Systemic Complement Activation in Age-Related Macular Degeneration

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes

Estimates of genomic heritability and genome-wide association study for fatty acids profile in Santa Inês sheep

Background: Despite the health concerns and nutritional importance of fatty acids, there is a relative paucity of studies in the literature that report genetic or genomic parameters, especially in the case of sheep populations. To investigate the genetic architecture of fatty acid composition of sheep, we conducted genome-wide association studies (GWAS) and estimated genomic heritabilities for fatty acid profile in Longissimus dorsi muscle of 216 male sheep. Results: Genomic heritability estimates for fatty acid content ranged from 0.25 to 0.46, indicating that substantial genetic variation exists for the evaluated traits. Therefore, it is possible to alter fatty acid profiles through selection. Twenty-seven genomic regions of 10 adjacent SNPs associated with fatty acids composition were identified on chromosomes 1, 2, 3, 5, 8, 12, 14, 15, 16, 17, and 18, each explaining ≥0.30% of the additive genetic variance. Twenty-three genes supporting the understanding of genetic mechanisms of fat composition in sheep were identified in these regions, such as DGAT2, TRHDE, TPH2, ME1, C6, C7, UBE3D, PARP14, and MRPS30. Conclusions: Estimates of genomic heritabilities and elucidating important genomic regions can contribute to a better understanding of the genetic control of fatty acid deposition and improve the selection strategies to enhance meat quality and health attributes

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p&lt;0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.ConclusionIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted

Quel poids donner aux atteintes des organes cibles ? l'exemple de la protéinurie

Dans la stratification du risque cardiovasculaire proposée par les dernières recommandations pour la prise en charge de l'hypertension de l'OMS et de l'International Society of Hypertension, l'atteinte des organes cibles a une place importante. Ainsi, la découverte d'une hypertrophie ventriculaire gauche, d'une créatinine élevée ou d'une protéinurie augmente considérablement la catégorie de risque d'un patient. Dans cet article, nous discutons le rôle de la protéinurie et de la microalbuminurie dans l'évaluation du risque cardiovasculaire d'un patient hypertendu non diabétique. Dans le cas de la protéinurie, il est important de préciser le diagnostic car le poids d'une protéinurie peut se révéler différent en fonction de la cause. La microalbuminurie est reconnue comme un facteur de mauvais pronostic rénal et cardiovasculaire chez le patient diabétique. Par analogie, la microalbuminurie est fréquemment mesurée dans l'hypertension artérielle sans que l'on sache vraiment si ce paramètre est aussi un indicateur utile dans ce diagnostic

Les inhibiteurs sélectifs de la cyclooxygénase de type 2: moins d'effets rénaux que les anti-inflammatoires non stéroïdiens classiques [Selective inhibitors of type 2 cyclooxygenase: less renal effects than the classical non-steroidal anti-inflammatory agents].

Prostaglandins play an important role in the regulation of renal hemodynamics and sodium excretion. Thus, the administration of non-steroidal anti-inflammatory drugs (NSAIDs) induces a renal vasoconstriction and sodium and potassium retention. In some high risk patients, this may lead to acute renal failure. The anti-inflammatory and renal effects of conventional NSAIDs are mediated by the non-selective inhibition of two cyclo-oxygenases, COX-1 and COX-2. Recently, highly selective COX-2 inhibitors have been developed such as celecoxib (Celebrex) and rofecoxib (Vioxx). These drugs were designed to preserve the analgesic and anti-inflammatory properties of NSAIDs while reducing their gastro-intestinal and renal side effects. Selective COX-2 inhibitors have indeed less gastro-intestinal side-effects. However, their renal profile is comparable to that of non-selective inhibitors as they induce a decrease in glomerular filtration rate and a sodium and potassium retention. Thus, despite the good gastro-intestinal safety profile of selective COX-2, one should be careful with the use of these agents in high risk patients as they may induce similar renal complications as non-selective NSAIDs