bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Endothelial Nitric Oxide Synthase Gene Polymorphisms in Predicting Aneurysmal Subarachnoid Hemorrhage in South Indian Patients
Authors: Koshy Linda , Easwer H. V. , Neetha N. V. , Natarajan Chandrasekhar , Bhattacharya R. N. , Banerjee Moinak
Published: June 2013

Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been implicated as predisposing genetic factors that can predict aneurysmal subarachnoid hemorrhage (aSAH), but with controversial results from different populations. Using a case‐control study design, we tested the hypothesis whether variants in eNOS gene can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We enrolled 122 patients, along with 224 ethnically matched controls. We screened the intron‐4 27‐bp VNTR, the promoter T‐786C and the exon‐7 G894T SNPs in the eNOS gene. We found marked interethnic differences in the genotype distribution of eNOS variants when comparing the South Indian population with the reported frequencies from Caucasian and Japanese populations. Genotype distributions in control and patient populations were found to be in Hardy‐Weinberg equilibrium. In patients, the allele, genotype and estimated haplotype frequencies did not differ significantly from the controls. Multiple logistic regression indicated hypertension and smoking as risk factors for the disease, however the risk alleles did not have any interaction with these risk factors. Although the eNOS polymorphisms were not found to be a likely risk factor for aSAH, the role of factors such as ethnicity, gender, smoking and hypertension should be evaluated cautiously to understand the genotype to phenotype conversion.
MTHFR Genetic Polymorphism As a Risk Factor in Egyptian Mothers with Down Syndrome Children
Authors: Meguid Nagwa A. , Dardir Ahmed A. , Khass Mohamed , Hossieny Lamia El , Ezzat Afaf , Awady Mostafa K. El
Published: June 2013

Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93–5.89) and 2.75 (95% CI 0.95–12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work.
Detecting Temporal and Spatial Effects of Epithelial Cancers with Raman Spectroscopy
Authors: Keller Matthew D. , Kanter Elizabeth M. , Lieber Chad A. , Majumder Shovan K. , Hutchings Joanne , Ellis Darrel L. , Beaven Richard B. , Stone Nicholas , Mahadevan-Jansen Anita
Published: June 2013

Epithelial cancers, including those of the skin and cervix, are the most common type of cancers in humans. Many recent studies have attempted to use Raman spectroscopy to diagnose these cancers. In this paper, Raman spectral markers related to the temporal and spatial effects of cervical and skin cancers are examined through four separate but related studies. Results from a clinical cervix study show that previous disease has a significant effect on the Raman signatures of the cervix, which allow for near 100% classification for discriminating previous disease versus a true normal. A Raman microspectroscopy study showed that Raman can detect changes due to adjacent regions of dysplasia or HPV that cannot be detected histologically, while a clinical skin study showed that Raman spectra may be detecting malignancy associated changes in tissues surrounding nonmelanoma skin cancers. Finally, results of an organotypic raft culture study provided support for both the skin and the in vitro cervix results. These studies add to the growing body of evidence that optical spectroscopy, in this case Raman spectral markers, can be used to detect subtle temporal and spatial effects in tissue near cancerous sites that go otherwise undetected by conventional histology.
K‐RAS and P53 Mutations in Association with COX‐2 and Htert Expression and Clinico‐Pathological Status of Nsclc Patients
Authors: Stražišar Mojca , Rott Tomaž , Glavač Damjan
Published: June 2013

