Archives of Medical Research

Early Lymphoid Development and Microenvironmental Cues in B-cell Acute Lymphoblastic Leukemia

Jessica Purizaca, Isaura Meza, Rosana Pelayo — 2012-04-04

B-cell acute lymphoblastic leukemia (B-ALL) is a hematological disorder characterized by malignant and uncontrolled proliferation of B-lymphoid precursor cells in bone marrow. Over the last few years remarkable advances have been made in identifying genetic aberrations, patterns of abnormal transcriptional activity controlling early fate decisions and environmental cues that may influence leukemic development. In this review we focus on the structure of the early lymphoid system and the current knowledge about cell composition and function of the hematopoietic microenvironment that might control progenitor cell activity and lead to differentiation, proliferation and survival of developing B leukemic precursors. Learning the biology of special leukemic niches is central to understanding the pathogenesis of B-ALL and for the development of novel therapies.

Osteopontin Upregulation in Atherogenesis Is Associated with Cellular Oxidative Stress Triggered by the Activation of Scavenger Receptors

2012-03-14

Background: Osteopontin (OPN) is a highly phosphorylated sialoprotein and a prominent component of mineralized extracellular matrices of bones and teeth. Although the structure of OPN has begun to be elucidated, the role of OPN overexpression in tissues distant from the bones and teeth remains poorly understood. In the present study, a rabbit model of hypercholesterolemia was employed to analyze the relationship between the vascular calcification process and OPN overexpression in the neointima of atherosclerotic plaques.Methods: OPN identification in the aorta of experimental animals fed with a high cholesterol diet was carried out by immunohistochemical procedures and Western blot analysis of tissue homogenates. Transmission electron microscopy was employed to localize target-like extracellular structures of atherosclerotic aortas. The human cell line T/G HA-VSMC was employed in the establishment of a ROS generation model employing the internalization of OxLDL particles.Results: Using immunohistochemical and Western blot analysis, OPN overexpression was detected in the aortas of rabbits fed a high-cholesterol diet. Results from the ultrastructural analysis of the rabbit neointima through transmission electron microscopy and from the detection of calcium phosphate precipitates by specific histochemical techniques, suggested that OPN may be functionally important as a regulator of vascular calcification. OPN was dramatically overexpressed by vascular smooth muscle cells in the presence of oxidized and acetylated LDL particles bound to scavenger receptors, thereby promoting cytosolic oxidative stress.Conclusions: This study establishes the in vivo role of OPN in the intima of the aorta regulating calcium phosphate precipitate deposition in response to oxidative stress.

Distortion of β-globin Chain of Hemoglobin Alters the Pathway of Erythrocytic Glucose Metabolism Through Band 3 Protein

Indrani Chakraborty, Raghwendra Mishra, Ratan Gachhui, Manoj Kar — 2012-02-27

Background and Aims: Band 3 is a transmembrane protein of erythrocytes and its cytosolic part regulates glucose metabolism to proceed along the pentose phosphate pathway (PPP) or glycolytic pathway by binding with the central cavity of the β chain of deoxygenated hemoglobin and with some glycolytic enzymes competitively. In β thalassemia major and hemoglobin (Hb)Eβ thalassemia, β chain is either absent or distorted and glucose metabolism may be disturbed. We estimated adenosine triphosphate (ATP), glucose 6-phosphate dehydrogenase (G6PD) and aldolase activity in oxygenated and deoxygenated state of erythrocytes of β major, HbEβ thalassemia and normal controls to understand the hypothesis that major glucose metabolism within the erythrocytes of these diseases may proceed through the PPP.Methods: Fifty of each group of patients and 52 normal controls were included. Patients' blood was collected 1 month prior to blood transfusion. G6PD and aldolase were estimated using a commercial kit. ATP was measured by spectrophotometric method.Results: Significantly low levels of erythrocytic ATP and higher levels of G6PD were found in two groups of patients. Aldolase level in deoxygenated hemolysate was significantly higher than oxygenated hemolysate in normal controls but no significant change was noticed in both types of thalassemic patients.Conclusions: In β thalassemia major and HbEβ thalassemia due to distortion of β chain, binding of deoxygenated hemoglobin with band 3 is inhibited and thus traffic control of glycolytic pathway is disturbed and shifted towards PPP.

Association of Promoter Polymorphisms in MMP2 and TIMP2 with Prostate Cancer Susceptibility in North India

Priyanka Srivastava, Tasleem A. Lone, Rakesh Kapoor, Rama Devi Mittal — 2012-02-27

Background and Aims: The importance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression is well documented. MMP2/TIMP2 system has a significant impact on the development and progression of cancer and genetic polymorphisms in the promoters of MMP2 (−1306C/T, 735C/T) and TIMP2 (−418G/A, −303C/T) are correlated with decreased enzyme activity. We sought to determine whether genetic polymorphisms in MMP2 and TIMP2 polymorphisms may be associated with varying risk of prostate cancer (PCa) in men in North India.Methods: Genotyping was done by PCR-restriction fragment length polymorphism method in 190 histologically confirmed PCa patients and 200 unrelated, healthy, age-matched individuals of similar ethnicity.Results: Patients with MMP2 (-1306) CT genotype as well as T allele were at higher risk of PCa (p = 0.018; OR = 1.68 and p = 0.015; OR = 1.52). This effect was even more evident in the case of the T allele carrier (CT + TT) (p = 0.011; OR = 1.71). MMP2 (735) C>T, TIMP2 (−418) G>C and TIMP2 (−303) C>T polymorphism demonstrated no association. However, TIMP2 (−418) GC was found to be involved in progression of PCa but not in initiation. Haplotype results demonstrated that MMP2 (1306T–735C) and TIMP2 (418G-303T) were associated with a 1.5- and 1.8-fold increased risk, respectively.Conclusions: Our data indicated that MMP2-1306C>T gene polymorphism contributes to PCa susceptibility. These findings suggested MMP2 variants as a predictor of PCa progression risk among North Indian men. We assume that analysis of these gene polymorphisms can help identify patient subgroups at high risk of poor disease outcome.

Intermittent Maximal Exercise Improves Attentional Performance Only in Physically Active Students

2012-02-29

Background and Aims: Regular physical activity participation seems to be linked to brain metabolism and to be one factor responsible for different effects of high intensity exercise on cognition. Due to this, we investigated the effect of an intermittent maximal exercise intervention on a neuropsychological test requiring sustained and selective attention in a group of low and high physically active subjects.Method: Forty six healthy students (age: M = 23.11, SD = 2.60 years) performed in a cross-over design an intermittent incremental exercise until they reached their maximal heart rate (HR Max; intervention condition) or rested for the same duration (control condition) followed by the administration of the d2-test.Results: A significant interaction between physical activity participation level and exercise effect on cognitive performance emerged, with only the more physically active participants improving the performance in the cognitive test after the intervention.Conclusion: These data extend the current knowledge base by showing that a higher participation rate in physical activity may lead to neurobiological adaptations that facilitate selected cognitive processes (i.e., attention) after high exercise intensities.

Lymphatic Microvessel Density Combined with CT Used in the Diagnosis of Mediastinal and Hilar Lymph Node Metastasis of Non-small Cell Lung Cancer

2012-03-01

Background and Aims: Lymphatic microvessel density (LMVD) has been demonstrated to correlate with tumor metastasis. The purpose of this study is to determine whether the criteria combining LMVD with computed tomography (CT) could improve the diagnostic accuracy of lymph node (LN) metastasis in non-small cell lung cancer (NSCLC).Methods: Ninety four patients with NSCLC who had chest CT scans preoperatively and LMVD tested by immunohistochemistry postoperatively were randomized into two groups: the training set (n = 66) and the test set (n = 28). Cut-off point of LMVD was selected to separate the LN metastasis-predictive positive and negative groups. On the basis of LMVD levels, chest CTs of the training set were re-analyzed and hypothetical criteria for LN metastasis diagnosis were established. Diagnostic characteristics for LN metastasis were tested by using the combined criteria in the test set as compared to those of CT alone.Results: There was a significantly positive correlation between LMVD and LN metastasis (p <0.01). For sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV), accuracy was 67, 81, 75, 81 and 79% for the combined criteria, respectively. Diagnostic efficacy of the combined criteria was significantly higher than that of CT only (p <0.05).Conclusions: Diagnosis of LN metastasis using a combination of LMVD and CT is superior to the CT-only diagnosis. In future clinical trials, it is necessary to evaluate the efficacy of adjuvant therapy for the selection of patients according to the combined criteria.

Effectiveness of Silver-enhanced In Situ Hybridization for Evaluating HER2 Gene Status in Invasive Breast Carcinoma: A Comparative Study

2012-04-03

Background and Aims: HER2 gene amplification occurs in breast cancers and has implications for treatment and prognosis. Recently, a new direct evaluation technique, silver enhanced in situ hybridization (SISH) was developed for evaluating HER2 gene status. This study was performed to evaluate the SISH technique for clinical use by comparing it to that of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).Methods: We studied 543 cases of excised breast specimens diagnosed as invasive ductal carcinoma by IHC, FISH, and SISH using a tissue microarray. IHC, FISH, and SISH results were interpreted according to the American Society of Clinical Oncology/College of American Pathologists guidelines. A total of seven English studies that reported the concordance rates of SISH and BDISH compared to FISH published before July 2011 were retrieved.Results: The consensus concordance rate between SISH and FISH was 96.69% (kappa value = 0.9175). The pooled sensitivity was 0.94 [95% confidence interval (CI) = 0.91–0.97], and the pooled specificity was 0.98 (95% CI = 0.96–099) in a meta-analysis of the retrieved studies and this study. Area under the receiver operating characteristics curve was 0.9906.Conclusions: SISH technique is an effective modality and is comparable with FISH for evaluating HER2 gene amplification in patients with breast carcinoma.

