RESUMO
The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and ß-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.
Assuntos
COVID-19 , Humanos , Enterócitos/metabolismo , SARS-CoV-2 , Proteínas de Ligação a Ácido Graxo/metabolismo , Biomarcadores , Morte Celular , LipídeosRESUMO
BACKGROUND: Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. METHODS: Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-ß, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. RESULTS: OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-ß signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. CONCLUSIONS: OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.
Assuntos
Cirrose Hepática/metabolismo , Osteopontina/metabolismo , Células-Tronco/metabolismo , Animais , Progressão da Doença , Regulação para Baixo/fisiologia , Imuno-Histoquímica , Fígado/patologia , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Fatores de Transcrição SOX9/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Regulação para Cima/fisiologia , Cicatrização/fisiologiaRESUMO
A cohort of injection drug users (IDU) have been identified who despite a long history of IDU and sharing of injecting equipment remain seronegative and aviraemic for hepatitis C virus (HCV). They have been termed HCV exposed uninfected (EU). The study of potential innate or adaptive immune mechanisms of resistance to HCV infection in this group is of interest. The aim of this study was to determine the levels of a broad range of cytokines in serum of exposed, uninfected individuals to ascertain whether there is a specific cytokine profile associated with apparent resistance to HCV. Sera from 22 EU individuals were analysed for a range of cytokines and chemokines, and compared to 16 treatment-naive chronic HCV cases (HCV Ab+ RNA+), 16 individuals with spontaneous resolution of HCV (HCV-Ab+ and HCV-RNA-) and 10 healthy unexposed controls. EU subjects had strikingly higher levels of both IL-6 (on average more than 100-fold, P = 0.001) and IL-8 (on average more than 10-fold, P < 0.001) than the comparison groups. Additionally higher levels of tumour necrosis factor-alpha (TNF-α; on average up to threefold, P = 0.02) were seen in EU individuals. The levels of interferon-alpha (IFN-α) were upregulated in all HCV exposed groups in comparison to healthy controls (P = 0.013). Adaptive immune cytokine levels were no different between the groups. Cytokine profiling demonstrated raised levels of pro-inflammatory innate immune cytokines and chemokines in EU IDU, in particular interleukin-6 and interleukin-8. These findings suggest innate immune activation may be the key to prevention of infection in this cohort.
Assuntos
Citocinas/sangue , Resistência à Doença , Hepatite C/prevenção & controle , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/imunologia , Adulto , Estudos de Coortes , Feminino , Hepatite C/imunologia , Humanos , Masculino , Uso Comum de Agulhas e SeringasRESUMO
BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in determining the therapeutic response in chronic hepatitis C virus (HCV) infection is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation together with interferon (IFN)-gamma and interleukin (IL)-10 production from peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or in combination with ribavirin, prospectively, before, during, and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at baseline but increased markedly during antiviral therapy, peaking around treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production. The main difference in T-cell reactivity of patients treated with IFN plus ribavirin was a significantly lower production of IL-10, whereas lymphocyte proliferation was similar to that in patients receiving IFN monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is associated with the development of HCV-specific T-cell responses with enhanced IFN-gamma and low IL-10 production. The greater efficacy of combination therapy with IFN-alpha plus ribavirin may be related to its ability to suppress HCV-specific IL-10 production.
Assuntos
Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Linfócitos T/imunologia , Adulto , Alanina Transaminase/sangue , Linfócitos T CD4-Positivos/virologia , Estudos de Coortes , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , Interferon alfa-2 , Interferon gama/biossíntese , Interleucina-10/biossíntese , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes , Linfócitos T/virologia , Carga ViralRESUMO
BACKGROUND/AIMS: Most patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated. METHODS: In vitro T helper (TH) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity. RESULTS: A TH response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-gamma production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA. CONCLUSIONS: Patients without viraemia after HCV infection frequently have strong TH lymphocyte responses of the TH1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective TH lymphocyte activation.