We evaluated the occurrence of mutations in P53, K‐RAS, COX‐2, expression of COX‐2 and hTERT and relations among clinicopathological signs. P53 mutations were identified in 34.4% of tumours, the majority of them occurring in SCC (squamous cell carcinoma, 55.6%). K‐RAS was mutated in 12.2% of NSCLC tumours, the majority of the mutations being found in ADC (adenocarcinoma, 27.0%). Mutational screening detected three different COX‐2 mutations and five different P53 mutations, published for the first time. With RT‐PCR we observed that the expression of the tested genes, hTERT and COX‐2, was highly significant for ADC (p < 0.01) and SCC (p < 0.05). Statistical analysis of the combined results revealed significant
correlation between expression of COX‐2 and hTERT (p < 0.001), hTERT expression and staging (p < 0.05) and survival (p <
0.01). A positive correlation between COX‐2 expression and K‐RAS mutation (p <0.05) was also observed. This study provides
insight into associations between the analysed biomarkers and the clinical‐pathological data of the patients.
Stem Cells in Spinal Cord Injury
Authors: Wrathall Jean R. , Lytle Judith M.
Published: June 2013

Traumatic injury to the adult spinal cord results in a massive loss of cells and permanent functional deficits. However, recent studies demonstrate that there is a proliferative response of endogenous glial precursors and progenitors and perhaps also pluripotent neural stem cells. These cells may prove to be an important new therapeutic target to improve recovery after injury to the spinal cord and brain.
Expression of MAGE‐A12 in Oral Squamous Cell Carcinoma
Authors: Mollaoglu Nur , Vairaktaris Eleftherios , Nkenke Emeka , Neukam Friedrich W. , Ries Jutta
Published: June 2013

Melanoma associated‐A antigens (MAGE‐A) are silent in normal tissues except testis. However, they are activated in
a variety of different tumors. Thus, their expression is highly specific to cancer cells. Reverse transcription‐nested polymerase
chain reaction (RT‐nPCR) is a highly sensitive technique that has been used successfully for the detection ofMAGE genes in tissue
samples. The aim of the study is to analyze the expression rate of MAGE‐A12 in oral squamous cell carcinoma (OSCC) using a
high sensitive RT‐nPCR. Total of 57 tissue samples obtained from patients with OSCC and 20 normal oral mucosal (NOM) probes
of otherwise healthy volunteers were included to this study. No expression of MAGE‐A12 was observed in the non‐neoplastic
NOM tissues. MAGE‐A12 was expressed in 49.1% of the investigated tumor samples. The correlation between malignant lesion
and MAGE‐A12 detection was significant (p < 0.001). It is concluded that results of this study may indicate MAGE‐A12 as
a useful additional diagnostic marker especially for the early detection of OSCC distinguishing neoplastic transformation and
detection of occult and/or rare disseminated cancer cells. In addition, MAGE‐A12 expression in OSCC may also determine a
new immunotherapeutic target and might be warranted to develop vaccine for OSCC.
Chromosome 9p21.3 is Associated with Early‐Onset Coronary Heart Disease in the Irish Population
Authors: Meng Weihua , Hughes Anne E. , Patterson Chris C. , Belton Christine , Kee Frank , McKeown Pascal P.
Published: June 2013

Coronary heart disease (CHD) remains a leading cause of death across the world. A region on chromosome 9p21.3 has been recently reported to be associated with CHD. We evaluated 3 SNPs and 3 common haplotypes in the 9p21.3 region in 1494 individuals from 580 Irish families, where at least 1 member had early‐onset (males ≤55yr, females ≤60yr) CHD. Genotypes were determined by multiplex SNaPshot technology. Using the combined TDT/S‐TDT test, the 3 single nucleotide polymorphisms (SNP), rs10757274, rs2383206 and rs1333049, were strongly associated with early‐onset CHD (p = 2.7 × 10-6, 2.7 × 10-6, 3.8 × 10-7, respectively). Analysis of haplotypes by the TRANSMIT program also showed that the GGC haplotype was associated with early‐onset CHD (p = 7.9 × 10-7). In conclusion, using a family‐based approach in the Irish population, we have confirmed previous reports of association between a region on chromosome 9p21.3 and early‐onset CHD.
Stem Cells in Niemann‐Pick Disease
Authors: Kim Sun-Jung , Park Joon-Suk , Kang Kyung-Sun
Published: June 2013

Neural stem cells are multi‐potent and able to self renew to maintain its character throughout the life. Loss of self renewal ability of stem cells prevents recovery or replacement of cells damaged by disease with new cells. The Niemann‐Pick type C1 (NPC1) disease is one of the neurodegenerative diseases, caused by a mutation of NPC1 gene which affects the function of NPC1 protein. We reported that NPC 1 gene deficiency could lead to lack of the self renewal ability of neural stem cells in Niemann pick type C disease. We also investigated many genes which are involved in stem cells proliferation and differentiation by gene profile in NPC mice.

