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Introduction:Neutrophil transmigration is multifactorial and primarily driven by selectins and ß2-integrins (CD11b/CD18), whose expression are dependent on the underlying stimulus. Ventilator-induced lung injury (VILI) results in a predominantly CD18-independent mechanism of neutrophil recruitment, while direct endotoxin-induced lung injury results from a CD18-dependent mechanism. We previously observed that lack of NADPH oxidases DUOX1 and DUOX2 resulted in reduced neutrophil influx in a VILI model of lung injury but had no influence on neutrophil influx after LPS exposure. Based on these observations, we hypothesized that DUOX1/DUOX2 are an important component of CD18-independent mechanisms of neutrophil recruitment in the lung. Methods:We exposed Duoxa -/- (KO) mice and Duoxa +/+ (WT) mice to either an intratracheal exposure of lipopolysaccharide (LPS/endotoxin)-or high tidal volume ventilation and compared expression of neutrophil markers between groups. WT mice (129S6/SvEvTac) were obtained from Taconic Biosciences (One Discovery Drive Suite 304; Rensselaer, NY 1244) and were allowed to acclimatize for one week prior to study enrollment. KO mice were generated as previously described [Grasberger 2012] and bred in-house on a 129S6 background. We provided positive-pressure ventilation at a tidal volume of 10 ml/kg with 2 cmH20 positive end-expiratory pressure (PEEP). Mice were assigned to groups consisting of KO (n = 5) and WT (n = 5) in each group and divided into non-ventilated, positive-pressure ventilation, or LPS IT exposure groups. Positive-pressure ventilation was instituted for 4-h using a FlexiVent (Flexiware 8.1, Scireq, Montreal, QC, Canada). Lipopolysaccharide (Salmonella enterica serotype tryphimurium L6143, Millipore Sigma) was administered via an intratracheal (IT) route at a dose of 0.1 mg/kg. Mice were humanely euthanized at 4-h post-injection consistent with the UC Davis IAUCAC-approved protocol. Results:As previously observed, neutrophilic influx into the airways was significantly impaired in the Duoxa -/- (KO) mice after VILI, but not after LPS exposure. LPS-induced lung injury resulted in upregulation of CD11b+ neutrophils and shedding of CD62L and CD162 regardless of DUOX expression, whereas VILI resulted in upregulation of CD49+ neutrophils in the Duoxa +/+ (WT) mice but not the Duoxa -/- (KO) mice. Conclusion:Our data suggest DUOX is required for CD18-independent mechanisms of neutrophil recruitment in the lung induced by acute lung injury, but not for canonical CD18depedent mechanisms after LPS exposure.
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Using silicon photodiodes with an ultrathin passivation layer, the average total energy lost to silicon target electrons (electronic stopping) by incident low energy ions and the recoil target atoms they generate is directly measured. We find that the total electronic energy deposition and the ratio of the total nuclear to electronic stopping powers for the incident ions and their recoils each follow a simple, universal representation, thus enabling systematic prediction of ion-induced effects in silicon. We also observe a velocity threshold at 0.05 a.u. for the onset of electronic stopping.
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OBJECTIVES: To determine if a relationship exists in mitral stenosis, in patients with either sinus rhythm or atrial fibrillation, between left atrial spontaneous echo contrast and the haematologic indices haematocrit, red cell concentration, mean corpuscular volume, platelet count and volume. METHODS: Left atrial spontaneous echo contrast severity was graded on a scale of 0-4 in 163 patients with symptomatic mitral stenosis (84 patients in sinus rhythm, 79 patients in atrial fibrillation) undergoing transesophageal echocardiography, cardiac catheterization and full blood examination as part of assessment prior to balloon mitral valvuloplasty. RESULTS: In sinus rhythm, spontaneous echo contrast grade was negatively correlated with cardiac index (r=-0.33), mitral valve area (r=-0.25) and mitral regurgitation grade (r=-0.22) and positively correlated with haematocrit (r=0.24) and red cell concentration (r=0.25). Spontaneous echo contrast grade was not correlated with left atrial diameter or mean corpuscular volume. In atrial fibrillation, spontaneous echo contrast grade was also negatively correlated with mitral valve area (r=-0.25) and mitral regurgitation (r=-0.36) but was positively correlated with left atrial diameter (r=0.34) and was not correlated with cardiac index, haematocrit or red cell concentration. There was no correlation between spontaneous echo contrast grade and platelet variables in either group. CONCLUSIONS: Natural variation in red cell concentration in patients with symptomatic mitral stenosis was an independent predictor of the severity of left atrial spontaneous echo contrast in sinus rhythm, but no relationship between red cell concentration and spontaneous echo contrast grade was evident in atrial fibrillation.