Assuntos
Especificidade de Anticorpos , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/imunologia , Viremia/imunologia , Adulto , Idoso , Citocinas/biossíntese , Feminino , Hepacivirus/imunologia , Hepatite C Crônica/sangue , Humanos , Interferon gama/biossíntese , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Hepatitis GB virus-C (HGBV-C)/hepatitis G virus (HGV) infection was investigated in 106 children with liver disease (54 boys and 52 girls, mean age 7.3 years); 12 with chronic hepatitis C virus infection, 29 with positive hepatitis B surface antigen, nine with idiopathic fulminant hepatic failure, seven with graft dysfunction after liver transplantation associated with autoimmune features, 20 with cryptogenic liver disease, and 29 with autoimmune liver disease. HGV RNA detected by reverse transcription polymerase chain reaction was found to be positive in 4/106 patients (3.8%). Risk factors were identified in three patients, including blood transfusion and/or medical treatment in Eastern Europe. The prevalence was higher than that of blood donors but lower than that of 2 adult patients with liver disease. HGV is not associated with any specific disease group and does not seem to be a major aetiological agent of liver disease in childhood in the UK.
Assuntos
Flaviviridae/isolamento & purificação , Hepatopatias/virologia , Adolescente , Adulto , Doenças Autoimunes/virologia , Criança , Pré-Escolar , Feminino , Encefalopatia Hepática/virologia , Hepatite B/complicações , Hepatite C Crônica/complicações , Hepatite Crônica/virologia , Hepatite Viral Humana/complicações , Humanos , Lactente , Transplante de Fígado , Masculino , Reação em Cadeia da Polimerase , RNA Viral/análise , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND/AIMS: The role of hepatitis C virus replication and different genotypes in the progression of cirrhosis to hepatocellular carcinoma is examined on the basis of a prospective follow-up of 1438 patients with histologically proven cirrhosis. METHODS: The presence of HCV RNA, anti-HCV and characterisation of virus genotypes were determined in 72 cases who developed hepatocellular carcinoma after a median follow-up of 5.3 years (range 1 to 16) and compared to 72 controls who had cirrhosis only, after a median follow-up of 4.8 years (range 1 to 16). Patients in the hepatocellular carcinoma group and controls were matched, one to one, for age, sex, nationality, HBsAg seropositivity, duration of follow-up and aetiology of cirrhosis. RESULTS: HCV RNA was detected in 31 of 72 (44%) patients who developed hepatocellular carcinoma, significantly more frequently than in 17 of 72 (23%) controls with cirrhosis (odds ratio 2.4, 95% confidence interval 1.2 to 5.0; p = 0.013). When cirrhosis of different aetiologies was analysed, hepatitis C virus replication was more frequently detected in patients developing hepatocellular carcinoma in association with cryptogenic cirrhosis (p = 0.007), alcoholic cirrhosis (p = 0.043) and hepatitis B virus seronegative cirrhosis (p = 0.05). Hepatitis C virus genotypes 1b and 4 were the most prevalent; they were found in 53% and 25%, respectively, of the patients studied, but were equally distributed between cirrhosis progressing to hepatocellular carcinoma and controls. CONCLUSIONS: Persistent hepatitis C virus replication is closely associated with hepatocellular carcinoma development in cirrhosis, and there is no preferential role of individual hepatitis C virus genotypes.