Diagnosis of NPC disease is difficult because it is accompanied by complicated symptoms and the fact that there is no effective treatment for NPC patients. Studies of these stem cells and their relationship to Niemann pick type C disease will provide new biomarkers for early diagnosis as well as a potential cure by use of targeted therapeutics for Niemann pick type C disease.
Correlates of High Serum C‐Reactive Protein Levels in a Socioeconomically Disadvantaged Population
Authors: Zhang Xianglan , Shu Xiao-Ou , Signorello Lisa B. , Hargreaves Margaret K. , Cai Qiuyin , Linton MacRae F. , Fazio Sergio , Zheng Wei , Blot William J.
Published: June 2013

Individuals from low socioeconomic backgrounds are disproportionately affected by the burden of cardiovascular disease (CVD), yet data regarding risk factors in this population are lacking, particularly regarding emerging biomarkers of CVD such as C‐reactive protein (CRP). We measured high‐sensitivity CRP and examined its association with demographic and lifestyle factors in a sample of 792 participants aged 40–79 years from the Southern Community Cohort Study, which has an over‐representation of socioeconomically disadvantaged individuals (over 60% with a total annual household income <$15,000). We found that within this population the prevalence of elevated CRP (>3 mg/L) varied significantly by sex, race, smoking status, and body mass index (BMI). The multivariable‐adjusted prevalence odds ratios (ORs) (95% CIs) for having elevated CRP were 1.6 (1.1–2.3) for women vs. men, 1.4 (0.9–2.0) for African Americans vs. whites, 2.3 (1.4–3.8) for African American women vs. white men, 1.8 (1.2–2.7) for current smokers vs. non‐smokers, and 4.2 (2.7–6.6) for obese (BMI 30.0–44.9 kg/m2) vs. healthy‐weight (BMI 18.3–24.9 kg/m2) participants. Further stratified analyses revealed that the association between BMI and elevated CRP was stronger among African Americans than whites and women than men, with prevalence ORs (95% CI) comparing obese vs. healthy‐weight categories reaching 22.8 (7.1–73.8) for African American women. In conclusion, in this socioeconomically disadvantaged population, sex, race, smoking, and BMI were associated with elevated CRP. Moreover, inflammatory response to obesity differed by race and sex, which may contribute to CVD disparities.
The Application of Biomarkers of Spermatogonial Stem Cells for Restoring Male Fertility
Authors: Ebata Kevin T. , Yeh Jonathan R. , Zhang Xiangfan , Nagano Makoto C.
Published: June 2013

Spermatogonial stem cells (SSCs) are defined by their ability to both self‐renew and produce differentiated germ cells that will develop into functional spermatozoa. Because of this ability, SSCs can reestablish spermatogenesis after testicular damage caused by cytotoxic agents or after transplantation into an infertile recipient. Therefore, SSCs are an important target cell for restoring male fertility, particularly for cancer patients who have to undergo sterilizing cancer therapies. In the mouse, the identification of SSC markers allows for the isolation of a highly enriched population of stem cells. This enriched stem cell population can be expanded in culture for an indefinite period of time, cryopreserved, and transplanted into infertile recipients to restore fertility. Thus, the identification of markers and the establishment of a long‐term culture system for human SSCs will be crucial for realizing the potential of these cells in a clinical setting. In this article, we focus on the markers that have been identified for mouse SSCs and discuss how human SSC markers may be used in the restoration of fertility.
C‐338A Polymorphism of the Endothelin‐Converting Enzyme (ECE‐1) Gene and the Susceptibility to Sporadic Late‐Onset Alzheimer’s Disease and Coronary Artery Disease
Authors: Scacchi Renato , Gambina Giuseppe , Broggio Elisabetta , Ruggeri Maria , Corbo Rosa Maria
Published: June 2013

The human endothelin‐converting enzyme (ECE) is involved in β‐amyloid synthesis and regulation of the endothelin‐1 (ET‐1) vasoconstricting peptide. We investigated the distribution of the C‐338A polymorphism of the ECE‐1b gene in sporadic late‐onset Alzheimer’s disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C‐338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively). The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.
Sialic Acid and Sialidase Activity in Acute Stroke
Authors: Nanetti L. , Vignini A. , Raffaelli F. , Taffi R. , Silvestrini M. , Provinciali L. , Mazzanti L.
Published: June 2013

Stroke is a heterogeneous syndrome caused by multiple disease mechanisms, resulting in a disruption of cerebral blood flow with subsequent tissue damage. It is well known that erythrocytes have a large amount of sialic acid and could represent a model to investigate changes occurring in a pathology like stroke. The aim of this study was to investigate a possible relationship among erythrocyte membrane, plasma and sialic acid content. The possible impact of the sialic acid content and the activity of sialidase on stroke severity was also evaluated.

The study population consisted of 54 patients with a first stroke and of 53 age‐and sex matched healthy volunteers.

The total bound sialic acid was substantially decreased in patients. There was a significant correlation between the sialidase activity values and the severity of the neurological deficit defined by the National Institute of Health Stroke Scale.

This study shows that low sialic acid erythrocyte concentrations with contemporary high sialic acid plasma levels and elevated sialidase activity can be considered as markers of ischemic stroke. Further investigations are needed to clarify the possible role of these biochemical changes in producing and sustaining cerebral ischemic damage.
A Common Polymorphism G‐50T in Cytochrome P450 2J2 Gene Is Associated with Increased Risk of Essential Hypertension in a Russian Population
Authors: Polonikov Alexey V. , Ivanov Vladimir P. , Solodilova Maria A. , Khoroshaya Irina V. , Kozhuhov Mikhail A. , Ivakin Vladimir E. , Katargina Ludmila N. , Kolesnikova Ol′ga E.
Published: June 2013

The present study was designed to test whether common polymorphism G‐50T within the promoter of human CYP2J2 gene is associated with increased risk of essential hypertension in a Russian population. We studied 576 unrelated subjects, including 295 patients with hypertension and 281 healthy subjects. Genotyping for polymorphism G‐50T of the CYP2J2 gene was performed by polymerase chain reaction and restriction fragment length polymorphism techniques. The frequency of a −50T variant allele of CYP2J2 gene was significantly higher in patients with hypertension versus healthy controls (OR 4.03 95%CI 1.80–9.04 p=0.0004). The association of a −50GT genotype with hypertension remained significant after adjustment for age, gender and family history of hypertension by multivariate logistic regression (OR 4.78 95%CI 1.87–12.27 p=0.001). It has been found that OR for −50GT genotype × gender interaction (OR 4.48 95%CI 1.93–10.39 p=0.00048) was slightly higher than OR for −50GT genotype (OR 4.43 95%CI 1.91–10.29 p=0.00052), suggesting a weak effect of gender on the risk of hypertension in the heterozygous carriers of −50GT genotype. A family history of hypertension has no effect on the association between a −50GT genotype and hypertension. In present study we demonstrate for the first time that a CYP2J2*7 allele of the CYP2J2 gene is clearly associated with an increased risk of essential hypertension. Furthermore, this study highlights the importance of P‐450 epoxygenase pathway of arachidonic acid metabolism in the pathogenesis of hypertensive disease.
Manganese Superoxide Dismutase Gene Polymorphism (V16A) is Associated with Diabetic Retinopathy in Slovene (Caucasians) Type 2 Diabetes Patients
Authors: Petrovič Mojca Globočnik , Cilenšek Ines , Petrovič Daniel
Published: June 2013

Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy. Two candidate genes that affect the oxidative stress are manganese mitochondrial superoxide dismutase (Mn‐SOD) and endothelial nitric oxide synthase (eNOS). The aim of the present study was to examine the role of the V16A polymorphism of the Mn‐SOD gene and the 4a/b polymorphism of the eNOS gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes.

In this cross sectional case‐control study 426 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 283 patients with diabetic retinopathy and the control group of 143 subjects with type 2 diabetes of duration of more than 10 years who had no clinical signs of diabetic retinopathy.

A significantly higher frequency of the VV genotype of the V16A polymorphism of the Mn‐SOD was found in patients with diabetic retinopathy compared to those without diabetic retinopathy (OR=2.1, 95% CI = 1.2–3.4; p = 0.006), whereas the 4a/b polymorphism of the eNOS gene failed to yield an association with diabetic retinopathy.

We may conclude that the VV genotype of the V16A polymorphism of the Mn‐SOD gene was associated with diabetic retinopathy in Caucasians with type 2 diabetes, therefore it might be used as a genetic marker of diabetic retinopathy in Caucasians.
Monocarboxylate Transporters 1 and 4 Are Associated with CD147 in Cervical Carcinoma
Authors: Pinheiro Céline , Longatto-Filho Adhemar , Pereira Sônia Maria Miranda , Etlinger Daniela , Moreira Marise A. R. , Jubé Luiz Fernando , Queiroz Geraldo Silva , Schmitt Fernando , Baltazar Fátima
Published: June 2013

Due to the highly glycolytic metabolism of solid tumours, there is an increased acid production, however, cells are able to maintain physiological pH through plasma membrane efflux of the accumulating protons. Acid efflux through MCTs (monocarboxylate transporters) constitutes one of the most important mechanisms involved in tumour intracellular pH maintenance. Still, the molecular mechanisms underlying the regulation of these proteins are not fully understood. We aimed to evaluate the association between CD147 (MCT1 and MCT4 chaperone) and MCT expression in cervical cancer lesions and the clinico-pathological significance of CD147 expression, alone and in combination with MCTs. The series included 83 biopsy samples of precursor lesions and surgical specimens of 126 invasive carcinomas. Analysis of CD147 expression was performed by immunohistochemistry. CD147 expression was higher in squamous and adenocarcinoma tissues than in the non-neoplastic counterparts and, importantly, both MCT1 and MCT4 were more frequently expressed in CD147 positive cases. Additionally, co-expression of CD147 with MCT1 was associated with lymph-node and/or distant metastases in adenocarcinomas. Our results show a close association between CD147 and MCT1 and MCT4 expressions in human cervical cancer and provided evidence for a prognostic value of CD147 and MCT1 co-expression.
LRRK2p.G2019S Mutation Is Not Common among Alzheimer’s Disease Patients in Brazil
Authors: Santos-Rebouças Cíntia Barros , Abdalla Cláudia Bueno , Martins Paloma Águia , Baldi Fábio José Rodrigues , Santos Jussara Mendonça , Motta Luciana Branco , de Borges Margarete Borges , Souza Dorotéia Rossi Silva , de Souza Pinhel Marcela Augusta , Laks Jerson , Pimentel Márcia Mattos Gonçalves
Published: June 2013

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson’s Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer’s Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.
Myocardial Biomarkers for Prediction of Cardiovascular Disease
Authors: Sundström Johan
Published: June 2013

