Journal of Investigative Medicine

Glutathione S-transferases (GSTs) are a polymorphic superfamily of multifunctional enzymes known to play an important role in the detoxification of several substances. GSTM1 and GSTT1 are present in the liver in relatively high levels. Polymorphisms of the GSTM1 and GSTT1 genes may affect ligandin functions that are important in bilirubin transportation.

The aim of this study was to investigate the role of GSTM1 and GSTT1 gene polymorphisms as risk factors for neonatal jaundice.

This study was conducted on 72 neonates with pathologic hyperbilirubinemia (bilirubin >15 mg/dL) and 112 neonates with bilirubin level less than 15 mg/dL as a control group. GSTM1 and GSTT1 genotypes were assessed by multiplex polymerase chain reaction.

GSTM1 null genotype was significantly higher in the patient compared with control groups (P = 0.005; odds ratio = 2.43; 95% confidence interval, 1.29–4.55) and was significantly associated with higher bilirubin levels compared with the wild genotype (P < 0.001). There was no statistically significant difference in the GSTT1 genotypes between the patient and the control groups. In the patient group, total bilirubin levels did not vary significantly among the null and wild GSTT1 genotypes (P = 0.108).

Neonates with the GSTM1 null genotype are at high risk to develop pathologic hyperbilirubinemia and may have higher bilirubin levels.

In subclinical hypothyroidism (SH), serum lipid and lipoprotein concentrations are frequently changed. Compared with the healthy population, the levels of oxidized low-density lipoprotein cholesterol are higher, and the levels of high-density lipoprotein cholesterol are lower. In patients with SH, the mechanism of atherosclerosis may beattributed to the lipid abnormalities. There is evidence showing that oxidation plays an important role during the process of atherosclerosis. Inthis study, we evaluated the activity of paraoxonase (PON) and arylesterase (ARE) in patients with SH and investigated their relation with oxidative stress.

The study enrolled 25 patients with SH and 20 sex- and age-matched healthy controls. The patient group and the control group were compared in terms of the activity of PON and ARE and the oxidative stress index.

Between 2 groups, no significant difference was found in terms of age, sex, serum levels of total cholesterol, low-density lipoprotein, and high-density lipoprotein. In the SH group, the activity of PON was significantly lower than that observed in the control group (P < 0.05). Arylesterase activity also was significantly lower in the group with SH, compared with the control group (P < 0.05). Oxidative stress index was found to be significantly higher in the patient group, compared with the healthy subjects (P < 0.01). Oxidative stress index showed a strong positive correlation with the levels of thyroid stimulating hormone in all cases (r = 0.60, P < 0.01).

The activity of PON and ARE were significantly decreased, and oxidative stress was increased in patients with SH. Lower activities of these 2 biomarkers indicate increased oxidative damage in SH. Atherosclerosis in SH can be attributed to increased oxidative stress.

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL) constitutes an aggressive variety of lymphomas characterized by increased extranodal involvement, relapse rate, and resistance to chemotherapy. Protein kinase C-beta (PKCβ) targeting showed promising results in preclinical and clinical studies involving a wide variety of cancers, but studies describing the role of PKCβ in AIDS-NHL are primitive if not lacking.

In the present study, 3 AIDS-NHL cell lines were examined: 2F7 (AIDS–Burkitt lymphoma), BCBL-1 (AIDS–primary effusion lymphoma), and UMCL01-101 (AIDS–diffuse large B-cell lymphoma).

Immunoblot analysis demonstrated expression of PKCβ1 and PKCβ2 in 2F7 and UMCL01-101 cells, and PKCβ1 alone in BCBL-1 cells. The viability of 2F7 and BCBL-1 cells decreased significantly in the presence of PKCβ-selective inhibitor at half-maximal inhibitory concentration of 14 and 15 μmol/L, respectively, as measured by tetrazolium dye reduction assay. In contrast, UMCL01-101 cells were relatively resistant. As determined using flow cytometric deoxynucleotidyl transferase dUTP nick-end labeling assay with propidium iodide staining, the responsiveness of sensitive cells was associated with apoptotic induction and cell cycle inhibition. Protein kinase C-beta–selective inhibition was observed not to affect AKT phosphorylation but to induce a rapid and sustained reduction in the phosphorylation of glycogen synthase kinase-3 beta, ribosomal protein S6, and mammalian target of rapamycin in sensitive cell lines.

The results indicate that PKCβ plays an important role in AIDS-related NHL survival and suggest that PKCβ targeting should be considered in a broader spectrum of NHL. The observations in BCBL-1 were unexpected in the absence of PKCβ2 expression and implicate PKCβ1 as a regulator in those cells.

Dietary sodium intake and left ventricular hypertrophy (LVH) on electrocardiogram (ECG) are both independent determinants of cardiovascular risk. Prior studies demonstrated that acute dietary sodium modulation significantly altered LVH-specific ECG voltage in hypertensive individuals, thus modifying cardiovascular risk prediction; but whether this phenomenon exists in normotensive individuals is not known. We evaluated the influence of dietary sodium intake on ECG voltage and ECG criteria for LVH in normotensive individuals.

Retrospective evaluation of ECGs of healthy normotensive individuals (n = 39) who were prospectively randomized to a dietary study protocol of 1 week of high-sodium diet (>200 mmol of sodium per day) and 1 week of low-sodium diet (<10 mmol/d) was conducted. Electrocardiogram voltage amplitudes and biochemical assessments were performed at the end of each dietary intervention.

As expected, blood pressure declined and measures of circulating renin-angiotensin-aldosterone system activity rose significantly with low-sodium diet. No significant changes in specific LVH voltage criteria or overall precordial or limb lead ECG voltage amplitudes were detected between diets.

Although immediate dietary sodium modulation has been shown to significantly alter LVH-specific ECG voltage and the detection of LVH in hypertensive individuals, dietary sodium intake did not influence ECG voltage in normotensive individuals. Healthy normotensive individuals may exhibit adaptive measures that dampen ECG voltage fluctuations in response to dietary sodium modulation. More specific cardiac imaging studies may provide additional insight into this observation and the influence of dietary sodium in cardiac health.

Previous studies demonstrated that G1359A polymorphism of cannabinoid receptor-1 (CNR1) was associated with cardiovascular risk factors including obesity, insulin resistance, dyslipidemia, and inflammation, which are also risk factors for developing type 2 diabetes mellitus (T2DM). Therefore, this study was aimed to determine whether G1359A polymorphism of CNR1 is associated with T2DM and the presence of coronary artery disease (CAD) in patients with T2DM.

A total of 450 patients with T2DM (259 patients with CAD and 191 patients without CAD) and 94 healthy subjects were genotyped using polymerase chain reaction and restriction fragment length polymorphism method.

No significant differences in genotype frequency of CNR1 were found between normal controls and patients with T2DM without CAD. GG genotype frequency of CNR1 was significantly higher in the patients with T2DM with CAD compared with those without CAD and healthy subjects (P = 0.003 and P = 0.005, respectively). Unconditional logistic regression analysis revealed that GG genotype was significantly associated with the presence of CAD in the patients with T2DM compared with GA and AA genotypes (odds ratio, 2.632; 95% confidence interval, 1.481–4.678; P < 0.001). In addition, GG genotype of CNR1 was significantly correlated with elevated levels of body mass index, systolic blood pressure, homeostasis model assessment of insulin resistance, and C-reactive protein, as well as decreased levels of high-density lipoprotein cholesterol in patients with T2DM.

G1359A polymorphism of CNR1 may be not associated with T2DM but may contribute to the genetic risk for the presence of CAD in patients with T2DM of Chinese Han population.

Although association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and cardiovascular diseases was reported by many studies, the relation between ACE I/D polymorphism and coronary collateral circulation (CCC) has not been studied yet. The aim of the present study was to investigate a possible relationship between ACE I/D polymorphism and CCC.

Patients who were subjected to coronary angiography in the 2006 to 2009 period and had at least a completely occluded major artery were included in this study. To classify collateral circulation, we used the Rentrop classification. Patients were classified as having poor CCC (Rentrop grades 0 to 1) or good CCC (Rentrop grades 2 to 3). Gene polymorphism was detected through the detailed melting curve analysis of polymerase chain reaction products after amplification using real-time polymerase chain reaction method and LightCycler 1.5 apparatus.

