Mast cells are responsible for the lack of anti-inflammatory effects of morphine in CBA mice.

BACKGROUND AND AIM: Morphine co-injection has anti-inflammatory effects on zymosan-induced peritonitis in several strains of mice except that of CBA. As peritoneal mast cells (pMCs) are much more numerous in CBA mice than in SWISS mice, therole of pMCs in morphine-modulated zymosan peritonitis is compared in CBA and SWISS males. METHODS: pMCs were treated in vitro with morphine or C48/80 for comparison of histamine release. In vivo accumulation of leukocytes and histamine in peritoneal exudate were recorded after intraperitoneal injection with morphine, zymosan, or zymosan plus morphine. RESULTS AND CONCLUSION: Morphine induces histamine release by pMCs from CBA mice but not SWISS mice. In vivo morphine-induced peritonitis is stronger in CBA mice than SWISS mice. Corollary, morphine anti-inflammatory effects on zymosan peritonitis are reversed in CBA mice by its pro-inflammatory action through CBA pMCs

IgA antiphospholipid antibodies and anti-domain 1 of beta 2 glycoprotein 1 antibodies are associated with livedo reticularis and heart valve disease in antiphospholipid syndrome

Background. Antiphospholipid syndrome (APS) is an autoimmune disease associated with venous or arterial thrombosis and pregnancy loss, but also infrequently with non-criteria APS manifestations such as thrombocytopenia, livedo reticularis and heart valve disease. The occurrence of antiphospholipid antibodies is necessary to diagnose APS and includes the presence of lupus anticoagulant and anticardiolipin as well as anti-β2-glycoprotein I antibodies, both in IgM and/or IgG isotype. Objectives. The aim of this study was to evaluate the associations between antiphospholipid antibodies including IgA isotype and IgG anti-domain I of β2-glycoprotein I (β-2GPI-D1) and non-criteria-related manifestations of APS. Material and Methods. Thirty-three consecutive APS patients (26 women, 7 men, aged 44.1 ± 15 years), including 23 (69.7%) subjects with primary APS, were enrolled. Together with standard antiphospholipid antibodies, IgA anticardiolipin, IgA anti-β2-glycoprotein I and IgG anti-β-2GPI-D1 antibodies in serum samples were evaluated by chemiluminescence using the QUANTA Flash® System. Results. Livedo reticularis (n = 8, 24.2%) was associated with increased levels of IgG anti-β-2GPI-D1 (p = 0.005), IgA anticardiolipin (p = 0.001) and IgA anti-β2-glycoprotein I (p = 0.002) antibodies. Heart valve disease (n = 9, 27.3%) was observed in patients with higher IgG anti-β-2GPI-D1 (p = 0.01). The associations of HVD with increased levels of IgA aCL and IgA anti-β-2GPI tended to be significant (p = 0.07). None of antiphospholipid antibodies showed association with thrombocytopenia (n = 6, 18.2%). Conclusions. Our study suggests that increased IgA antiphospholipid antibodies and IgG anti-β-2GPI-D1 antibodies may be involved in the development of livedo reticularis and heart valve disease in APS patients

Association of the C-Reactive protein gene (CRP) rs1205 C>T polymorphism with aortic valve calcification in patients with aortic stenosis

Elevation in C-reactive protein (CRP) levels have been shown in patients with aortic valve stenosis (AS). Minor allele of the CRP gene (CRP) rs1205 C>T polymorphism has been associated with lower plasma CRP concentrations in cohorts of healthy and atherosclerotic patients. Considering the existing similarities between atherosclerosis and AS, we examined the effect of CRP rs1205 C>T polymorphism on the AS severity. Three hundred consecutive Caucasian patients diagnosed with AS were genotyped for the rs1205 C>T polymorphism using the TaqMan assay. Severity of the AS was assessed using transthoracic echocardiography. The degree of calcification was analyzed semi-quantitatively. Carriers of the rs1205 T allele were characterized by elevated serum CRP levels (2.53 (1.51–3.96) vs. 1.68 (0.98–2.90) mg/L, p < 0.001) and a higher proportion of the severe aortic valve calcification (70.4% vs. 55.1%, p = 0.01) compared with major homozygotes. The effect of CRP rs1205 polymorphism on CRP levels is opposite in AS-affected than in unaffected subjects, suggesting existence of a disease-specific molecular regulatory mechanism. Furthermore, rs1205 variant allele predisposes to larger aortic valve calcification, potentially being a novel genetic risk marker of disease progression

