The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1_{rs3901533 T/T} and Dectin-1_{rs7309123 G/G} genotypes and DC-SIGN_{rs4804800 G}, DC-SIGN_{rs11465384 T}, DC-SIGN_{7248637 A} and DC-SIGN_{7252229 C} alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37–22.77; OR = 4.91 95%CI 1.52–15.89; OR = 2.75 95%CI 1.27–5.95; OR = 2.70 95%CI 1.24–5.90; OR = 2.39 95%CI 1.09–5.22 and OR = 2.05 95%CI 1.00–4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1_{rs3901533_T} allele and Dectin-1_{rs7309123_G/G} genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1_rs7309123 polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

OBJECTIVE: Thyroid disorders are accompanied by important changes in haemodynamic and cardiac functions and renal sodium handling. Since nitric oxide (NO) plays a crucial role in regulating vascular tone and renal sodium excretion, the present paper was designed to determine whether changes in the activity of NO synthase (NOS) participate in the cardiovascular and renal manifestations of thyroid disorders. METHODS: We measured NOS activity in the heart (left and right ventricles), vessels (aorta and cava) and kidney (cortex and medulla) of euthyroid, hyperthyroid and hypothyroid rats after 6 weeks of treatment. NOS activity was determined by measuring the conversion of L-[(3)H]-arginine to L-[(3)H]-citruline. RESULTS: NOS activity was higher in all tissues from hyperthyroid rats when compared with controls, except in the right ventricle. In the hypothyroid group, NOS activity showed a more heterogeneous pattern, with significant increases in both ventricles but significant reduction in the aorta, while in the vena cava, renal cortex and medulla the enzyme activity also tended to be higher, but significance was not reached. CONCLUSIONS: These data indicated that NOS activity was upregulated in tissues primarily related to blood pressure control in hyperthyroid rats, suggesting that an increased NO production may contribute to the hyperdynamic circulation in hyperthyroidism and may have a protective homeostatic effect in the target organs of the hypertension that accompanies this endocrine disease. The aortic and renal findings in hypothyroid rats suggested a possible role for NOS in the increased peripheral resistance and the normal pressure-diuresis-natriuresis response of these hypotensive animals, although hypothyroidism produced a heterogeneous tissue response in NOS activity.

Background: The link between colorectal cancer (CRC) and type 2 diabetes mellitus (T2D) has been extensively studied. Although it is commonly accepted that T2D is a risk factor for CRC, the underlying mechanisms are still poorly understood. Research Design and Methods: Given that the genetic background contributes to both traits, it is conceivable that genetic variants associated with T2D may also influence the risk of CRC. We selected 26 T2D-related single-nucleotide polymorphisms (SNP) previously identified by genome-wide association studies and assessed their association with CRC and their interaction with known risk factors (gender, T2D, and body mass index) of CRC. Selected SNP were genotyped in 1798 CRC cases and 1810 controls from the population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study (Germany). Results: Patients carrying the TCF7L2_rs7903146_T allele had an increased risk of CRC (P_trend = 0.02), whereas patients harboring the IL13_rs20541_T allele had a reduced risk (P_trend = 0.02). A further analysis revealed gender-specific effects: the TCF7L2_rs7903146_T allele was associated with an increased risk of CRC in women (P_trend = 0.003) but not in men (P_interaction = 0.06); the LTA_rs1041981_A allele was associated with a decreased risk for CRC in women (P_trend = 0.02), with an opposite effect in men (P_trend = 0.05; P_interaction = 0.002); the CDKAL1_rs7754840_C allele was associated with a decreased risk for CRC in men (P_trend = 0.03), with no effect in women (P_interaction = 0.03). The risk associated with the presence of T2D was modified both by IGF2BP2_rs4402960 and PPARγ_rs1801282 SNP (P_interaction = 0.04 and 0.04, respectively). None of the findings were significant after correction for multiple comparisons. Conclusions: These findings suggest that T2D-related variants modify CRC risk independently and/or in an interactive manner according to the gender and the presence or absence of T2D.