Assuntos
Carcinoma Hepatocelular/virologia , Hepatite C/complicações , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Adulto , DNA Viral/análise , Feminino , Seguimentos , Genótipo , Hepacivirus/genética , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Replicação ViralAssuntos
Ablação por Cateter/efeitos adversos , Paralisia/etiologia , Nervo Frênico , Síndrome de Wolff-Parkinson-White/cirurgia , Idoso , Eletrocardiografia , Humanos , Período Intraoperatório , Masculino , Paralisia/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/etiologia , Período Pós-Operatório , Radiografia Torácica , Síndrome de Wolff-Parkinson-White/fisiopatologiaRESUMO
Technologies which ablate or debulk tissue may result in better angiographic outcomes by altering the elastic properties of the vessel wall. Accordingly, the procedural outcomes of 88 vein graft lesions treated by either excimer laser angioplasty with adjunct balloon angioplasty (PELCA + PTCA, n = 44) (Spectranetics CVX-300, 1.4-, 1.7-, or 2.0-MM catheters) or balloon angioplasty alone (PTCA, n = 44) were analyzed by quantitative angiography (Cardiac Measurement System). Lesions were individually matched for vessel position, reference diameter (RD), and minimal luminal diameter (MLD). Matching was deemed adequate as the preprocedure MLD (PELCA + PTCA, 1.14 +/- 0.48 mm; PTCA, 1.20 +/- 0.47 mm) and RD (PELCA + PTCA, 3.23 +/- 0.56 mm; PTCA, 3.25 +/- 0.57 mm) were not significantly different. There were also no significant differences between PELCA + PTCA- and PTCA-treated lesions with respect to patient age, graft age, lesion length, symmetry, and plaque area. Balloon diameter at maximal inflation was 2.77 +/- 0.55 mm (PELCA + PTCA group) and 2.84 +/- 0.59 mm (PTCA group), P = NS. Final MLD postprocedure was 2.17 +/- 0.54 mm and 2.19 +/- 0.55 mm for PELCA + PTCA- and PTCA-treated lesions (P = NS), respectively. Vessel stretch [(balloon diameter - MLD pre)/RD], elastic recoil [(balloon diameter - MLD post)/RD], and acute gain [(MLD post - MLD pre)/RD] were calculated and normalized for vessel size (RD). Vessel stretch (PELCA + PTCA, 0.60 +/- 0.22; PTCA, 0.59 +/- 0.24; P = NS), elastic recoil (PELCA + PTCA, 0.28 +/- 0.18; PTCA, 0.26 +/- 0.16), and acute gain (PELCA + PTCA, 0.34 +/- 0.24; PTCA, 0.31 +/- 0.23; P = NS) were not significantly different between the two treatment groups. In a matched population of successfully treated vein graft lesions, PELCA + PTCA did not reduce elastic recoil or improve immediate angiographic outcome, as compared with PTCA alone.
Assuntos
Angioplastia Coronária com Balão , Angioplastia com Balão a Laser , Angioplastia a Laser , Ponte de Artéria Coronária , Doença das Coronárias/cirurgia , Oclusão de Enxerto Vascular/cirurgia , Veias/transplante , Adulto , Idoso , Idoso de 80 Anos ou mais , Cineangiografia , Doença das Coronárias/diagnóstico por imagem , Feminino , Seguimentos , Oclusão de Enxerto Vascular/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The T helper (Th) cell response to hepatitis B core antigen (HBcAg) was analyzed in 76 chronic hepatitis B virus (HBV) carriers with varying degrees of hepatic inflammation and HBV replication. Fifty-five patients had active viral replication, 28 with minimal histological changes and normal alanine transaminase (ALT) and 27 with active hepatic inflammation and elevated ALT. The remaining 21 chronic hepatitis B surface antigen (HBsAg) carriers had undetectable HBV replication, minimal histological activity, and normal ALT. In addition, 34 chronic HBV carriers were studied prospectively during treatment with alpha-interferon. The HBcAg-specific Th cell response was evaluated by a proliferative assay using 3H-thymidine uptake and gamma-interferon production by peripheral blood mononuclear cells. The proliferative response and gamma-interferon production of patients with active hepatic inflammation were significantly higher than in patients with minimal histological changes and in controls. In the longitudinal analysis during alpha-interferon treatment, 22 of 34 patients sustained an ALT flare accompanied by a parallel, significant Th cell response, which preceded or coincided with the ALT flare. The elevation in the Th cell response and the ALT flare were followed by a significant rise in the serum immunoglobulin (Ig) M anti-HBc index. Ten of twenty-two patients with an enhanced Th cell response and an ALT flare seroconverted after alpha-interferon treatment. The Th cell activity in the 10 responders rapidly subsided after hepatitis B e antigen (HBeAg) to anti-HBe seroconversion, whereas in the 12 nonresponders it remained elevated.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Doença Crônica , DNA Viral/sangue , Hepatite B/terapia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Humanos , Interferon-alfa/uso terapêutico , Interferon gama/biossíntese , Leucócitos Mononucleares/metabolismo , Estudos Prospectivos , Replicação ViralRESUMO
BACKGROUND/AIMS: Interferon treatment causes a sustained loss of virus replication only in a proportion of patients with chronic hepatitis B. This study investigated whether genomic variations in the precore/core gene of hepatitis B virus affect the response to interferon alfa. METHODS: The precore/core region was sequenced in 46 serum samples obtained before, during, and after interferon treatment of 12 patients. RESULTS: In 23 samples from 7 responders (group A), there were 24 missense mutations, whereas in 23 samples from 5 patients who did not respond or relapsed after treatment (group B), there were 141 missense mutations (P < 0.001). All group B patients had cirrhosis, but only 2 of 7 patients in group A had cirrhosis (P = 0.026). Substitutions in amino acids 21-27 of the core protein, known to diminish HLA-A2-restricted cytotoxic T-cell function, were found in all nonresponders but in none of the responders. No significant changes occurred in the precore/core region in responders after seroconversion to antibody to hepatitis B e antigen, but multiple variations persisted in group B during treatment and new mutations appeared with the relapse of hepatitis. CONCLUSIONS: Specific mutations in the core protein that can interfere with T-cell function occur frequently in patients with advanced chronic hepatitis B and may affect the response to interferon.
Assuntos
Vírus da Hepatite B/genética , Hepatite B/genética , Hepatite B/terapia , Interferon-alfa/uso terapêutico , Proteínas do Core Viral/genética , Adulto , Idoso , Sequência de Aminoácidos , Doença Crônica , Resistência a Medicamentos/genética , Feminino , Genes Virais/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , Resultado do TratamentoRESUMO
A total of 495 patients underwent treatment with excimer laser angioplasty for 545 saphenous vein graft stenoses. Clinical success was achieved in 455 of 495 patients (92%), as indicated by < or = 50% residual stenosis at every target lesion and no complication during hospitalization. At least 1 in-hospital complication occurred in 30 of 495 patients (6.1%): death (1.0%), bypass surgery (0.6%), and Q-wave (2.4%) or non-Q-wave (2.2%) myocardial infarction. Relative risk analysis showed that ostial lesions (n = 65) tended to have higher clinical success (success rate = 95%, adjusted odds ratio [OR] = 2.1 [95% confidence interval (CI) 0.62, 6.88]; p = 0.24) and lower complications (complication rate = 0%, OR = 0.10 [CI 0.01, 0.79]; p = 0.03) than lesions in the body of the vein graft. Lesions > 10 mm (n = 131) had lower success (success rate = 84%, OR = 0.30 [CI 0.16, 0.56]; p = 0.001) and higher complications (complication rate = 12%, OR = 3.3 [CI 1.6, 6.6]; p = 0.004) than discrete lesions. Lesions in small vein grafts < 3.0 mm (n = 76) tended to have increased success (success rate = 94%, OR = 1.55 [CI 0.70, 3.44]; p = 0.39) and lower complications (complication rate = 2.2%, OR = 0.31 [CI 0.10, 0.94]; p = 0.03). Thus, excimer laser-facilitated angioplasty has the most favorable outcome for discrete lesions located at the ostium of all grafts and in the body of smaller saphenous vein grafts.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Angioplastia com Balão a Laser , Ponte de Artéria Coronária , Doença das Coronárias/cirurgia , Oclusão de Enxerto Vascular/cirurgia , Veia Safena/transplante , Idoso , Angioplastia Coronária com Balão , Angioplastia com Balão a Laser/efeitos adversos , Angioplastia com Balão a Laser/métodos , Aterectomia Coronária , Terapia Combinada , Angiografia Coronária , Doença das Coronárias/patologia , Embolia/patologia , Embolia/cirurgia , Feminino , Seguimentos , Previsões , Oclusão de Enxerto Vascular/patologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Recidiva , Veia Safena/patologia , Veia Safena/cirurgia , Stents , Taxa de Sobrevida , Resultado do Tratamento , Úlcera/patologia , Úlcera/cirurgiaRESUMO
