Adriano de Paula Sabino

Factor V Leiden and increased risk for arterial thrombotic disease in young Brazilian patients.

The contribution of mutations in the prothrombin (FII G20210A), methylenetetrahydrofolate reductase (C677T) genes and factor V Leiden (FVL) to the pathogenesis of arterial thrombosis remains controversial. In this study, these polymorphisms were investigated by polymerase chain reaction–restriction fragment length polymorphism in a group of 53 patients that presented arterial thrombosis other than myocardial infarction as a first thrombotic event and 275 control subjects living in the state of Minas Gerais, Brazil. Odds ratio (OR) and χ2 tests were applied for statistical comparisons. Similar frequencies were detected among patients and control subjects for the C677T mutation. The 20210A mutation was present in 3.6% of the control subjects but was not detected among ischemic stroke patients. Significant differences were detected only for factor V Leiden (odds ratio 7.11; 95% confidence interval 1.55–32.73). Our data indicate that, among these genetic factors, factor V Leiden was identified as an important risk factor for arterial thrombosis in this group of patients. In addition, our results indicate regional differences in the incidence of these genetic factors in Brazil, as compared to the incidences reported in other studies.

Inflammation, neoangiogenesis and fibrosis in peritoneal dialysis

Peritoneal dialysis (PD) is a form of renal replacement therapy used in patients with end stage renal disease (ESRD). It is based on using the peritoneum as a semipermeable membrane through which ultrafiltration (UF) and diffusion occur. Despite several benefits, PD has long-term complications, including inflammation, neoangiogenesis and fibrosis. Several inflammatory molecules can be found in the dialysate of PD patients including: interleukins (IL), tumor necrosis factor α (TNF-α) and C-reactive protein (CRP). Angiogenesis results in increased effective surface area exchange. Consequently, the glucose-driven osmotic pressure of the peritoneal dialysis fluid (PDF) is significantly reduced leading to UF failure (UFF). Several factors are implicated in the development of peritoneal fibrosis (PF) in PD patients. The most important factor is the conventional bio-incompatible PD solution, which contains high concentration of glucose and glucose degradation products (GDP). Although there are several studies elucidating the mechanisms leading to UFF in PD patients, more studies needed to be developed in this area and more research is required to find mechanisms to delay or to minimize the occurrence of many deleterious changes in peritoneal membrane (PM) during PD.

Low prevalence of the JAK2V617F in patients with ischemic stroke or cerebral venous thrombosis.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with increased risks for bleeding and the expression and storage of urokinase plasminogen activator (u-PA) in platelets, despite normal u-PA in plasma (reviewed in [1]). In the recent article on QPD published in this journal [1], QPD was proposed to result from defective u-PA regulation by megakaryocytes. However, the levels of u-PA in other QPD cells and urine have not been reported. Individuals with QPD are at increased risk of experiencing bleeding following hemostatic challenges, and approximately 50% experience episodic, spontaneous hematuria, which is associated with higher levels of platelet u-PA [2]. As urine normally contains significant amounts of u-PA (40–80 mg/ml) [3], we investigated whether individuals with QPD have an increased urinary u-PA as a potential contributor to their urinary tract bleeding.

ApoB/ApoA-I ratio in young patients with ischemic cerebral stroke or peripheral arterial disease.

Although smoking and hypertension are classic risk factors for atherothrombotic diseases, the relationship of dyslipidemia and vascular diseases, other than myocardial infarction, is less clearly established, especially in young subjects. In the current study, a detailed analysis of the lipid and apolipoprotein profiles was conducted in young patients of ischemic cerebral stroke (IS) and peripheral arterial disease (PAD). Plasma levels of C-reactive protein (hs-CRP), total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), and apolipoproteins A-I (ApoA-I) and apolipoproteins B (ApoB), which include the ApoB/ApoA-I ratio, were analyzed in a group of 81 patients who presented with IS (n = 46) or PAD (n = 35) as well as in 167 control subjects. Significant differences were observed for hs-CRP, TC, HDLc, LDLc, TG, ApoA-I, and ApoB levels, as well as for the ApoB/ApoA-I ratio, between the control and the IS or PAD groups. However, after adjustment for sex, age, smoking, hypertension, hs-CRP, and dyslipidemia (LDLc, TC, HDLc, TG, ApoA, ApoB, and ApoB/ApoA-I ratio), hs-CRP, ApoB, and the ApoB/ApoA-I ratio were independently associated with increased risks of IS or PAD. Increased ApoB/ApoA-I ratio and hs-CRP levels are independently associated with occurrence of IS and PAD in young patients and are significant markers of alterations on lipid and apolipoproteic profiles and inflammatory responses, respectively, in these patients.

High-sensitivity C-reactive protein in subjects with type 2 diabetes mellitus and/or high blood pressure

Type 2 diabetes mellitus (DM2) and high blood pressure (HBP) may contribute to the development of cardiovascular disease, and inflammation may be an important factor in these diseases. In the present study, plasma levels of high-sensitivity C-reactive protein (hs-CRP) were measured in subjects with DM2 and/or HBP and compared to those of normal subjects. Eighty-nine subjects were analyzed for hs-CRP, including 13 normotensive patients with DM2, 17 patients with HBP, 34 hypertensive patients with DM2 (DM2+HBP) and 25 normal subjects. The plasma hs-CRP levels were significantly lower in the controls than in the HBP+DM2 group (p < 0.05). DM2 associated with HBP was also correlated with increased plasma hs-CRP levels (n = 89, r = 0.25, p = 0.0162). Only hypertensive patients with DM2 had higher levels of hs-CRP, a circulating inflammatory marker, than normal subjects. This finding suggests that patients with two associated diseases have a more active inflammatory state.

