Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study

Objective

Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix in the arterial wall. Collagen I is associated with vascular smooth muscle cell (VSMC) migration and monocyte differentiation. MMP-8 is expressed in atherosclerotic plaque and preferentially cleaves collagen type I. The aim of this study was to investigate the associations of two MMP-8 promoter polymorphisms, rs11225395 (−799 C/T) and rs1320632 (−381 A/G), with carotid plaque occurrence, and the influence of these polymorphisms on MMP-8 mRNA expression in plaque tissue.

Methods

The study included a total of 766 participants: 277 controls and 489 patients with carotid atherosclerosis undergoing endarterectomy. The two investigated polymorphisms were genotyped by PCR-RFLP. The gene expression analysis was performed by real-time PCR.

Results

In females only, a significantly higher frequency of the −381G allele was found in patients with carotid atherosclerosis compared to controls (OR, 1.7; 95% CI 1.1–2.9; p = 0.001). Significant up-regulation of MMP-8 gene expression was observed in patients carrying the −381G allele compared to those with the AA genotype (mean factor, 3.54; S.E. range, 0.643–19.551; p = 0.007). Carotid plaque tissue of the haplotype G₋₃₈₁T₋₇₉₉ showed a significantly higher mRNA level compared with the reference A₋₃₈₁C₋₇₉₉ haplotype (p = 0.003).

Conclusion

Our preliminary results indicate that MMP-8 −381A/G and −799 C/T gene polymorphisms could be risk factors for carotid atherosclerosis. Further validation and functional studies are needed to establish the potential regulatory role of these polymorphisms and their impact on susceptibility to carotid atherosclerosis.     

Comparison of genetic and clinical aspects in patients with acute myeloid leukemia and myelodysplastic syndromes all with more than 50% of bone marrow erythropoietic cells

Background

The World Health Organization separates acute erythroid leukemia (erythropoiesis in ≥50% of nucleated bone marrow cells; ≥20% myeloblasts of non-erythroid cells) from other entities with increased erythropoiesis – acute myeloid leukemia with myelodysplasia-related changes (≥20% myeloblasts of all nucleated cells) or myelodysplastic syndromes – and subdivides acute erythroid leukemia into erythroleukemia and pure erythroid leukemia subtypes. We aimed to investigate the biological/genetic justification for the different categories of myeloid malignancies with increased erythropoiesis (≥50% of bone marrow cells).

Design and Methods

We investigated 212 patients (aged 18.5–88.4 years) with acute myeloid leukemia or myelodysplastic syndromes characterized by 50% or more erythropoiesis: 108 had acute myeloid leukemia (77 with acute erythroid leukemia, corresponding to erythroid/myeloid erythroleukemia, 7 with pure erythroid leukemia, 24 with acute myeloid leukemia with myelodysplasia-related changes) and 104 had myelodysplastic syndromes. Morphological and chromosome banding analyses were performed in all cases; subsets of cases were analyzed by polymerase chain reaction and immunophenotyping.

Results

Unfavorable karyotypes were more frequent in patients with acute myeloid leukemia than in those with myelodysplastic syndromes (42.6% versus 13.5%; P<0.0001), but their frequency did not differ significantly between patients with acute erythroid leukemia (39.0%), pure erythroid leukemia (57.1%), and acute myeloid leukemia with myelodysplasia-related changes (50.0%). The incidence of molecular mutations did not differ significantly between the different categories. The 2-year overall survival rate was better for patients with myelodysplastic syndromes than for those with acute myeloid leukemia (P<0.0001), without significant differences across the different acute leukemia subtypes. The 2-year overall survival rate was worse in patients with unfavorable karyotypes than in those with intermediate risk karyotypes (P<0.0001). In multivariate analysis, only myelodysplastic syndromes versus acute myeloid leukemia (P=0.021) and cytogenetic risk category (P=0.002) had statistically significant effects on overall survival.

Conclusions

The separation of acute myeloid leukemia and myelodysplastic syndromes with 50% or more erythropoietic cells has clinical relevance, but it might be worth discussing whether to replace the subclassifications of different subtypes of acute erythroid leukemia and acute myeloid leukemia with myelodysplasia-related changes by the single entity, acute myeloid leukemia with increased erythropoiesis ≥50%.     

The association of V249I and T280M fractalkine receptor haplotypes with disease course of multiple sclerosis

We investigated the association of CX3CR1 genotypes/haplotypes with MS and performed the prediction analysis of protein sequence variants' effects on CX3CL1/CX3CR1 interaction. We found no association of CX3CR1 with MS susceptibility. Frequency of I(249)T(280) haplotype was significantly lower in SP compared to RR patients (RR>10 years, OR=0.30, 95%CI=0.11-0.79, p=0.01; OR=0.53, 95%CI=0.18-1.56, p=0.2, in SP<10 years vs. RR>10 years). Prediction analysis showed that I249 T280 protein variant would significantly affect CX3CL1/CX3CR1 interaction. Our results suggest that CX3CR1 I???T??? haplotype could have protective effect for switch to SP MS. Further research is warranted to validate and replicate currently observed results.     

Malignant potential of pleomorphic xanthoastrocytoma

Pleomorphic xanthoastrocytoma (PXA) is a low-grade astrocytic tumour that occasionally progresses to a higher grade. We have extensively reviewed the literature on the potential for malignant transformation of PXA. An illustrative case of a PXA transforming to glioblastoma multiforme is presented.     

Immunomodulation by poly-YE reduces organophosphate-induced brain damage

Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4⁺ T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.