The identification of those persons in the population who have the highest risk of future cardiovascular events is important for targeting intensive preventive efforts. This can be reliably done using a handful of long since established risk factors. The unmet need for new molecular biomarkers for prediction of cardiovascular events in the general population is therefore low. In order for a new biomarker to be used clinically for risk prediction, a statistically significant association of levels of the biomarker to adverse outcome is not enough, but the biomarker should also be demonstrated to add discriminative capacity beyond established risk factors. In contrast to the limited value of new biomarkers for risk prediction, their usefulness for unraveling the pathophysiology of cardiovascular disease is large. The myocardium is the source of a vast number of interesting biomarkers, of which a few may be useful for risk prediction in the general population. Two of these, troponin-I and the N-terminal fragment of brain natriuretic peptide, have passed tests of added discriminatory value. Numerous other biomarkers produced by cardiomyocytes or non-cardiomyocytes in the myocardium are promising, and if they are not proven useful for risk prediction, they will unquestionably enhance our understanding of cardiovascular disease.
Molecular Network Analysis Suggests Aberrant CREB-Mediated Gene Regulation in the Alzheimer Disease Hippocampus
Authors: Satoh Jun-ichi , Tabunoki Hiroko , Arima Kunimasa
Published: June 2013

The pathogenesis of Alzheimer disease (AD) involves the complex interaction between genetic and environmental factors affecting multiple cellular pathways. Recent advances in systems biology provide a system-level understanding of AD by elucidating the genome-wide molecular interactions. By using KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the curated knowledgebase, we characterized molecular network of 2,883 all stages of AD-related genes (ADGs) and 559 incipient AD-related genes (IADGs) identified by global gene expression profiling of the hippocampal CA1 region of AD brains in terms of significant clinical and pathological correlations (Blalock et al., Proc Natl Acad Sci USA 101: 2173-2178, 2004). By the common upstream search, KeyMolnet identified cAMP-response element-binding protein (CREB) as the principal transcription factor exhibiting the most significant relevance to molecular networks of both ADGs and IADGs. The CREB-regulated transcriptional network included upregulated and downregulated sets of ADGs and IADGs, suggesting an involvement of generalized deregulation of the CREB signaling pathway in the pathophysiology of AD, beginning at the early stage of the disease. To verify thein silicoobservationsin vivo, we conducted immunohistochemical studies of 11 AD and 13 age-matched control brains by using anti-phoshorylated CREB (pCREB) antibody. An abnormal accumulation of pCREB imunoreactivity was identified in granules of granulovacuolar degeneration (GVD) in the hippocampal neurons of AD brains. These observations suggest that aberrant CREB-mediated gene regulation serves as a molecular biomarker of AD-related pathological processes, and support the hypothesis that sequestration of pCREB in GVD granules is in part responsible for deregulation of CREB-mediated gene expression in AD hippocampus.
Phenotype Variation in Human Immunodeficiency virus Type 1 Transmission and Disease Progression
Authors: Cavarelli Mariangela , Scarlatti Gabriella
Published: June 2013

Human immunodeficiency virus type I (HIV-1) infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly CCR5 and CXCR4. Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. Thus, R5 and X4 virus use respectively CCR5 and CXCR4, whereas R5X4 virus can use either CCR5 or CXCR4. This review describes the central role played by co-receptor expression and usage for HIV-1 cell tropism, transmission and pathogenesis. We discuss various hypotheses proposed to explain the preferential transmission of R5 viruses and the mechanisms driving the change of HIV-1 co-receptor usage in the course of infection. Recent insights in the intrinsic variability of R5 viruses and their role in influencing disease progression in both adults and children are also discussed.
XbaI GLUT1 Gene Polymorphism and the Risk of Type 2 Diabetes with Nephropathy
Authors: Stefanidis Ioannis , Kytoudis Kyriakos , Papathanasiou Afroditi A. , Zaragotas Dimitrios , Melistas Lambros , Kitsios Georgios D. , Yiannakouris Nikolaos , Zintzaras Elias
Published: June 2013