Earlier generations of excimer lasers, designed for industrial or non-cardiovascular medical applications, have been previously shown consistently to induce vasorelaxation of vascular smooth muscle in vitro. Such lasers were typically characterized by pulse durations of < or = 15 nanoseconds (ns). Excimer lasers currently employed for cardiovascular applications were designed with longer pulse durations (up to 220 ns) to facilitate fibreoptic transmission. Because arterial spasm has been observed in patients undergoing percutaneous revascularization with such lasers, we investigated the effect of so-called 'stretched pulse' excimer laser irradiation on vasomotor reactivity. A total of 69 rings of aorta harvested from New Zealand white rabbits were mounted isometrically in Krebs buffer solution and exposed to 308 nm from an excimer laser with a pulse duration of 120 ns. Fifty rings were exposed without pharmacological pre-treatment. The remaining 19 rings were exposed after pharmacological pre-treatment: 11 were precontracted with norepinephrine (NE, 10(-9)-10(-5) M), while eight were irradiated in Ca(2+)-free buffer after pre-relaxation with nitroglycerin (NTG, 7 x 10(-5) M). Without pharmacological pre-treatment, the vasomotor response to the excimer laser was variable: vasoconstriction was observed in 27 rings (16.1 +/- 0.8% (mean +/- SEM) of response to 5-HT), vasorelaxation in 21 rings (43.2 +/- 17.0% of response to 5-HT), and a heterogeneous response (vasoconstriction 4.9 +/- 1.0%, vasorelaxation 12.9 +/- 0.3%) in two rings. The vector of vasomotor response in non-precontracted rings was not predicted by fluence, frequency or temperature rise. A consistent vasomotor response was recorded only when pharmacological pre-treatment was employed. Among 11 rings pre-contracted with NE, the excimer laser produced vasorelaxation in 34/34 (100%) exposures; in contrast, among eight rings pre-relaxed with NTG in Ca(2+)-free buffer, the excimer laser produced vasoconstriction in 40/40 (100%) exposures. For all rings, including pre-contracted, pre-relaxed and those which were not pharmacologically pre-treated, the vector of vasomotor response was endothelium-independent. The magnitude of all vasomotor responses, including vasoconstriction in non-precontracted rings, could be diminished by limiting the duration of exposure. Thus, in contrast to the earlier generation, short-pulse excimer lasers, long pulse-duration excimer lasers in current clinical trials produce an unpredictable, heterogeneous vasomotor response. This in-vitro finding is consistent with the unpredictable development of vascular spasm in patients undergoing excimer laser angioplasty. Furthermore, these findings support the concept of employing abridged pulse trains to diminish the likelihood of laser-induced vasoconstriction during excimer laser angioplasty.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Angioplastia a Laser/instrumentação , Músculo Liso Vascular/lesões , Vasoconstrição/fisiologia , Sistema Vasomotor/lesões , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/lesões , Aorta Torácica/fisiopatologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Técnicas de Cultura , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Nitroglicerina/farmacologia , Pré-Medicação , Coelhos , Vasoconstrição/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiopatologiaRESUMO
In continuation of our studies on stress situations in female reproductive life span, serum lipid peroxide levels in terms of malondialdehyde (nmol/ml) have been determined in females [(n = 40) (aged between 35-40 years)] to undergo total abdominal hysterectomy (due to dysfunctional uterine bleeding). There occurred a statistically significant though within physiological limits, progressive rise in serum lipid peroxide levels right from preoperative stage 3.51, per operatively 3.56 to a maximum of 4.10 postoperative stage I with a tendency of fall at postoperative stage II 3.94 in comparison with self control on admission 2.97. It is suggestive of the balancing and protective role of scavenging enzyme system like superoxide dismutase also backed by improvement in health status of abdominal hysterectomy patients in terms of ambulation, free intake of food and behavioural positive attitude within 24 hours following operation presumably due to relief from stress of DUB. It is felt from the results of the present investigation that patients undergoing abdominal hysterectomy were free from free radical toxicity.
Assuntos
Histerectomia , Peróxidos Lipídicos/sangue , Estresse Fisiológico/sangue , Adulto , Feminino , HumanosRESUMO
5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic agent. Among the various toxicities associated with 5-FU, cardiovascular toxicity, consisting principally of acute myocardial ischemia and/or myocardial infarction, has been reported in up to 8.5% of patients treated with this drug. While 5-FU-induced coronary vasospasm has been considered as a potential basis for such clinical toxicity, this hypothesis remains unsubstantiated by laboratory investigation. Accordingly, the present study was designed to investigate the hypothesis that 5-FU induces reversible vasoconstriction of vascular smooth muscle and to study the cellular mechanisms of such vasomotor alterations. To investigate the effects of 5-FU on the vasoreactivity of vascular smooth muscle, 479 exposures were performed in 105 rings of aorta freshly isolated from 23 New Zealand white rabbits. Vasoconstriction was documented in 20 of 86 (23%) rings exposed to 5-FU at 7 x 10(-5) M, 45 of 83 (54%) rings exposed to 5-FU at 7 x 10(-4) M, and 41 of 49 (84%) rings exposed to 5-FU at 7 x 10(-3) M. In each case, 5-FU-induced vasoconstriction was endothelium independent. Pretreatment of rings with 10(-9) M staurosporine, a protein kinase C (PK-C) inhibitor, reduced 5-FU-induced vasoconstriction from 25.0 +/- 6.5 to 2.5 +/- 1.7 mg; staurosporine at a concentration of 10(-8) M abolished 5-FU-induced vasoconstriction. Pretreatment of rings with 10(-7) M phorbol-12,13-dibutyrate, an activator of PK-C, increased the magnitude of 5-FU-induced vasoconstriction 23-fold, from 49.7 +/- 11.1 mg before to 1163.6 +/- 276.4 mg after phorbol-12,13-dibutyrate (P = 0.0002). Neomycin, an inhibitor of phosphoinositide turnover, did not alter the magnitude of 5-FU-induced vasoconstriction. Membrane receptor blockers, including the alpha-adrenergic receptor blocker phentolamine, the beta-adrenergic receptor blocker propranolol, the H1 receptor inhibitor diphenhydramine, the H2 receptor inhibitor cimetidine, the Ca2+ channel blockers verapamil and diltiazem, and the cyclooxygenase inhibitor indomethacin all failed to alter the magnitude of 5-FU-induced vasoconstriction. Furthermore, the 5-FU-related compounds uracil and floxuridine did not produce vasoconstriction. Finally, 5-FU-induced vasoconstriction was abolished by nitroglycerin. These results indicate that (a) 5-FU causes direct, endothelium-independent vasoconstriction of vascular smooth muscle in vitro, (b) this vasomotor response involves activation of PK-C, and (c) this response is independent of vasoactive cell membrane receptors, phosphoinositide turnover, or activation of the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Fluoruracila/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/enzimologia , Proteína Quinase C/fisiologia , Vasoconstrição/fisiologia , Animais , Antineoplásicos/toxicidade , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/fisiologia , Interações Medicamentosas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Fluoruracila/antagonistas & inibidores , Técnicas In Vitro , Masculino , Músculo Liso Vascular/metabolismo , Isquemia Miocárdica/fisiopatologia , Nitroglicerina/farmacologia , Fosfatidilinositóis/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Proteína Quinase C/metabolismo , Coelhos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/fisiologia , Relação Estrutura-Atividade , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/toxicidadeRESUMO
The angiographic patency and histologic characteristics of a new balloon-expandable tantalum stent were studied after implantation intervals ranging from 1 to 32 weeks in atherogenic miniature swine peripheral and coronary arteries. Stents were placed in 34 arteries (10 coronary and 24 iliac arteries) in a total of 13 swine. Two swine died within 24 h of stent implantation. Follow-up angiography was performed before death was induced in 11 swine (8 coronary and 19 iliac arteries) and revealed 100% patency without evidence of lumen stenosis, thrombosis or migration of the stents. The neointimal thickening was maximal at 4 weeks after stent implantation and was at its minimum at 32 weeks after implantation with reendothelialization of the stents generally complete at that time. An advantage of this balloon-expandable device is its inherent longitudinal flexibility. The coil configuration allowed the nondeployed stent to negotiate acute bends in coronary arteries to reach the site of implantation and also allowed the deployed stent to conform to the natural contour of tortuous coronary arteries. The tantalum device was remarkable for its radiographic visibility, which greatly aided its placement under fluoroscopic guidance. This study demonstrates this stent's ease of implantation, excellent patency rate and absence of restenosis due to neointimal proliferation for up to 8 months in this atherogenic swine model.