Adiponectin Level and Gene Variability Are Obesity and Metabolic Syndrome Markers in a Young Population

2012-02-27

Background and Aims: Human obesity is accepted as an important risk factor for development of MetS. Adiponectin is linked to central obesity and ADIPOQ variants are promising markers for understanding the genetic base of obesity-related disorders. We performed analyses of adiponectin concentrations and ADIPOQ variants and tested their associations with obesity and MetS in young subjects of Croatian origin.Methods: Biochemical and anthropometric parameters of MetS were obtained for 149 unrelated subjects. Adiponectin levels were measured by ELISA assay. ADIPOQ −11391G>A and −11377C>G were genotyped by real-time PCR.Results: BMI and WC, TG and GLUC showed inverse correlation, whereas HDL-C showed a positive correlation with adiponectin concentrations. For central obesity, we found association with −11377C>G and with −11391G>A polymorphisms. ADIPOQ −11377GG and −11391GA significantly increased the risk for the development of central obesity (OR 5.57 and OR 3.37, respectively). Significant association was found between −11391A, −11377G allele and haplotype and increased TG. −11377C>G and −11391G>A variant were significantly associated with the incidence of MetS. C>G mutation at position −11377 significantly increased the risk of MetS development (OR = 2.93). Compared with the −11391G homozygotes, carriers of the A allele had a significantly increased risk for the development of MetS (OR = 3.15). The test of overall association showed a statistically significant correlation of MetS with −11377C>G and −11391G>A haplotypes (p = 0.008).Conclusions: Analysis of adiponectin concentration and ADIPOQ −11391G>A and −11377C>G gene variants may be clinically meaningful for estimation of MetS risk in a young population.

Association Between Val158Met Functional Polymorphism in the COMT Gene and Risk of Preeclampsia in a Chinese Population

2012-04-03

Background and Aims: The catechol-O-methyltransferase (COMT) gene is a potential candidate in altering risk for preeclampsia due to the important enzymatic effects in the metabolism of steroid hormones. It contains a non-synonymous G–A base change at codon 158 in the membrane bound isoform, which leads to a valine-to-methionine amino acid substitution. In the soluble isoform the polymorphism rs4680 is located in codon 108. The variant allele is the Met (A) allele and the Val (G) allele is the wild type allele. Despite its previously reported association with preeclampsia in genotypes in three selected ethnic groups, further studies in other populations are required.Methods: We genotyped the Val158Met polymorphism in the COMT gene by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) analysis in a Chinese population.Results: In the case–control study that included 187 patients with preeclampsia (cases) and 189 normal subjects (controls), the AA genotype and variant Met allele frequencies of Val158Met in the COMT gene were significantly higher in patients with preeclampsia than those in the control group (both p <0.05). The odds ratio for the risk of preeclampsia was 2.395 [95% confidence interval (CI): 1.061–5.408] in women homozygous for the variant COMT allele (χ2 = 4.649, p = 0.031). Furthermore, it showed that obese women homozygous for the variant COMT allele (Met/Met) had higher diastolic blood pressure levels during pregnancy than wild-type homozygotes (Val/Val) (p = 0.034).Conclusions: Our study provided evidence in favor of COMT being a candidate gene for conferring genetic susceptibility to preeclampsia in a South West Chinese population.

Airflow Obstruction in Never Smokers in Five Latin American Cities: The PLATINO Study

2012-04-03

Background: Although chronic obstructive pulmonary disease (COPD) is mostly related to tobacco smoking, a variable proportion of COPD occurs in never smokers. We investigated differences between COPD in never smokers compared with smokers and subjects without COPD.Methods: PLATINO is a cross-sectional population-based study of five Latin American cities. COPD was defined as postbronchodilator FEV1/FVC <0.70 and FEV1 <80% of predicted values.Results: Among 5,315 subjects studied, 2278 were never smokers and 3036 were ever smokers. COPD was observed in 3.5% of never smokers and in 7.5% of ever smokers. Never smokers with COPD were most likely older and reported a medical diagnosis of asthma or previous tuberculosis. Underdiagnosis was as common in obstructed patients who never smoked as in ever smokers.Conclusions: Never smokers comprised 26% of all individuals with airflow obstruction. Obstruction was associated with female gender, older age and a diagnosis of asthma or tuberculosis.