Altered expression of the facilitated glucose transporter GLUT1 affects pathways implicated in the pathogenesis of diabetic nephropathy. There is indication that variation of GLUT1 gene (SLC2A1) contributes to development of microangiopathy in diabetes mellitus type 2 (DM) patients. A genetic association study involving Caucasians was carried out to investigate the role of XbαI polymorphism in the GLUT1 gene in diabetic nephropathy (DN). Study population (n= 240) consisted of 148 unrelated patients with DM (92 cases with diabetic nephropathy (DN)), and of 92 matched healthy control subjects. Diabetic nephropathy was defined as persistent albuminuria (> 300 mg/24 h) and/or renal failure, in the absence of non-diabetes induced renal disease. The analysis showed that the risk of developing DM and DN in XbaI(−) carriers, when healthy individuals were considered as controls, was two-fold: odds ratio (OR) 2.08 [95% confidence interval (1.14–3.79)]. However, there was no evidence of association between XbaI(−) and DN when patients with DM and without DN were considered as controls: OR = 1.12 (0.55–2.26). Thus, the GLUT1 XbaI(−) allele is associated with DM, and possibly with a more severe form of the disease that can lead to development of DN.
Metastatic Breast Cancer Survival according to HER2 and Topo2a Gene Status
Authors: Todorović-Raković N. , Nešković-Konstantinović Z. , Nikolić-Vukosavljević D.
Published: June 2013

The aim of this study was to determine the relationship between amplification of HER2 (Human epidermal growth factor receptor 2) and Topo2a (topoisomerase 2a) and their influence on prognosis in metastatic breast cancer (MBC) patients. Amplification of both HER2 and Topo2a genes was determined by chromogenic in situ hybridization (CISH) in primary tumor tissue of 71 MBC patients. Starting point for follow-up was the time of diagnosis of metastatic disease. Although there was significant correlation between HER2 amplification and Topo2a alterations, Topo2a amplification was not strictly related to HER2 amplification. Follow-up of patients showed that there was no difference in MBC survival between HER2-nonamplified and HER2-amplified patients for subgroup as whole, but there was significant difference in MBC survival between patients with and without Topo2a amplification. HER2 amplification showed prognostic value in subgroups of patients, as well as Topo2a. Combination of these two genes with different status (nonamplified, amplified, coamplified) indicated that they might have additive effect. Also, it has been shown that Topo2a-amplified cases have poorer survival than Topo2a-nonamplified, when treated with CMF therapy.

Topo2a amplification seems to be more promising biomarker of MBC survival, than HER2, and potential marker of resistance to CMF therapy.
Serum Cystatin C Is a Determinant of Paraoxonase Activity in Hemodialyzed and Renal Transplanted Patients
Authors: Varga Éva , Seres Ildikó , Harangi Mariann , Sztanek Ferenc , Asztalos László , Lõcsey Lajos , Borbás Béla , Szegedi János , Kárpáti István , Paragh Gyórgy
Published: June 2013

Background: Human paraoxonase-1 (PON1) inhibits LDL-oxidation and atherogenesis, and possesses lactonase activity. Decreased PON1 activity was found in hemodialyzed and renal transplanted patients. Cystatin C plays a protective role in atherosclerosis, and is a new, sensitive marker of renal function. The relationship between these two markers in renal failure has not been investigated.

Aims: The goal of this study was to clarify the relationship between PON1 activity, cystatin C and homocysteine in chronic renal failure. We also determined the levels of oxidatively modified LDL (oxLDL) and thiobarbituric acid reactive substances (TBARS) to characterize lipid peroxidation.

Patients and methods: 74 hemodialized (HD), 171 renal transplanted patients (TRX), and 110 healthy controls (C) were involved in the study. PON1 activity and TBARS levels were measured spectrophotometrically. OxLDL level was determined with sandwich ELISA.

Results: There was a negative correlation between PON1 activity and cystatin C level. Homocysteine level correlated negatively with PON1 activity, and positively with cystatin C level. OxLDL and TBARS levels were significantly higher in the HD and TRX groups compared to C.