Assuntos
Arteriosclerose/terapia , Doença da Artéria Coronariana/terapia , Stents , Tantálio , Grau de Desobstrução Vascular , Angioplastia Coronária com Balão , Animais , Arteriosclerose/patologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Dieta Aterogênica , Desenho de Equipamento , Feminino , Artéria Ilíaca/patologia , Masculino , Recidiva , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Previous in vitro experiments performed in our laboratory have shown that low-level laser energy may produce prompt reduction in isometric tension of vascular smooth muscle. The present study was designed to extend these previous in vitro findings to an in vivo model and thereby investigate the hypothesis that laser light delivered percutaneously in vivo could successfully reverse arterial spasm. METHODS AND RESULTS: Spasm defined as greater than 50% reversible reduction in luminal diameter persisting for greater than or equal to 5 minutes was successfully provoked by injection of histamine (100-400 micrograms/kg) in 13 arteries among 10 atherosclerotic Yucatan microswine; the magnitude of histamine-induced vasoconstriction was then documented angiographically by repeated injections of contrast media for as long as 30 minutes (controls). After return of angiographic luminal diameter to baseline, spasm was reproduced with a second injection of histamine into the same artery. Representative wavelengths generated by ultraviolet (UV), visible, and infrared lasers were then delivered percutaneously via conventional fiberoptics to the site of spasm, and angiographic assessment was repeated for as long as 30 minutes (treatment trial). In three arteries treated with UV (351 nm) light from an excimer laser, angiographic luminal diameter narrowing decreased from 100% to 23.9%, 50.0% to 9.3%, and 76.0% to 42.3%, respectively. The magnitude of laser-induced increase in luminal diameter was 50.2 +/- 22.7%, which was significantly greater than the magnitude of relaxation observed spontaneously during the control trials (10.9 +/- 9.8%, p = 0.02). Visible light from a helium-neon (632 nm) laser accomplished complete reversal of histamine-induced spasm in two of four arteries; in the remaining two arteries, luminal diameter narrowing percentages were reduced from 57.0% to 20.0% and from 76.5% to 30.8%, respectively. The magnitude of helium-neon laser-induced relaxation (55.8 +/- 17.9%) was again significantly greater than that observed during the control trials (0.9 +/- 1.9%, p = 0.01). Finally, infrared irradiation from a diode-pumped neodymium:yttrium aluminum garnet (1,064 nm) laser decreased histamine-induced luminal diameter narrowing in three arteries from 100% to 21.4%, 56.0% to 8.7%, and 68.3% to 35.3%, respectively. The magnitude of infrared laser-induced improvement in luminal diameter narrowing was 53.0 +/- 23.3%, which was significantly greater than that observed during the control trials (12.9 +/- 10.7%, p = 0.01). In three additional arteries, fiberoptic sham trials (without laser irradiation) failed to produce relaxation of histamine-induced spasm. CONCLUSIONS: These findings document for the first time that light-induced relaxation of vascular smooth muscle, previously documented in vitro, may be reproduced in vivo.