Optymalizacja leczenia antagonistami witaminy K - rola polimorfizmów genowych

The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40-50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 - have been identified and they determined 99% of genetic variability of this enzyme. The presence of -1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8-12% and 3-8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile. Kardiol Pol 2010; 68, supl. V: 428-435Na wielkość stabilnej dawki antagonistów witaminy K (VKA) w leczeniu przeciwzakrzepowym, oprócz znanych czynników klinicznych, środowiskowych i demograficznych, duży wpływ mają również czynniki genetyczne. Ich udział w przewidywaniu dawki VKA ocenia się na 40–50%. Kluczowe znaczenie mają polimorfizmy genetyczne 2 enzymów uczestniczących w metabolizmie witaminy K i/lub VKA - podjednostka 1 reduktazy epoksydu witaminy K (VKORC1) i izoformy 2C9 cytochromu P450 (CYP2C9). Mniejsze lub niewielkie znaczenie mają genetyczne polimorfizmy innej izoformy P450 (CYP4F2), apolipoproteiny E (APOE) oraz γ-karboksylazy (GGCX). W populacji europejskiej wyróżnia się 3 haplotypy VKORC1: VKORC1*2, VKORC1*3 i VKORC1*4, determinujące 99% zmienności genetycznej tego enzymu. Obecność polimorfizmu VKORC1 -1639G>A wiąże się z większym zapotrzebowaniem na VKA. Warianty alleliczne CYP2C9*2 i CYP2C9*3 (występujące odpowiednio u 8-12% i 3-8% chorych) warunkują wolniejszy metabolizm VKA i tym samym zwiększają ryzyko krwawień, zwłaszcza na początku terapii. Dostępne algorytmy farmakogenetyczne uwzględniające polimorfizmy genów VKORC1 i CYP2C9 ułatwiają przewidzenie dawki VKA, szczególnie gdy zapotrzebowanie na lek jest małe lub umiarkowane. Wciąż jednak brak przekonujących danych o zmniejszeniu ważnych klinicznie powikłań leczenia VKA dzięki znajomości profilu farmakogenetycznego pacjenta. Kardiol Pol 2010; 68, supl. V: 428-43

Optimalisation of treatment with vitamin K antagonists : the role of gene polymorphisms

Na wielkość stabilnej dawki antagonistów witaminy K (VKA) w leczeniu przeciwzakrzepowym, oprócz znanych czynników klinicznych, środowiskowych i demograficznych, duży wpływ mają również czynniki genetyczne. Ich udział w przewidywaniu dawki VKA ocenia się na 40–50%. Kluczowe znaczenie mają polimorfizmy genetyczne 2 enzymów uczestniczących w metabolizmie witaminy K i/lub VKA — podjednostka 1 reduktazy epoksydu witaminy K (VKORC1) i izoformy 2C9 cytochromu P450 (CYP2C9). Mniejsze lub niewielkie znaczenie mają genetyczne polimorfizmy innej izoformy P450 (CYP4F2), apolipoproteiny E (APOE) oraz g-karboksylazy (GGCX). W populacji europejskiej wyróżnia się 3 haplotypy VKORC1: VKORC1*2, VKORC1*3 i VKORC1*4, determinujące 99% zmienności genetycznej tego enzymu. Obecność polimorfizmu VKORC1 –1639G>A wiąże się z większym zapotrzebowaniem na VKA. Warianty alleliczne CYP2C9*2 i CYP2C9*3 (występujące odpowiednio u 8–12% i 3–8% chorych) warunkują wolniejszy metabolizm VKA i tym samym zwiększają ryzyko krwawień, zwłaszcza na początku terapii. Dostępne algorytmy farmakogenetyczne uwzględniające polimorfizmy genów VKORC1 i CYP2C9 ułatwiają przewidzenie dawki VKA, szczególnie gdy zapotrzebowanie na lek jest małe lub umiarkowane. Wciąż jednak brak przekonujących danych o zmniejszeniu ważnych klinicznie powikłań leczenia VKA dzięki znajomości profilu farmakogenetycznego pacjenta.The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40–50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 — have been identified and they determined 99% of genetic variability of this enzyme. The presence of –1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8–12% and 3–8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile