Supplementary management with Pycnogenol® in patients with lupus vasculitis in remission phases: a pilot, concept registry study.

BACKGROUND: The aim of this pilot study was the supplementary management of minimal, residual symptoms of systemic Lupus (SLE) with vasculitis (LV) in remission phases, using a natural, anti-inflammatory, antioxidant agent (Pycnogenol®) extracted from French maritime pine bark. Pycnogenol® has a significant clinical anti-inflammatory activity; it is a standardized supplement with a high-safety profile. METHODS: Subjects with Lupus vasculitis were included in the study. The standard management (SM) was used in all subjects for 8 weeks; one group added Pycnogenol® (150 mg/day) to SM. RESULTS: The two groups completing 8 weeks were comparable at baseline with 12 subjects managed with SM and 14 subjects supplemented with Pycnogenol®. No side effects due to Pycnogenol® were observed; Pycnogenol® was associated with an optimal tolerability. The proportion of patients with photosensitivity, oral ulcers, renal-associated hematuria (minimal), leukopenia, lymphopenia, thrombocytopenia, positive anti-DNA and positive antiphospolipids tests were significantly lower in the Pycnogenol® group (P<0.05) at 8 weeks in comparison with controls. No difference in activity between SM and supplementation was observed for rash, serositis, anemia, neurological symptoms (all mild at inclusion) and anti-Smith. Considering additional clinical parameters such as the need for corticosteroids, peripheral ischemia, oxidative stress, the effects of Pycnogenol® appeared to be superior to SM alone (P<0.05). The decrease in oxidative stress was significantly higher with Pycnogenol® (P<0.05) compared to SM. This is particularly interesting as it has not been observed before in LV. Considering microvascular parameters, the number of subjects with 'cold' hypoperfused thermographic areas was significantly lower in the supplement group (P<0.05) and distal flux (laser Doppler) was higher with the supplement (P<0.05) at 8 weeks. CONCLUSIONS: This pilot registry indicates that Pycnogenol® can be safely used in subjects with LV with mild symptoms (in remission) possibly avoiding some drug treatments that may cause side effects. A larger study in progress is evaluating the effects of Pycnogenol® on recurrent symptoms in subjects in remission.

Enfermedad de Kawasaki / Malaltia de Kawasaki / Kawasaki´s disease

La malaltia de Kawasaki (MK) és una vasculitis sistèmica aguda d'etiologia desconeguda. El diagnòstic es basa en criteris clínics que inclouen febre, exantema, conjuntivitis, canvis en les extremitats, eritema de la mucosa oral i llavis, i adenopaties cervicals. No obstant això, aquests criteris tenen una sensibilitat i una especificitat baixes i, per tant, altres característiques clíniques i de laboratori poden ser útils per establir el diagnòstic, sobretot en els casos d'MK atípica o incompleta. El pronòstic depèn de l'extensió de l'afectació cardíaca; els aneurismes coronaris, que es de-sen volupen en el 20-25% dels pacients no tractats, poden provocar infart de miocardi o mort sobtada en l'edat adulta. El tractament amb altes dosis d'immunoglobulina intrave-nosa és eficaç per reduir el risc d'aneurismes coronaris en la majoria dels casos i és el tractament d'elecció. En aquesta revisió analitzem la clínica, l'epidemiologia i el tractament d'aquesta malaltia típica de l'edat pediàtrica

La enfermedad de Kawasaki (EK) es una vasculitis sistémica aguda de etiología desconocida. El diagnóstico se basa en criterios clínicos que incluyen fiebre, exantema, conjuntivitis, cambios en las extremidades, eritema de la mucosa oral y labios, y adenopatías cervicales. Sin embargo, estos criterios tienen una sensibilidad y una especificidad bajas y, por tanto, otras características clínicas y de laboratorio pueden ser útiles para establecer el diagnóstico, sobre todo en los casos de MK atípica o incompleta. El pronóstico depende de la extensión de la afectación cardiaca; los aneurismas coronarios, que se desarrollan en el 20-25% de los pacientes no tratados, pueden provocar infarto de miocardio o muerte súbita en la edad adulta. El tratamiento con altas dosis de inmunoglobulina intravenosa es eficaz para reducir el riesgo de aneurismas coronarios en la mayoría de los casos y es el tratamiento de elección. En esta revisión analizamos la clínica, la epidemiología y el tratamiento de esta enfermedad típica de la edad pediátrica (AU)