Assuntos
Arteriosclerose/fisiopatologia , Histamina/farmacologia , Terapia a Laser , Doenças Vasculares/radioterapia , Vasoconstrição/efeitos da radiação , Animais , Arteriosclerose/patologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/patologia , Artéria Femoral/efeitos da radiação , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/patologia , Artéria Ilíaca/efeitos da radiação , Raios Infravermelhos , Masculino , Espasmo/patologia , Espasmo/fisiopatologia , Espasmo/radioterapia , Suínos , Porco Miniatura , Raios Ultravioleta , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologiaAssuntos
Doenças Cardiovasculares/induzido quimicamente , Cocaína/efeitos adversos , Hemodinâmica/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/complicações , Animais , Arritmias Cardíacas/induzido quimicamente , Cardiomiopatias/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Humanos , Infarto do Miocárdio/induzido quimicamenteRESUMO
Cocaine abuse is now firmly associated with several cardiac complications. Acute myocardial infarction is the best documented of these complications and appears to result from cocaine-induced coronary arterial spasm. Myocarditis and/or cardiomyopathy have also been reported in a smaller number of patients. Finally, life-threatening cardiac arrhythmias may also result from cocaine abuse.
Assuntos
Cocaína , Cardiopatias/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Arritmias Cardíacas/etiologia , Cardiomiopatia Dilatada/etiologia , Humanos , Infarto do Miocárdio/etiologia , Miocardite/etiologiaRESUMO
Abortion, primarily as a measure of population control, certainly continues to be an emotional, frustrating and stressful event. In continuation of our work on stressful situations in the female life span and biochemical parameters, serum lipid peroxide levels in terms of malondialdehyde (nmol/ml) have been determined in females undergoing abortion [suction curettage (n = 30), Emcredil-induced abortion (n = 30) and spontaneous abortion (n = 40)] and were compared with appropriate gestational controls. Irrespective of the type of abortion, the serum lipid peroxide levels before abortion [mean malondialdehyde concentrations (nmol/ml): suction curettage 2.67, Emcredil-induced abortion 3.22, and spontaneous abortion 3.49] were found to be significantly elevated in comparison with those after abortion (suction curettage 1.91, Emcredil 1.97 and spontaneous abortion 1.95), indicating a maximum at peak time of stress and a minimum at the end of stress. The levels of serum lipid peroxide encountered before abortion were found to be significantly elevated in case of Emcredil-induced abortion and spontaneous abortion when compared with controls (second trimester mean levels 1.82 and first trimester 2.4) whereas the levels before suction curettage were found to be nonsignificant in comparison with controls, indicating a lesser degree of stress. It is felt that monitoring of serum lipid peroxide levels in serum and tissues (placenta), backed by scavenging enzyme superoxide dismutase, can be more helpful for corroborating safety and the risk of free radical toxicity in pregnancy and abortion.
PIP: Abortion, primarily as a measure of population control, continues to be an emotional, frustrating, and stressful event. As an extension of the work the authors have done on stressful situations in the lifespan of the female and its biochemical parameters, serum lipid peroxide levels in terms of malondialdehyde (nmol/mI) have been determined in women undergoing abortion (n=30 for suction curettage), Emcredil-induced abortion (n-30), and spontaneous abortion (n-40) and were compared with appropriate gestational controls. Regardless of the type of abortion, the serum lipid peroxide levels before abortion (mean malondialdehyde concentrations [nmol/ml]: suction curettage 2.67, Emcredil-induced abortion 3.22, and spontaneous abortion 3.49) were significantly elevated in comparison with those after abortion (suction curettage 1.91, Emcredil 1.97, and spontaneous abortion 1.95), indicating a maximum at peak time of stress and a minimum at the end of stress. Levels of serum lipid peroxide encountered prior to abortion were significantly elevated in cases of Emcredil-induced abortion and spontaneous abortion when compared with controls (2nd trimester mean levels 1.82 and 1st trimester 2.4), whereas the levels prior to suction curettage were nonsignificant in comparison with controls. This indicates a lesser degree of stress. It was decided that monitoring of serum lipid peroxide levels in serum and tissues (placenta), backed up by scavenging enzyme superoxide dismutase, can be more helpful in corroborating safety and the risk of free radical toxicity in pregnancy and abortion.