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Atrios Cardíacos/citología , Atrios Cardíacos/diagnóstico por imagen , Estenosis de la Válvula Mitral/sangre , Válvula Mitral/química , Válvula Mitral/citología , Adulto , Anciano , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Ecocardiografía , Ecocardiografía Transesofágica , Índices de Eritrocitos/fisiología , Eritrocitos , Femenino , Atrios Cardíacos/química , Hematócrito , Humanos , Masculino , Persona de Mediana Edad , Estenosis de la Válvula Mitral/complicaciones , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Análisis de Regresión , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Use of the Amplatzer Septal Occluder device to close selected secundum atrial septal defects is ever-increasing. This article illustrates the central role of the echocardiologist before, during, and after percatheter closure with the Amplatzer Septal Occluder device. Figures, diagrams, and tables detail each stage of the evaluation, procedure, and postprocedural assessment.
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Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/terapia , Prótesis e Implantes , Cateterismo Cardíaco , Ecocardiografía Tridimensional , Ecocardiografía Transesofágica , Humanos , Diseño de PrótesisRESUMEN
Visual and quantitative assessments of percent diameter stenosis on coronary angiography correlate poorly with functional testing, particularly in intermediate-severity (40%-70%) lesions, yet are frequently relied on to make decisions regarding revascularization. Coronary flow velocity reserve (CFVR) and relative CFVR (RCFVR) are promising methods for on-line functional assessment of lesion severity in the catheterization laboratory. We sought to determine the agreement between maximal, mean, and relative CFVR and stress echocardiography in intermediate-severity stenoses. The results of exercise or dobutamine stress echocardiography and CFVR measured by intracoronary Doppler were compared in 28 patients referred for assessment of intermediate-severity stenoses, using 15 patients with either angiographically normal coronary arteries or diameter stenoses > 70% as reference groups. CFVR was measured at least three times in response to a bolus of adenosine in the target vessel distal to the stenosis. RCFVR (target/normal vessel CFVR) was also measured in 27 patients. Maximal, mean (of three measures), and relative CFVR were calculated. CFVR > or = 2.0 and RCFVR > or = 0.75 were accepted as normal. A minority (29%) of patients in the intermediate-severity stenosis group had a positive test by either method. There was good to very good agreement between stress echocardiography and maximal CFVR (84%, kappa = 0.62, P < 0.0001) and RCFVR (81%, kappa = 0.59, P < 0.001) across the entire patient cohort, though in the intermediate subgroup concordance was only fair. Using the mean (of three measures of) CFVR for the same comparison improved the agreement in the intermediate subgroup to good (86%, kappa = 0.58, P = 0.002), and in the entire cohort the agreement was very good (88%, kappa = 0.74, P < 0.0001). There was only fair correlation between measures of CFVR and percent coronary stenosis. CFVR improved from 1.8 +/- 0.8 to 2.7 +/- 0.7 after percutaneous intervention (n = 12, P < 0.0001). These results suggest that there is good agreement between CFVR and stress echocardiography across a wide range of coronary lesion severity. The mean of three CFVR measurements distal to the target vessel stenosis increases diagnostic accuracy. Intracoronary Doppler flow velocity measurements at the time of cardiac catheterization may facilitate improved decision-making by providing the ability to assess the functional significance of coronary stenoses on-line.
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Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/fisiopatología , Ecocardiografía Doppler , Adulto , Anciano , Velocidad del Flujo Sanguíneo/fisiología , Angiografía Coronaria , Vasos Coronarios/fisiología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/-SD) age 29+/-7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha-tocopherol from 39.5+/-9.6 to 75.7+/-33.8 micromol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9+/-1.7 to 4.9+/-0.8 mmol/L and low- density lipoprotein (LDL) from 4.8+/-1.7 to 3.0+/-0.7 mmol/L (both P < 0.001), although total and LDL-cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1+/-0.3 to 2.4+/-0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1+/-4.2 to 36.1+/-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E-simvastatin groups. NG-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination.
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Anticolesterolemiantes/farmacología , Antioxidantes/farmacología , Endotelio Vascular/efectos de los fármacos , Antebrazo/irrigación sanguínea , Músculo Liso Vascular/efectos de los fármacos , Vasodilatación/fisiología , Adulto , Volumen Sanguíneo/efectos de los fármacos , Ejercicio Físico/fisiología , Hemodinámica/efectos de los fármacos , Humanos , Lípidos/sangre , Masculino , Tono Muscular/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacosAsunto(s)
Cateterismo , Estenosis de la Válvula Mitral/mortalidad , Estenosis de la Válvula Mitral/terapia , Índice de Severidad de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estenosis de la Válvula Mitral/patología , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
During deployment of an Amplatzer atrial septal occluder device to close a secundum ASD, the right atrial disk and waist of the device twisted, resulting in the cobrahead malformation. Postulated mechanisms for this complication include twisting of the device during loading into the delivery catheter and catching of leading edge of the device on the LA free wall or appendage, causing twisting during deployment. Retrieval of the device into the catheter and even removal of the device from the patient to allow manual untwisting may be required to allow the device to return to its original conformation for successful redeployment.
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Cateterismo Cardíaco/instrumentación , Ecocardiografía Transesofágica/métodos , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/terapia , Anciano , Cateterismo Cardíaco/métodos , Diseño de Equipo , Falla de Equipo , Femenino , Estudios de Seguimiento , Humanos , Medición de Riesgo , Resultado del TratamientoRESUMEN
Over a period of 11 years from 1988 to 1999, 201 patients underwent balloon mitral valvuloplasty (BMV) at Monash Medical Centre, Australia. Before BMV,133 patients (66%) were symptomatic with minimal activity or at rest. BMV increased mitral valve area and cardiac output, and reduced transmitral, left atrial and pulmonary pressures, with infrequent procedural complications (<8%). At the initial 3-month follow up after BMV, symptoms were absent or minimal in 178 patients (89%), with 85% remaining event free at 12 months. At long-term follow up (median: 30 months; range: 0-129 months), cumulative event-free survival was 73% after 5 years. After BMV, 37 patients (18%) underwent mitral valve surgery, while a repeat BMV was performed in three patients (1.5%). The results of this series provide additional data for the growing body of evidence which suggests that BMV is a relatively safe and effective procedure for producing long-term benefit in patients with symptomatic mitral stenosis.
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Cardiovascular malformations are common in patients with Turner's syndrome. Aortic coarctation and bicuspid aortic valve are the most frequently occurring abnormalities, and are associated with cystic medial necrosis of the aortic wall. Aortic dissection is an uncommon but catastrophic complication of the 'aortopathy' of Turner's syndrome. We report the unusual case of a Turner's syndrome patient (with a bicuspid aortic valve and previous coarctation repair) who died following an intramural haemorrhage of the aortic root that was complicated by dissection and rupture, with no evidence of aortic intimal tear. The role of intramural haemorrhage in the pathogenesis of acute aortic syndromes in Turner's syndrome patients is unclear. The condition may be associated with atypical clinical presentations, it can be difficult to confirm with imaging techniques, and it carries a high risk of progression to classical aortic dissection and death. This case therefore highlights the need for a high index of suspicion when assessing Turner's syndrome patients presenting with chest pain syndromes. Furthermore, the effective management of Turner's syndrome patients with cardiovascular abnormalities requires the development of evidence-based preventive (such as echocardiographic surveillance of aortic dilatation) and interventional strategies.