Kawasaki disease (MK) is an acute systemic vasculitis of unknown etiology. The diagnosis is based on clinical criteria that includes fever, rash, conjunctivitis, changes in the limbs, erythema of the oral mucosa and lips, and cervical lymphadenopathy. However, these criteria have a low sensitivity and specificity and, therefore, other clinical and laboratory features may be helpful in establishing the diagnosis, especially in cases of atypical or incomplete MK. The prognosis depends on the extent of heart involvement; coronary aneurysms, which develop in 20-25% of untreated patients can cause a heart attack or sudden death in adulthood. Treatment with high doses of intravenous immunoglobulin is effective to reduce the risk of coronary aneurysms in most cases and is the treatment of choice. In this review we analyze the symptoms, epidemiology and treatment of this disease, typical of paediatric patients (AU)

Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice.

BACKGROUND: Omega-3 polyunsaturated fatty acids (ω3 PUFAs) suppress inflammation through activation of free fatty acid receptor 4 (FFAR4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR4 activation by ω3 PUFAs in the process of vascular inflammation and neointimal hyperplasia in mice. METHODS AND RESULTS: We used mice with disruption of FFAR4 (Ffar4(-/-)), along with a strain that synthesizes high levels of ω3 PUFAs (fat-1) and a group of crossed mice (Ffar4(-/-)/fat-1), to elucidate the role of FFAR4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR4 in vascular-associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFAs endogenously generated in fat-1 mice (n=9), but not in compound Ffar4(-/-)/fat-1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl3. Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl3 injury in fat-1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4(-/-)/fat-1 mice. CONCLUSIONS: These results indicate that ω3 PUFAs mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR4 in mice. Moreover, the ω3 PUFA-FFAR4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration.

Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III.

BACKGROUND: Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways. METHODS: Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h. RESULTS: Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II. CONCLUSIONS: Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.

Soluble RAGE-modulating drugs: state-of-the-art and future perspectives for targeting vascular inflammation.

The expression of the Receptor for Advanced Glycation Endproducts (RAGE) is upregulated at sites of vascular inflammation and plays a crucial role in vessel homeostasis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. sRAGE has recently emerged as a biomarker in several RAGE-mediated vascular disorders, including coronary artery disease, hypertension, diabetic vasculopathy and Kawasaki disease. Given the pivotal role played by RAGE and sRAGE in numerous vascular disorders, there is a growing need to understand how drugs can modulate the RAGE axis in different disease conditions. In this regard, there is evidence to suggest that traditional cardiovascular drugs (statins, thiazolidinediones, ACE-inhibitors, AT-1 receptor antagonists) as well as nutraceuticals (grape seed proanthocyanidin extract) could modulate RAGE expression and circulating sRAGE levels in cardiovascular disease states characterized by enhanced RAGE activation. Additionally, the production of genetically engineered sRAGE may hold promise for targeting the activation of RAGE by proinflammatory ligands in the setting of vascular inflammation. The present review considers current vascular drugs as modulators of the RAGE axis, and highlights future directions in the context of RAGE-directed therapy in cardiovascular disease.

Endothelial dysfunction is associated with increased levels of biomarkers in essential hypertension.

To assess the correlation between endothelial dysfunction and the serum levels of biomarkers of inflammation, remodelling and oxidative stress in essential hypertension, 78 treatment-naïve essential hypertensives (mean age 43 years) underwent measurement of endothelial dysfunction, using the maximal acetylcholine-induced forearm vasodilation and serum levels of adhesion molecules, selectins, chemokines, metalloproteinases, copper, zinc, selenium, vitamins, homocysteine, malondialdehyde, erythrocyte glutathione peroxidase and erythrocyte superoxide dismutase. Mean (+/-s.e.m.) maximal acetylcholine-induced vasodilation was 367+/-20%. Patients with a more impaired acetylcholine-dependent vasodilation (first tertile) had increased levels of e-selectin (P=0.009), p-selectin (P<0.001), monocyte chemotactic protein type 1 (MCP-1; P=0.012) and the tissue inhibitor of metalloproteinases type 1 (TIMP-1; P=0.044), which in turn showed significant inverse correlations with maximal endothelium-dependent vasodilation. Serum levels of selenium (P=0.012), vitamin C (P=0.038), erythrocyte glutathione peroxidase (P<0.001) and superoxide dismutase (P=0.022) activities were reduced in patients with a more impaired endothelium-dependent vasodilation. Recently diagnosed treatment-naïve essential hypertensives showed a relationship between the endothelial dysfunction, serum markers of inflammation and remodelling and levels of antioxidant substances. These could be potentially helpful markers of high risk in hypertensive patients.