We prospectively studied 113 patients who had at least 1 totally occluded major epicardial coronary artery. Forty-seven patients had poor CCC and 67 patients had good CCC. There were no differences among groups in age, sex, risk factors, lipid profile, uses of cardiovascular drugs, and number of diseased vessels. Plasma ACE levels were significantly higher in poor CCC group (P < 0.001). The frequency of DD polymorphism was higher in the poor CCC group (P < 0.001). In allele frequency, we found that the frequency of the D allele was higher in poor CCC group than in the good CCC group (95% confidence interval [CI], 2.16–7.38; P < 0.001). Multiple regression analysis with CCC development as the dependent variable revealed that the presence of total occlusion of the left circumflex artery (95% CI, 1.29–6.6; P = 0.001), ACE DD genotype (95% CI, 2.55–12.79; P = 0.001), presence of diabetes (95% CI, 1.03–3.16; P = 0.005), and pulse pressure (95% CI, 1.04–1.56; P = 0.045) were independent determinants of poor coronary collateral development.

This study showed that ACE DD polymorphism is associated with poor CCC. Poor collateral circulation in patients carrying the D allele may be associated with endothelial dysfunction and elevated blood ACE levels in these patients.

Flow cytometry immunophenotyping (FCIP) is used for rapid, specific diagnosis of B-chronic lymphoproliferative disorders (BCLPDs). However, cases may deviate from the typical immunophenotype; therefore, there is a need for adding new marker(s) for differentiating BCLPDs.

Lately, few researches highlighted CD200 expression in some BCLPDs. Our aim was to evaluate CD200 expression in different BCLPDs and whether adding CD200 to BCLPD-FCIP routine panels could improve the ability of their differential diagnosis.

We evaluated CD200 expression in 49 BCLPD patients and 26 age- and sex-matched control subjects. Flow cytometry immunophenotyping first panel included CD5, CD19, sIg, CD23, CD22, CD79b, and FMC7; for BCLPDs other than chronic lymphocytic leukemia (CLL) and mantle cell lymphoma, CD11c, CD103, CD25, and CD10 were evaluated.

Using tricolor FCIP, CD200 showed high bright expression on CD5/19-positive clone in all B-CLL patients (100%), with a mean of 94% (SD, 11%); in the 2 cases of hairy cell leukemia, CD200 was brightly expressed on 96% and 99% of cells. In all other BCLPDs including mantle cell lymphoma, follicular lymphoma and splenic marginal zone lymphoma, CD200 expression (on CD19/22-positive cells) was less than 20% with a mean of 10% (SD, 8%) and a dim pattern. CD200 expression was significantly higher in CLL compared with non-Hodgkin lymphoma groups (P < 0.001).

Evaluating CD200 expression has a great impact on accurate BCLPDs diagnosis and could be added to the BCLPD routine panels. The high expression of CD200 in B-cell CLL and hairy cell leukemia could open the option for targeted immune (anti-CD200) therapy.

Patients with rheumatoid arthritis (RA) are known to be at increased cardiovascular risk. Etanercept is a tumor necrosis factor α (TNF-α) blocking agent that has been successfully used in the treatment of RA. We sought to assess the effects of etanercept on cardiac functions and lipid profile in RA patients without overt cardiac disease.

Sixteen patients with active RA were recruited to the study prospectively. Etanercept was administered subcutaneously twice a week for 6 months. Clinical and laboratory predictors of RA activity and lipid profile were evaluated at baseline and at 6 months. The systolic and diastolic function parameters of the left ventricle were obtained by echocardiographic examination and included mitral inflow Doppler and tissue Doppler imaging.

Sixteen patients (13 women; median age, 48 years [range, 27–69 years]) completed the study. Patients’ 28-item Disease Activity Score and Health Assessment Questionnaire scores were significantly reduced by treatment (6.35 to 4.45 [P < 0.001] and 2.0 to 0.75 [P = 0.005], respectively). Diastolic dysfunction was detected in 6 patients (37.5%) (3 in grade 1 and 3 in grade 2) by mitral inflow Doppler and the tissue Doppler parameters before the treatment. No significant change in diastolic dysfunction was observed during follow-up (6/16 to 5/16, P = 0.164). In addition, there were also no significant differences in the left ventricular ejection fraction (65.8–66.9, P = 0.168) and lipid profiles after 6 months of etanercept treatment.

Etanercept treatment was safe for use as regards cardiac functions and lipid profiles and effective on RA parameters during 6-month follow-up in patients with active RA.