Homocysteine and methylenetetrahydrofolate reductase in subjects undergoing coronary angiography

OBJECTIVE To determine plasma homocysteine levels and the incidence of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD), as well as investigate the correlation between hyperhomocysteinemia and the presence of polymorphism. METHODS Twenty subjects with no coronary atheromatosis (controls), fourteen subjects with mild/moderate atheromatosis, and twenty-nine subjects with severe atheromatosis were evaluated. RESULTS Significant differences were observed in mean homocysteine levels between the control and the severe atheromatosis groups (p < 0.001). No significant differences were observed among the other groups. The severe atheromatosis group showed rates of 62.0% and 6.9% for the C677T MTHFR gene polymorphism, in heterozygous and homozygous subjects, respectively. However, there was no correlation between the presence of mutation and hyperhomocysteinemia. A positive correlation of 41.91% (p < 0.001) was found between hyperhomocysteinemia and CAD. CONCLUSION The most important finding of this study was the association between hyperhomocysteinemia and coronary stenosis > 70%; yet, whether elevated plasma homocysteine worsens atherosclerosis or is a consequence remains to be established.

Peritoneal dialysis and inflammation

Peritoneal dialysis (PD) is a kidney replacement therapy for end stage renal disease (ESRD) patients. Despite being a lifesaving treatment, the rate of mortality in patients under PD is elevated, mainly due to the chronic peritoneal dysfunction which is characterized by inflammation, peritoneal fibrosis and neoangiogenesis. The inflammatory process is trigged and modulated by the type of the peritoneal dialysis solutions (PDSs) used during PD. Currently, different PDSs are commercially available: (i) the conventional solutions; (ii) solutions of neutral pH containing low concentration of glucose degradation products (GDPs); (iii) solutions with icodextrin; and (iv) solutions containing taurine. Therefore, the aim of this review is to describe the different types of peritoneal dialysis solutions used during PD and their relationship with systemic and intraperitoneal inflammation. Some studies suggested that solutions of neutral pH containing low concentration of GDPs, icodextrin and taurine have better biocompatibility and lower influence on the inflammatory process compared to the conventional one. On the other hand, the studies, in general, were performed with a small population and for a short period of time. Therefore, further well-designed and -controlled clinical trials with larger number of individuals are required in order to better understand the role of different peritoneal dialysis solution types in the development of inflammation in patients with chronic peritoneal dialysis. Accordingly, studies that are more well-designed, well-controlled and with a larger number of patients are needed to explain and define the role of different types of PDS in the inflammation development in patients with chronic peritoneal dialysis.

Apo B/Apo A-I ratio in central and peripheral arterial diseases

BACKGROUND The apo B/apo A-I ratio represents the balance between atherogenic particles, rich in apo B, and the antiatherogenic ones, apo A-I rich. This study investigated the association between atherosclerotic diseases in different anatomical sites and apo B/apo A-I ratio. METHODS Lipids, lipoproteins, and apolipoproteins A-I and B were assessed in 30 subjects with coronary artery disease (CAD), 26 with ischemic stroke (IS), 30 with peripheral arterial obstructive disease (PAOD), and 38 healthy subjects (controls). RESULTS HDLc and Apo A-I were significantly lower in PAOD and CAD groups, respectively, than in other groups. Significantly higher levels of triglycerides were observed for CAD and PAOD groups than for controls. Apo B was significantly higher in IS group than in control and PAOD groups. The apo B/apo A-I ratio showed significantly higher in CAD and IS groups when compared to control and PAOD groups (p < 0.001). CONCLUSION The apo B/apo A-I ratio was important for identifying an increased trend for coronary and cerebral atherosclerosis. In spite of the increased trend for apo B/apo A-I ratio in IS and CAD groups, the studied variables cannot be considered in an isolated way, given as those parameters were analyzed together by a binary logistic regression, no association has been demonstrated.

Synthesis and in vitro evaluation of novel triazole/azide chalcones

A series of 30 novel triazole/azide chalcone derivatives were synthesized by Claisen-Schmidt and Cu(I)-catalyzed cycloaddition reactions. The antiproliferative activity of each compound was evaluated against HeLa, RKO-AS45-1 and Wi-26VA4 cell lines. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays indicated that compounds 4j and 5j significantly reduced the HeLa and RKO-AS45-1cell populations compared to the controls. The relative expression of the TP53 gene revealed changes in both cell lines after exposure to compounds 5j and 4j. The increased expression of the TP53 gene suggests a cellular attempt to repair DNA damage and indicates these triazole/azide chalcone derivatives as promising anticancer agents.

Advances in chronic lymphocytic leukemia pharmacotherapy

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that affects B lymphocytes in most cases. Leukemic lymphocytes have prolonged longevity, defined by resistance to apoptosis. These cells can accumulate in peripheral blood, bone marrow, and solid lymphoid organs. CLL may be indolent or aggressive and has a range of prognostic factors such as expression of CD38 and ZAP-70, immunophenotypic and cytogenetic changes, imbalanced apoptosis proteins, and others. Although CLL has a low mortality rate, this disease is generally not considered curable until today. CLL treatment involves alkylating agents and glucocorticoids, purine analogs, monoclonal antibody therapies, and bone marrow transplantation. In recent decades, new drugs have appeared focusing on new targets and specific molecules, such as the BCR receptor, Brutons tyrosine kinase, phosphatidylinositol 3-kinase, spleen tyrosine kinase, apoptosis proteins and microRNAs. The most appropriate treatment for CLL is one that involves in its protocol a combination of drugs according to the prognostic factors presented by each patient. In this sense, treatment individualization is essential. This article examines standard treatments for CLL and explores new treatments and potential new targets, as well as schematic protocols to understand where we are, how the treatment has evolved, and the advantages and disadvantages of new targets for CLL therapy.