Portuguese Authorship in Published Clinical Trials: Differences in Industry and Investigator Initiated Trials.

INTRODUCTION: The aim of this study was to investigate the Portuguese authorship in publications resulting from trials initiated by the industry or investigators and run in Portugal. MATERIAL AND METHODS: Clinical trials with Portuguese institutions as sponsor or recruiting centers, and registered in four clinical trial registries, in the last 14 years, were assessed. Publications of completed trials, from both the initiative of the industry and investigatorswere screened and compared. RESULTS: The percentage of published trials initiated by industry and investigators was similar (28.0%). However, the percentage of completed investigator-initiated trials (43.6%) was lower when compared to industry trials (69.7%). There was a higher percentage of Portuguese authorship in published investigator-initiated trials when compared with industry-initiated trials (47.1% vs 8.5%, respectively). Moreover, industry-initiated trials with Portuguese authors were published in journals with lower journal impact factor when compared with those published without authorship of Portuguese investigators. Oncology was the therapeutic area with the highest number of clinical trial registrations and publications. However, in publications with Portuguese authors, industry Initiated trials mainly focused on neurology while investigator-initiated trials had a higher number of papers in the fields of gastroenterology and infection diseases. Published trials with Portuguese authorship, initiated by the industry or investigators, also targeted different populations and had different purposes. In both cases, no significant differences were observed in terms of the journal impact factor or in the alignment of the published randomized trials with the respective reporting guidelines. DISCUSSION: When compared with previous publications, this study showed an increasing trend in the number of clinical trials in Portugal, published within similar timeframes, after trial conclusion. Even though both industry and investigator trials are published within the standards for reporting trials, the low number of Portuguese authorships in industry publications might underline the need for invigorating these independent clinical trials in Portugal by capacitating and empowering national clinical research teams. CONCLUSION: This study confirmed that even though all registered trials had the involvement of Portuguese institutions as a recruiting center, not all the published trials had Portuguese investigators as authors, mainly those initiated by the industry.

Introdução: Este estudo teve por objetivo investigar a autoria Portuguesa em publicações que resultem de ensaios clínicos iniciados pela indústria e por investigadores, que tenham decorrido em Portugal. Material e Métodos: Quatro plataformas de registo de ensaios clínicos foram utilizadas para encontrar ensaios clínicos tendo instituições Portuguesas como promotor ou centro de recrutamento nos últimos 14 anos. Foram analisadas e comparadas as publicações dos estudos completos, da iniciativa da indústria e de investigadores Resultados: A percentagem de ensaios da iniciativa da indústria e de investigadores que são publicados era semelhante (~ 28,0%). Porém, a percentagem de ensaios completos da iniciativa de investigadores era mais baixa (43,6%) quando comparada com os ensaios completos da indústria (69,7%). Existiu uma maior percentagem de autores portugueses em ensaios publicados da iniciativa do investigador quando comparado com os ensaios da iniciativa da indústria (47,1% vs 8,5%). Para além disso, ensaios da iniciativa da indústria com autores portugueses foram publicados em jornais com fatores de impacto inferiores quando comparados com aqueles publicados sem autores portugueses. A oncologia foi a área terapêutica com maior número de ensaios registados e publicados. No entanto, em publicações com autores Portugueses, a indústria focou-se sobretudo na neurologia e os investigadores em gastroenterologia e doenças infeciosas. Ensaios publicados com autores portugueses, iniciados tanto pela indústria como por investigadores, focaram-se em populações diferentes e têm propósitos diferentes. Em ambos os casos, não foram encontradas diferenças estatisticamente significativas no fator de impacto dos jornais, nem no alinhamento dos ensaios aleatorizados publicados com as normas sobre escrita de artigos científicos. Discussão: Quando comparado com publicações anteriores, este estudo mostrou uma tendência de crescimento no número de ensaios clínicos em Portugal, sendo publicados em intervalos de tempo semelhantes após a sua conclusão. Embora os ensaios publicados da iniciativa da indústria e de investigadores estejam alinhados com as normas sobre escrita de artigos científicos, o baixo número de autorias nacionais em publicações de ensaios da indústria, sublinha a necessidade de revigorar os ensaios clínicos da iniciativa de investigadores através da capacitação e emancipação das equipas de investigação nacionais. Conclusão: Apesar de todos os ensaios registados terem o envolvimento de instituições portuguesas como centros de recrutamento, nem todos os ensaios têm autores portugueses nas publicações, principalmente aqueles que são iniciados pela indústria.