Advances in childhood vasculitis.

PURPOSE OF REVIEW: To provide an update on new developments in paediatric vasculitis. RECENT FINDINGS: New classification criteria for childhood vasculitis have recently been proposed and are currently undergoing validation. Infectious triggers are still implicated in the aetiopathogenesis of Kawasaki disease and Henoch-Schonlein purpura. Several genetic polymorphisms in vasculitides have now been described that may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. However, new challenges are looming with regard to the role of inflammation in endothelial health and the long-term cardiovascular morbidity for children with primary systemic vasculitis. SUMMARY: As our understanding of disease pathogenesis in vasculitis of the young has advanced, novel therapeutic approaches have been adapted. International multicentre collaboration is of great importance to further increase and standardize the scientific base of investigating and treating childhood vasculitis.

Nitric oxide involvement in lipid emulsion-induced vascular pain in anesthetized rats.

We examined the vascular pain induced by arterial infusion of 20% lipid emulsion by using a flexor reflex model in anesthetized rats. Arterial infusion of 20% lipid emulsion at doses of 0.6 to 2 ml/2 min induced flexor reflexes that were late in onset, persistent, and intense compared with those induced by 2.7% amino acid and 7.5% glucose solution, 5% sodium chloride solution, 1% propofol, and capsaicin. The flexor reflex induced by 20% lipid emulsion was significantly inhibited by preinjected procaine hydrochloride (4 mg/rat, i.a.) but not by the critical dose of indomethacin (10 mg/kg, i.p.). These results suggest that the flexor reflex might reflect a 20% lipid emulsion-induced vascular pain response and that the site of action of noxious agents involved in this event might be a vascular bed, but the production of prostanoids through cyclooxygenase might not be involved in the action mechanisms. The 20% lipid emulsion-induced vascular pain was significantly inhibited by preinjection of 10 mg/kg N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide (NO) synthase inhibitor, and the inhibition by l-NAME was recovered by the addition of sodium nitroprusside (30 microg/kg/min), which is an endothelium-independent NO donor to 20% lipid emulsion. These results indicate that increased NO production is responsible for 20% lipid emulsion-induced vascular pain. In summary, the arterial infusion of 20% lipid emulsion induced a delayed, persistent and intense flexor reflex, presumably indicating vascular pain in rats that might be induced by NO production through the activation of NO synthase.

Aspectos clínicos novedosos en la enfermedad de Behçet / New clinical aspects of Behçet’s disease

La etiopatogenia del síndrome o enfermedad de Behçet (EB) sigue siendo esquiva y sus manifestaciones clínicas, muy complejas, y genera una buena cantidad de artículos científicos. Por ejemplo, una búsqueda simple en PubMed muestra que en los últimos 5 años se han publicado 1.394 artículos, 159 de ellos revisiones. Además de los estudios básicos sobre etiopatogenia y mecanismos de la enfermedad, las diversas manifestaciones clínicas y sus tratamientos, también es fuente de debate la propia definición de la enfermedad, su clasificación y los criterios de clasificación y diagnóstico. En este artículo revisamos algunos aspectos en debate, así como las últimas alternativas terapéuticas y la situación de la EB en España (AU)

Behçet’s disease/syndrome (BD) continues being aloof in his etiopathogenesis and very complex in its clinical manifestations. BD generates a good amount of scientific articles. For example, a simple search in PubMed sample that in the last 5 years has been published 1394 articles, 159 of them revisions. In addition to the basic studies on etiopahtogenesis and disease mechanisms, the diverse clinical manifestations and their treatments, also the own definition of the disease, its classification and the criteria of classification and diagnosis are debate source. In this article we reviewed some aspects in discussin as well as the last therapeutic alternatives and the situation of the EB in Spain (AU)