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OBJECTIVE: To calculate the costs of elective coronary angioplasty and stenting (CAS) in the public and private healthcare systems and to compare these costs with the charges levied and the revenues obtained. DESIGN: A prospective health economics study. SETTING: A tertiary care public hospital and a co-located tertiary care private hospital in the 12 months from February 1998. STUDY POPULATION: 186 consecutive patients (124 public, 62 private) undergoing elective CAS. MAIN OUTCOME MEASURES: Outcome of CAS; exact costs of CAS in the two hospitals; exact charges to private patients; estimated charges in a typical, not co-located, "industry standard private hospital"; estimated costs to the Federal Government of CAS in the public and private system. RESULTS: The immediate and six-month outcomes in the two groups were similar. The average cost of CAS in public patients was $5,516, compared with $5,844 in private patients. The length of stay, number of stents per case and use of nonstent consumables was similar for both groups. Average charges for CAS in patients in the co-located private hospital were $13,347, and estimated average charges for CAS in an industry standard private hospital were $14,978. Estimated current costs to the government for CAS in a public hospital, a co-located private hospital, and an industry standard private hospital were $5664, $5,394 and $6,201, respectively. CONCLUSIONS: Despite similar treatments and similar treatment costs, CAS in the private system, as a consequence of the charges levied, is more than twice as expensive as in the public system, with government costs similar for both systems. These data (together with data from other studies showing that CAS is performed more frequently in private patients) suggest that encouraging more people to take out private health insurance will, paradoxically, increase government costs for CAS as well as increasing overall health expenditure.
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Angioplastia Coronaria con Balón/economía , Precios de Hospital , Costos de Hospital , Hospitales Privados/economía , Hospitales Públicos/economía , Stents/economía , Cateterismo Cardíaco/economía , Femenino , Financiación Gubernamental/economía , Humanos , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud/economía , Estudios Prospectivos , Resultado del Tratamiento , VictoriaRESUMEN
AIMS: To compare short-term safety and outcome of percutaneous coronary intervention (PCI) in the elderly in their ninth decade with those in their eighth decade. METHODS: Five-hundred and eighty-nine patients aged 70 years undergoing coronary angioplasty were stratified into two groups, those 80 years old (Group 1, n = 65) and those 70Eth 79 years old (Group 2, n = 524). RESULTS: Group 1 comprised more females than Group 2 (57% vs. 40%, respectively; p = 0.009), patients with hypertension (70% vs. 56%, respectively), untreated hyperlipidemia (18% vs. 7%, respectively), acute coronary syndromes (75% vs. 53%, respectively) and multi-vessel disease (63% vs. 54%, respectively). Angiographic success per lesion was similar in Groups 1 and 2 (96% vs. 99%, respectively) as was clinical success per lesion (89% vs. 89%, respectively). Groups 1 and 2 also had a similar incidence of in-hospital death (1.5% vs. 1.1%, respectively), Q-wave myocardial infarction (0.0% vs. 0.6%, respectively), non-Q wave myocardial infarction (6.2% vs. 2.9%, respectively), emergency coronary artery bypass surgery (0.0% vs. 1. 3%, respectively), repeat PCI (3.0% vs. 1.7%, respectively), stroke (1.5% vs. 0.4%, respectively) and local vascular complications (4.6% vs. 4.4%, respectively). However, Group 1 had a longer in-hospital stay (4 days) than Group 2 (2 days) (p < 0.001). CONCLUSION: Our data suggest that short-term procedural and clinical outcomes after PCI are similar for patients in their eighth decade compared to those in their ninth decade.
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Angioplastia Coronaria con Balón/métodos , Enfermedad Coronaria/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/estadística & datos numéricos , Distribución de Chi-Cuadrado , Enfermedad Coronaria/mortalidad , Femenino , Humanos , Masculino , Probabilidad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.
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Anticoagulantes/síntesis química , Compuestos Aza/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Trombina/antagonistas & inhibidores , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Anticoagulantes/química , Anticoagulantes/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Indoles/química , Indoles/farmacología , Cinética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n=22) and those with increased (group 2; n=15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P<0.005) and left atrial (P<0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial-venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P<0.005); however, in contrast with group 1, the left atrial level decreased (P<0.03) and as a result the left-atrial-venous difference fell (P<0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial-venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.