The role of high-density lipoprotein in the regulation of the immune response: implications for atherosclerosis and autoimmunity.

Inflammation and immune dysfunction have been increasingly recognized as crucial mechanisms in atherogenesis. Modifications in cell lipid metabolism, plasma dyslipidaemia and particularly low high-density lipoprotein (HDL) levels occur both in atherosclerosis and in autoimmune rheumatic diseases (which are strongly associated with an increased risk of atherosclerosis), suggesting the presence of a crucial link. HDL, the plasma lipoprotein responsible for reverse cholesterol transport, is known for its several protective effects in the context of atherosclerosis. Among these, HDL immunomodulatory effects are possibly the less understood. Through the efflux of cholesterol from plasma cell membranes with the consequent disruption of lipid rafts and the interaction with the cholesterol transporters present in the plasma membrane, HDL affects both the innate and adaptive immune responses. Animal and human studies have demonstrated a predominance of HDL anti-inflammatory effects, despite some pro-inflammatory actions having also been reported. The HDL role on the modulation of the immune response is further suggested by the detection of low levels together with a dysfunctional HDL in patients with autoimmune diseases. Here, we review the current knowledge of the immune mechanisms of atherosclerosis and the modulatory effects HDL may have on them.

The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies.

The antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.

Antibodies towards high-density lipoprotein components in patients with psoriasis.

Psoriasis is a chronic inflammatory immune disorder associated with an increased risk of atherosclerosis. This increased risk is not fully understood. High-density lipoproteins (HDL) play an important role in the prevention of atherosclerosis and any factors that may hamper HDL function such as anti-HDL antibodies (aHDL) might be associated with an increased cardiovascular risk. We aimed to determine whether anti-HDL antibodies (aHDL) are present in patients with psoriasis. Sixty-seven patients with psoriasis were compared with a healthy control group. Epidemiologic and clinical data were recorded. IgG and IgM aHDL, IgG anti-apolipoprotein A-I (aApoA-I), anti-apolipoprotein E (aApoE), and anti-paraoxonase 1 (aPON1) antibodies, as well as VCAM-1, IL-6, and TNF-α were assessed by ELISA. Apolipoprotein A-I (ApoA-I) and Apolipoprotein E (ApoE) were measured by immunoturbidimetric immunoassay. Patients with psoriasis had higher titers of IgG aHDL (p < 0.001), IgG aApoA-I (p = 0.001) and aApoE antibodies (p < 0.001). IgG aHDL and aApoE titers were higher in patients with severe psoriasis (p = 0.010 and p = 0.018, respectively). Multiple regression analysis, considering all clinical and biological variables, showed that aApoE, IL-6, and aPON1 are the biological variables that best explain aHDL variability. This is the first report showing the presence of aHDL, aApoA-I, and aApoE antibodies in patients with psoriasis. These antibodies were associated with increased disease severity and may contribute to the pathogenesis of atherosclerosis in psoriasis. They may fulfill the clinical need for biomarkers of cardiovascular risk associated with psoriasis that would help to stratify patients for prevention and therapeutic approaches.

ELISA methods comparison for the detection of auto-antibodies against apolipoprotein A1.

BACKGROUND: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgG) have emerged as an independent biomarker for cardiovascular disease and mortality. Across studies, different ELISA methods have been used to measure the level of circulating anti-apoA1 IgG which could lead to substantial result differences between assays. OBJECTIVES: To make a comparative study of available anti-apoA1 IgG detection methods and to determine whether the choice of matrix sample (serum vs plasma) could influence the results. METHODS: Blood samples were obtained from 160 healthy blood donors and collected on 4 different matrixes (serum, plasma-EDTA, -citrate, -lithium-heparinate). Anti-apoA1 IgG was measured using two homemade (Geneva's and Lisbon's) and one commercial ELISA kits. Passing-Bablok and Bland-Altman were used to compare the results. Anti-apoA1 IgG seropositivity cut-offs were defined according to the user's/manufacturer's criterion. RESULTS: The current results showed substantial differences between those 3 assays. The dynamic ranges were significantly different, the commercial kit displaying the narrowest one. Passing-Bablok analysis demonstrated important proportional and constant biases between assays. The anti-apoA1 IgG seropositivity rate in Geneva, Lisbon and commercial assays varied between 24.5% and 1.9%. Matrix comparisons demonstrated that the matrix choice (plasma versus serum) influenced anti-apoA1 IgG results as well as the seropositivity rate in an assay-dependent manner. The coating antigen source was identified as important factor underlying results heterogeneity across assays. CONCLUSIONS: These results highlight the impact of the method and the cut-off used on anti-apoA1 IgG results and emphasize the need of standardizing existing assays. Given the important matrix influence, we suggest to use serum as matrix of choice.

Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease.

Quantitative and qualitative defects of high-density lipoprotein (HDL) are important in atherogenesis. In this study, we investigated whether antibodies against HDL components had additional value to conventional cardiovascular risk factors for the diagnosis of ischaemic stroke (IS) and coronary artery disease (CAD). Cross-sectional study was conducted on 53 patients with IS, 51 with CAD and 55 healthy controls, and in vitro studies to validate findings of the clinical study. We determined serum immunoglobulin G (IgG) antibodies against HDL (aHDL), apolipoproteins (aApoA-I, aApoA-II and aApoC-I) and paraoxonase-1 (aPON1) as well as PON1 activity (PON1a), total antioxidant capacity and biomarkers of endothelial activation (serum nitric oxide metabolites, 3-nitrotyrosine, VCAM-1 and ICAM-1); in vitro assays tested the capacity of IgG aHDL purified from high titer patients to inhibit PON1a and to reverse protective effect of HDL on endothelial cells. IgG aHDL, aApoA-I and aPON1 were higher in IS and CAD than controls (p < 0.001), predicted negatively PON1a and positively VCAM-1 and ICAM-1. By adding IgG aHDL and aApoA-I to a traditional cardiovascular risk factors model for IS and by adding IgG aHDL in a similar model for CAD, we obtained better discrimination of IS and CAD from healthy controls. IgG aHDL purified from IS and CAD inhibited PON1a by 38% (p < 0.01) and abrogated the protective effect of HDL on VCAM-1 expression by 126% compared with non-specific human IgG (p < 0.001). IgG against HDL components interfere with the antioxidant and anti-inflammatory properties of HDL and may represent novel biomarkers for vascular disease that need to be investigated in prospective studies.

Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

AIMS: Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 µg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.

Nitric oxide metabolites, nitrative stress, and paraoxonase activity in hepatopulmonary syndrome.

AIM: To investigate possible abnormalities of vasoactive compounds, nitrative stress, and antioxidant activity of paraoxonase (PONa) in human hepatopulmonary syndrome (HPS), we determined endothelin-1 (ET), nitric oxide (NOx) metabolites, PONa alongside crude plasma nitrotyrosine (NT) as surrogate marker of nitrative stress. MATERIAL AND METHODS: Liver cirrhosis (LC) patients with HPS (n = 12) were matched by age, sex, and Child-Pugh score to LC patients without HPS (n = 15) and to healthy controls (CTR) (n = 15); plasma NO2(-) (nitrite) (vascular metabolite), NO3(-) (nitrate) (inflammatory metabolite), and PONa were determined by a colorimetric assay, ET, and NT by immunoassays. RESULTS: HPS patients showed higher level of ET (p = 0.0002), NO2(-) (p = 0.002), NO3(-) (p = 0.0001), NT (p < 0.0001), and lower PONa (p = 0.0004) than CTR; post-hoc analysis revealed greater ET (p < 0.05) and NO3(-) (p < 0.005) in LC patients with HPS than in LC patients without HPS. NT correlated to Child-Pugh score within HPS (p = 0.04) and LC (p = 0.02). CONCLUSION: Our HPS patients are characterized by elevated plasma levels of ET and NOx metabolites and lower PONa. Reduced PONa alongside elevated NO3(-) and NT suggests that defective antioxidation may favor nitrative stress and both may be implicated in the pathogenesis of HPS.

Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus.

