AT2-R blockers (losartan and PD123319, respectively) at doses of 10(-7) to 10(-5) M for 48 hours. The Ang II-stimulated CF reduced collagenase activities by only 24% (p = 0.004); however, the MMP-2 and MMP-9 gelatinase activities were reduced by 42% and 39%, respectively (p = 0.022). The losartan dose dependently increased MMP-2 (p = 0.02) and MMP-9 (ns). PD123319 at 10(-5) M significantly reduced MMP-2 and MMP-9 activities compared with the Ang II group (p = 0.014 and p = 0.02, respectively). The doses of PD123319 at 10(-6) and 10(-7) M increased the MMP-2 and MMP-9 enzymatic activities significantly above the Ang II only group. Thus, Ang II and AT1-R and AT2-R differentially affect the collagenase and gelatinase MMPs activities released by cardiac fibroblasts.
Assuntos
Angiotensina II/farmacologia , Fibroblastos/ultraestrutura , Metaloproteinases da Matriz/efeitos dos fármacos , Miocárdio/citologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Células Cultivadas , Colagenases , Fibroblastos/enzimologia , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Metaloproteinases da Matriz/metabolismo , CamundongosRESUMO
Cardiac remodeling in response to pressure overload involves reorganization of the myocytes and extracellular matrix (ECM). Neurohormonal pathways have been described as effector pathways in left ventricular ECM reorganization in response to pressure overload; we now are assessing the role of the T lymphocyte in this process. Mice with defined differences in T-lymphocyte function (C57BL/6 SCID, C57BL/6 WT, and BALB/c) were treated with 50 mg/L of N(G)-nitro-l-arginine methyl ester in their drinking water for 30 days. The immune function of C57BL/6 WT mice was T-helper type 1 (TH1), BALB/c was TH2, and C57BL/6 SCID was null. The arterial blood pressure increased by 30% in all of the strains of mice. However, ventricular stiffness significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. The characterization of matrix metalloproteinase induction and activation on day 30 was associated with T-lymphocyte function. The total cardiac fibrillar collagen, percentage of fibrillar collagen cross-linking, and the activity of the cross-linking enzyme lysyl oxidase-like-3 (LOXL-3) significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. This study revealed that the LOXL-3 pathway, namely, gene expression, enzymatic activities, and LOXL-3-mediated collagen cross-linking, was associated with ventricular stiffness and incongruence with lymphocyte function. These data support the concept that the T lymphocytes may play a fundamental regulatory role in cardiac ECM composition through modulation of collagen synthesis, degradation, and cross-linking.
Assuntos
Matriz Extracelular/imunologia , Hipertensão/complicações , Linfócitos T/fisiologia , Remodelação Ventricular/imunologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Colágeno/química , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hipertensão/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Camundongos Endogâmicos C57BL/imunologia , Camundongos SCID/imunologia , NG-Nitroarginina Metil Éster/farmacologia , Especificidade da Espécie , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/imunologiaRESUMO
The adrenal steroid hormone dehydroepiandrosterone (DHEA) and its sulfated derivative [DHEA(S)] have been extensively studied for their potential anti-aging effects. Associated with aging, DHEA levels decline in humans, whereas other adrenal hormones remain unchanged, suggesting that DHEA may be important in the aging process. However, the effect of DHEA(S) supplementation on cardiac function in the aged has not been investigated. Therefore, we administered to young and old female mice a 60-day treatment with exogenous DHEA(S) at a dose of 0.1 mg/ml in the drinking water and compared the effects on left ventricular diastolic function and the myocardial extracellular matrix composition. The left ventricular stiffness (beta) was 0.30 +/- 0.06 mmHg/mul in the older control mice compared with 0.17 +/- 0.02 mmHg/mul in young control mice. Treatment with DHEA(S) decreased left ventricular stiffness to 0.12 +/- 0.03 mmHg/mul in the older mice and increased left ventricular stiffness to 0.27 +/- 0.04 mmHg/mul in young mice. The mechanism for the DHEA(S)-induced changes in diastolic function appeared to be associated with altered matrix metalloproteinase activity and the percentage of collagen cross-linking. We conclude that exogenous DHEA(S) supplementation is capable of reversing the left ventricular stiffness and fibrosis that accompanies aging, with a paradoxical increased ventricular stiffness in young mice.