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Cateterismo/métodos , Atrios Cardíacos/metabolismo , Estenosis de la Válvula Mitral/terapia , Protrombina/análisis , Adulto , Anciano , Biomarcadores/sangre , Hemodinámica , Humanos , Persona de Mediana Edad , Estenosis de la Válvula Mitral/sangre , Trombina/biosíntesisRESUMEN
BACKGROUND: Studies have shown that chronic oestrogen treatment improves both lipid profile and vascular reactivity in postmenopausal women, in whom it also appears to have a beneficial effect on vascular haemodynamics and compliance. Whether oestrogen has a similar effect in men is unknown. OBJECTIVE: To determine whether long-term oestrogen treatment alters arterial compliance and haemodynamics in biological males. METHODS: We compared the effects of chronic oestrogen treatment on blood pressure, heart rate and arterial compliance in 21 male-to-female transsexuals prescribed long-term oestrogen treatment with those in 20 age-matched healthy males. Systemic arterial compliance was assessed using the 'area method', by the simultaneous measurement of aortic flow and driving pressure. RESULTS: Mean systemic arterial compliance was similar in transsexuals and age-matched males (mean +/- SE 0.66 +/- 0.06 ml/mmHg compared with 0.58 +/- 0.05 ml/mmHg, P = 0.34). These results did not differ after the exclusion of transsexuals with coronary risk factors or vascular disease. Heart rate (67 +/- 2 beats/min compared with 64 +/- 3 beats/min, P = 0.41), systolic blood pressure (119 +/- 3 mmHg compared with 119 +/- 2 mmHg, P = 0.95), pulse pressure (55 +/- 3 mmHg compared with 50 +/- 2 mmHg, P = 0.13), diastolic blood pressure (64 +/- 2 mmHg compared with 69 +/- 2 mmHg, P = 0.06) and mean arterial pressure (84 +/- 2 mmHg compared with 89 +/- 2 mmHg, P = 0.09) were also similar at baseline between the two groups. Serum testosterone (an index of oestrogen treatment) was markedly suppressed in the transsexuals compared with the males (0.8 +/- 0.5 nmol/l compared with 25.3 +/- 12.6 nmol/l, P < 0.0001). Univariate analysis revealed that the best predictors of arterial compliance were the pulse pressure (rs = -0.41, P = 0.02) and the systolic blood pressure (rs = -0.35, P = 0.02). On multivariate analysis, the best combination of predictors of compliance were the pulse pressure, testosterone and low-density lipoprotein cholesterol concentrations (R2 = 0.29, P = 0.01). CONCLUSIONS: Although previous evidence suggests chronic oestrogen treatment can improve endothelium-dependent vasodilatation and favourably alter the lipid profile in biological males, these changes are not reflected in changes in systemic arterial compliance. Changes in arterial compliance may not be central to the beneficial effects of oestrogen on vascular function, at least in males.
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Arterias/efectos de los fármacos , Estrógenos/farmacología , Hemodinámica/efectos de los fármacos , Adulto , Arterias/fisiología , Estrógenos/uso terapéutico , Humanos , Lípidos/sangre , Masculino , Valor Predictivo de las Pruebas , Análisis de Regresión , Factores de Tiempo , Transexualidad , Vasodilatación/efectos de los fármacosRESUMEN
Novel benzo[b]thiophene diamine thrombin inhibitors were investigated, focusing on a contracted C4'-side chain series. SAR studies identified compounds with either a pyrrolidino or morpholino group as potent, active site directed thrombin inhibitors when the amino group was connected to the C3-phenyl ring with a methylene linker at the C4' position of the phenyl ring.