INTRODUCTION: Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM). MATERIAL AND METHODS: Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro-thromboxane B2 (11 dhTxB2), 8-iso-prostaglandin-F2α (8-isoPGF2α) and serum sP-Selectin, nitrite (NO(2)(-)), nitrate (NO(3)(-)) and paraoxonase 1 (PON1) activity. RESULTS: Compared to baseline controls, baseline DM had higher mean levels of 11 dhTxB2 (3,665 ± 2,465 vs 2,450 ± 1,572 pg/mg creatinine, p=0.002), 8-isoPGF2α (1,457 ± 543 vs 1,009 ± 412 pg/mg creatinine, p<0.0001), NO(2)(-) (11.8 ± 7.3 vs 4.8 ± 5.3 µM, p<0.0001), NO(3)(-) (50.4 ± 39.3 vs 20.9 ± 16.7 µM, p<0.0001) and sP-Selectin (120.8 ± 56.7 vs 93.0 ± 26.1 ng/mL, p=0.02), and the same held for post-ASA levels (p<0.0001). ASA demonstrated no effect on 8-isoPGF2α, NO(2)(-), NO(3)(-), sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11 dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2α excretion was greater in DM ASA poor responders than good responders (p<0.009). CONCLUSIONS: This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A(2)-adenosine receptors stimulation and attenuated by D(2)-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A(2A)-adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.

Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome.

OBJECTIVE: To assess the role of nitrite (NO(2)(-)), nitrate (NO(3)(-)), and nitrative stress in thrombotic primary antiphospholipid syndrome (PAPS). METHODS: We investigated 46 patients with PAPS: 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE), and 29 healthy controls (CTR). IgG anticardiolipin (aCL), IgG anti-beta(2)-glycoprotein I (anti-ß(2)-GPI), IgG anti-high density lipoprotein (aHDL), IgG anti-apolipoprotein A-I (aApoA-I), crude nitrotyrosine (NT) (an indicator of nitrative stress), and high sensitivity C-reactive protein (CRP) were measured by immunoassays. Plasma nitrite (NO(2)(-)), nitrate (NO(3)(-)), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays. RESULTS: Average plasma NO(2)(-) was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO(3)(-) was highest in SLE (p < 0.0001), whereas average NT was higher in PAPS and SLE (p = 0.01). In thrombotic PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO(2)(-) (p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO(3)(-) (p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO(3)(-) (p = 0.03). In the SLE group IgG aCL negatively predicted NO(2)(-) (p = 0.03) and NO(3)(-) (p = 0.02). CONCLUSION: PAPS is characterized by decreased NO(2)(-) in relation to type and number of vascular occlusions and to aPL titers. Nitrative stress and low grade inflammation are linked phenomena in PAPS and may have implications for thrombosis and atherosclerosis.

Acute hypoxia modifies cAMP levels induced by inhibitors of phosphodiesterase-4 in rat carotid bodies, carotid arteries and superior cervical ganglia.

BACKGROUND AND PURPOSE: Phosphodiesterase (PDE) inhibitors are useful to treat hypoxia-related diseases and are used in experiments studying the effects of oxygen on 3'-5'-cyclic adenosine monophosphate (cAMP) production. We studied the effects of acute hypoxia on cAMP accumulation induced by PDE inhibitors in oxygen-specific chemosensors, the carotid bodies (CBs) and in non-chemosensitive CB-related structures: carotid arteries (CAs) and superior cervical ganglia (SCG). EXPERIMENTAL APPROACH: Concentration-response curves for the effects of a non-specific PDE inhibitor [isobutylmethylxanthine (IBMX) ], PDE4 selective inhibitors (rolipram, Ro 20-1724) and a PDE2 selective inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine) on cAMP levels were obtained in normoxic (20% O(2)/5% CO(2)) or hypoxic (5% O(2)/5% CO(2)) conditions. KEY RESULTS: Responses to the PDE inhibitors were compatible with the presence of PDE4 in rat CBs, CAs and SCG but in the absence of PDE2 in CAs and CBs. Acute hypoxia enhanced the effects of IBMX and PDE4 inhibitors on cAMP accumulation in CAs and CBs. In SCG, acute hypoxia reduced cAMP accumulation induced by all the four PDE inhibitors tested. Differences between the effects of Ro 20-1724 and rolipram on cAMP were found in CAs and CBs during hypoxia. CONCLUSIONS AND IMPLICATIONS: The effects of PDE4 inhibitors could be potentiated or inhibited by acute hypoxia depending on the PDE isoforms of the tissue. The similarities between the characterization of PDE4 inhibitors at the CBs and CAs, under normoxia and hypoxia, did not support a specific role for cAMP in the oxygen-sensing machinery at the CB and suggested that no direct CB-mediated, hyperventilatory, adverse effects would be expected with administration of PDE4 inhibitors.

Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome.