Association Between MTHFR C677T Polymorphism and Diabetic Nephropathy in a Chinese Population: Appraisal of a Recent Meta-analysis

Yan-Feng Zou — 2012-02-27

I read with great interest the recent paper by Cui et al. . The authors performed a meta-analysis of 12 case-control studies to examine the association of the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene with diabetes mellitus (DM) or diabetic nephropathy (DN) in a Chinese population. Their meta-analysis suggests that the C677T polymorphism in MTHFR gene may be a risk factor for DN, but not for DM, in a Chinese population. It is an interesting study. Nevertheless, I would like to raise several concerns related to this article.

Reply: Is the C677T Polymorphism in Methylenetetrahydrofolate Reductase Gene a Risk Factor for Diabetic Nephropathy or Diabetes Mellitus in a Chinese Population?

2012-03-14

We are grateful to the authors who shared their comments and suggestions about the Letter to the Editor regarding several limitations of our meta-analysis . After reviewing the author’s comments and carefully checking the original studies, we are pleased to reply and to clarify the author’s questions, one by one, related to our paper published in Archives of Medical Research .

Need for Clarification of Data in the Recent Meta-analysis About 1858 C/T Polymorphism of the Protein Tyrosine Phosphatase Nonreceptor 22 Gene and Rheumatoid Arthritis Risk

Zhi-Hua Zhang, Lin-Sheng Yang, Ye-Huan Sun — 2012-04-05

Recently, we have read with great interest the article “1858 C/T Polymorphism of the Protein Tyrosine Phosphatase Nonreceptor 22 Gene and Rheumatoid Arthritis Risk in Europeans: A Meta-analysis based on 19 Case-Control Studies” published online in the December 2011 issue of Archives of Medical Research . The study of Nong et al. performed a meta-analysis to estimate the association between the 1858 C/T polymorphism of the PTPN22 gene and rheumatoid arthritis (RA) risk in Europeans, and the results showed that PTPN22 1858T allele was significantly associated with increased risk of RA.

Reply: Clarification of Data from 1858 C/T Polymorphism of the Protein Tyrosine Phosphatase Nonreceptor 22 Gene and Rheumatoid Arthritis Risk in Europeans: A Meta-analysis

Ren Ke-Wei, Mi Yuan-Yuan, Xu Nan-Wei — 2012-04-05

Thank you very much for forwarding me the Letter to the Editor. After reviewing the comments and checking the original papers and the raw data carefully, we are glad to reply and to clarify their questions one by one.

Editorial Board

2012-02-01

Archives of Medical Research

Early Lymphoid Development and Microenvironmental Cues in B-cell Acute Lymphoblastic Leukemia

Osteopontin Upregulation in Atherogenesis Is Associated with Cellular Oxidative Stress Triggered by the Activation of Scavenger Receptors

Distortion of β-globin Chain of Hemoglobin Alters the Pathway of Erythrocytic Glucose Metabolism Through Band 3 Protein

Association of Promoter Polymorphisms in MMP2 and TIMP2 with Prostate Cancer Susceptibility in North India

Intermittent Maximal Exercise Improves Attentional Performance Only in Physically Active Students

Lymphatic Microvessel Density Combined with CT Used in the Diagnosis of Mediastinal and Hilar Lymph Node Metastasis of Non-small Cell Lung Cancer

Effectiveness of Silver-enhanced In Situ Hybridization for Evaluating HER2 Gene Status in Invasive Breast Carcinoma: A Comparative Study

Adiponectin Level and Gene Variability Are Obesity and Metabolic Syndrome Markers in a Young Population

Association Between Val158Met Functional Polymorphism in the COMT Gene and Risk of Preeclampsia in a Chinese Population

Airflow Obstruction in Never Smokers in Five Latin American Cities: The PLATINO Study

Association Between MTHFR C677T Polymorphism and Diabetic Nephropathy in a Chinese Population: Appraisal of a Recent Meta-analysis

Reply: Is the C677T Polymorphism in Methylenetetrahydrofolate Reductase Gene a Risk Factor for Diabetic Nephropathy or Diabetes Mellitus in a Chinese Population?

Need for Clarification of Data in the Recent Meta-analysis About 1858 C/T Polymorphism of the Protein Tyrosine Phosphatase Nonreceptor 22 Gene and Rheumatoid Arthritis Risk

Reply: Clarification of Data from 1858 C/T Polymorphism of the Protein Tyrosine Phosphatase Nonreceptor 22 Gene and Rheumatoid Arthritis Risk in Europeans: A Meta-analysis

Editorial Board

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