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Antitrombinas/química , Antitrombinas/farmacología , Tiofenos/química , Tiofenos/farmacología , Relación Estructura-ActividadRESUMEN
A proportion of patients with mitral stenosis have increased left atrial thrombin generation, with elevated left atrial but normal peripheral venous levels of prothrombin fragment 1+2 (F1+2). Whether this pattern of left atrial and venous F1+2 levels is related to limited spillover of F1+2 from the left atrium into the systemic circulation, or to washout of increased left atrial F1+2 production into the arterial circulation with subsequent systemic clearance, is unclear. We examined the relationship between arterial and venous F1+2 levels in mitral stenosis patients without left atrial thrombus. The study group comprised 36 patients with either a normal (n=29) or prolonged (n=7) international normalized ratio (INR; a measure of clotting time) who were undergoing percutaneous balloon mitral valvuloplasty. Baseline arterial and venous blood samples were collected at the beginning of the valvuloplasty procedure, and left atrial and venous samples were collected after trans-septal puncture. The left atrial F1+2 level exceeded the corresponding venous level in patients with a normal INR (P<0.03); however, baseline arterial and venous F1+2 levels were similar. Arterial and venous F1+2 levels were also similar in the subgroup of patients with evidence of a regional increase in left atrial thrombin generation, and were not different from arterial and venous F1+2 levels in patients without such an increase. Baseline arterial and venous F1+2 levels were both lower in the presence of a prolonged INR. Thus the pattern of increased left atrial but normal venous F1+2 levels in mitral stenosis is due to limited spillover from the left atrium into the systemic circulation.
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Estenosis de la Válvula Mitral/metabolismo , Miocardio/metabolismo , Fragmentos de Péptidos/metabolismo , Precursores de Proteínas/metabolismo , Protrombina/metabolismo , Trombina/biosíntesis , Adulto , Anciano , Femenino , Arteria Femoral/metabolismo , Vena Femoral/metabolismo , Atrios Cardíacos/metabolismo , Hemodinámica , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana EdadRESUMEN
1. The aim of the present study was to determine the effects of long-term oestrogen on resistance vessel reactivity in biological males. 2. Recent studies have demonstrated that long-term oestrogen therapy favourably alters the lipid profile and improves vasodilator function in the conduit arteries of biological males. Whether a similar benefit is exerted on the resistance circulation is not known. Therefore, we examined the effects of long-term oestrogen therapy on skeletal muscle resistance vessel function in biological males and the potential mechanisms by which it may exert its effects. 3. Forearm blood flow (FBF) and resistance were compared in 15 male-to-female transsexuals being prescribed oestrogen, with 14 age-matched healthy males, at rest and in response to the endothelium-dependent nitric oxide (NO) vasodilator acetylcholine (ACh), the endothelium-independent but NO-mediated vasodilator sodium nitroprusside (SNP), the endothelium-independent and non-NO-mediated vasodilator verapamil (VER) and the endothelium-independent vasoconstrictor phenylephrine (PE). 4. Basal blood flows were similar in the two groups. However, the male-to-female transsexuals had a significant upward and leftward shift in FBF responses to ACh compared with males, with a 52% increase in FBF responses at the highest dose of ACh used. Forearm blood flow in transsexuals rose from a mean (+/- SEM) baseline level of 3.02 +/- 0.25 to a maximum of 19.5 +/- 2.59 mL/min per 100 mL forearm tissue (compared with 3.24 +/- 0.41 and 9.43 +/- 1.97 mL/min per 100 mL forearm tissue, respectively, in males) with the highest dose of ACh (+2.73 micrograms/min per 100 mL; P < 0.0005). Forearm vascular resistance was also significantly reduced in transsexuals compared with males (P < 0.05). Vasodilator responses to SNP, VER and PE were similar in both groups. 5. There were no differences observed in total cholesterol and low-density lipoprotein-cholesterol levels. However, male-to-female transsexuals had 20% higher high-density lipoprotein-cholesterol levels compared with males (1.57 +/- 0.11 vs 1.26 +/- 0.08 mmol/L, respectively; P < 0.05) and 47% higher triglyceride levels (P < 0.005). Serum testosterone levels (an index of oestrogen therapy) was a predictor of responses to endothelium-dependent vasodilation (rs = -0.50; P < 0.01). 6. Long-term oestrogen therapy enhances endothelium-dependent vasodilation in the skeletal muscle microcirculation of biological males. The effects appear to be selective because endothelium-independent vasodilation and vasoconstriction are not altered.
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Acetilcolina/farmacología , Endotelio Vascular/efectos de los fármacos , Estrógenos/farmacología , Antebrazo/irrigación sanguínea , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Adulto , Análisis de Varianza , Endotelio Vascular/fisiología , Humanos , Lipoproteínas/sangre , Lipoproteínas/efectos de los fármacos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Testosterona/sangre , Transexualidad , Vasodilatación/fisiologíaRESUMEN
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.