CONTEXT: Accelerated atherosclerosis has been described in antiphospholipid syndrome, but the vascular abnormalities and the underlying mechanisms remain unclear. OBJECTIVES: To compare vascular structure and function in patients with positive antiphospholipid antibodies (aPL) with controls and to assess their relationship with paraoxonase activity. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 77 women with positive antiphospholipid antibodies from a lupus outpatient clinic in London, England (90% of the eligible population) and 77 controls matched on frequency basis for age and cardiovascular risk factors between June 2006 and April 2009. Carotid intima media thickness (CIMT), flow-mediated dilatation, pulse wave velocity, and paraoxonase activity were measured in all patients. Anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL) were examined. MAIN OUTCOME MEASURES: CIMT, pulse wave velocity, flow-mediated dilatation, and paraoxonase. RESULTS: Women with aPL had greater CIMT and pulse wave velocity compared with controls (mean [SD], 0.75 [0.16] vs 0.64 [0.09] mm; 95% confidence interval [CI], -0.14 to -0.06; P < .001; and 9.2 [1.6] vs 8.5 [1.8] m/s; 95% CI, -1.14 to -0.06; P = .04) and lower flow-mediated dilatation (6.2% [4.1%] vs 9.6% [4.2%]; 95% CI, 2.02%-4.69%; P < .001). Paraoxonase activity was lower in women with aPL vs controls (median [interquartile range], 91.2 [64.3-105.1] vs 103.0 [80.5-111.5] micromol p-nitrophenol/L/serum/min; 95% CI, 0.004-0.007; P = .005) and was inversely associated with CIMT and pulse wave velocity in women with aPL (standardized beta coefficient = -0.4 and -0.3, respectively; P < .05 for both), but not in the control group. High-density lipoprotein from women with aPL inhibited endothelial nitric oxide production in human aortic endothelial cells, in contrast with controls. The beneficial effects of HDL from women with aPL on vascular cell adhesion molecule 1 expression, superoxide production, and monocyte adhesion following activation of human aortic endothelial cells were largely blunted. CONCLUSIONS: Compared with controls, women with aPL had greater functional and structural arterial abnormalities, which were associated with lower activity of paraoxonase. In patients with aPL, HDL reduced nitric oxide bioavailability and had impaired anti-inflammatory and antioxidant properties.

Humoral mechanisms of atherogenesis.

The concept that atherosclerosis is an autoimmune disease is no longer controversial. Attention has been paid to cellular immune response, but current research is now focused on the humoral component of this complex disease. Heat shock proteins, oxidized low-density lipoproteins, beta2-glycoprotein 1, cardiolipins, and, more recently, high-density lipoproteins have been considered to be autoantigens that play a part in atherogenesis. The characterization and understanding of the mechanisms associated with the presence of these antigens and their respective autoantibodies might contribute to elucidating the atherosclerotic process. In the near future, immune modulation might constitute a very effective therapy of atherosclerosis.

An antagonistic interaction between A2B adenosine and D2 dopamine receptors modulates the function of rat carotid body chemoreceptor cells.

We have previously demonstrated that adenosine controls the release of catecholamines (CA) from carotid body (CB) acting on A2B receptors. Here, we have tested the hypothesis that the control is exerted via an interaction between adenosine A2B and dopamine D2 receptors present in chemoreceptor cells. Experiments were performed in vitro in CB from 3 months rats. The effect of A2B adenosine and D2 dopamine agonists and antagonists applied alone or in combination were studied on basal (20%O2) and hypoxia (10%O2)-evoked release of CA and cAMP content of CB. We have found that adenosine A2 agonists and D2 antagonists dose-dependently increased basal and evoked release CA from the CB while A2 antagonists and D2 agonists had an inhibitory action. The existence of A2B-D2 receptor interaction was established because the inhibitory action of A2 antagonists was abolished by D2 antagonists, and the stimulatory action of A2 agonists was abolished by D2 agonists. Further, A2 agonists increased and D2 agonist decreased cAMP content in the CB; their co-application eliminated the response. The present results provide direct pharmacological evidence that an antagonistic interaction between A2B adenosine and D2 dopamine receptors exist in rat CB and would explain the dopamine-adenosine interactions on ventilation previously observed.

Subclinical atherosclerosis in primary antiphospholipid syndrome.

To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 +/- 12 years), in 25 patients with inherited thrombophilia (mean age 40 +/- 10 years), and in 34 normal controls (mean age 38 +/- 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P = 0.01), at the bifurcation (P = 0.003), and at the internal carotid (P = 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.