Conclusions: Cystatin C may be a good predictive factor not only for homocysteine levels but for the antioxidant status in patients with renal failure and renal transplantation.
Soluble CD26 Levels and Its Association to Epidemiologic Parameters in a Sample Population
Authors: De Chiara Loretta , Rodríguez-Piñeiro Ana M. , Cordero Oscar J. , Rodríguez-Berrocal Francisco J. , Ayude Daniel , Rivas-Hervada Francisco J. , de la Cadena María Páez
Published: June 2013

Introduction: Previous studies have suggested the use of soluble CD26 (sCD26) as a tumour marker for the detection of colorectal cancer (CRC) and advanced adenomas. The aim of this study was to assess the sCD26 concentration in a large cohort to evaluate its association to epidemiologic parameters and CRC-related symptoms/pathologies.

Subjects and methods: Serum samples were collected from 2,754 putatively healthy individuals with ages ranging from 30–65 years, and with personal or familial history of polyps, CRC and/or CR symptoms. sCD26 levels were measured by ELISA.

Results: No association was found between the sCD26 concentration and age (< 50 and ≥ 50), the personal or familial history of polyps or CRC, rectal bleeding, haemorrhoids or diverticula. However, sCD26 was related to non-inflammatory benign pathologies (excluding rectal bleeding, changes in bowel habits, haemorrhoids, diverticula) and to inflammatory benign pathologies.

Discussion: Our results confirm that the sCD26 can be easily offered and evaluated in a large cohort. Additionally, the validation of sCD26 as a tumour marker for screening and case-finding purposes requires a further comparison with an established non-invasive test like the faecal occult blood.
Functional Haplotypes in the Promoter Region of Transcription FactorNrf2in Chronic Obstructive Pulmonary Disease
Authors: Hua Chung-Ching , Chang Liang-Che , Tseng Jo-Chi , Chu Chien-Ming , Liu Yu-Chih , Shieh Wen-Bin
Published: June 2013

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects against oxidative stress which is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). Three single nucleotide polymorphisms and 1 triplet repeat polymorphism are found in the promoter region of theNrf2gene. Molecular haplotyping of theNrf2promoter region was performed using DNA obtained from the peripheral blood of 69 COPD patients. The luciferase activities ofNrf2promoter constructs containing all possible combinations of the 4 polymorphisms were determined and found to differ among the 16 haplotypes.The haplotypes isolated from the subjects were divided into 3 groups (L: low; M: medium; H: high) on the basis of luciferase activities. The proportions of subjects belonging to global initiative for chronic obstructive lung disease stage 3 or 4 decreased from the group with the LL haplotype to that with the HH haplotype. Presence of the LH or MM haplotype (hazard ratio, 3.36; 95% confidence interval, 1.16–9.69), gender (0.13; 0.02–0.67), and post-bronchodilator FEV1value of predicted (0.95; 0.91–0.99) are significant predictors of respiratory failure development.The haplotype of theNrf2gene promoter affects its activity, and is associated with the severity and the development of respiratory failure in COPD.
Functional Inference of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Enzyme Stability as a Potential Risk Factor for Down Syndrome in Croatia
Authors: Vraneković Jadranka , Babić Božović Ivana , Starčević Čizmarević Nada , Buretić-Tomljanović Alena , Ristić Smiljana , Petrović Oleg , Kapović Miljenko , Brajenović-Milić Bojana
Published: June 2013

Understanding the biochemical structure and function of the methylenetetrahydrofolate reductase gene (MTHFR) provides new evidence in elucidating the risk of having a child with Down syndrome (DS) in association with two commonMTHFRpolymorphisms, C677T and A1298C. The aim of this study was to evaluate the risk for DS according to the presence ofMTHFRC677T and A1298C polymorphisms as well as the stability of the enzyme configuration. This study included mothers from Croatia with a liveborn DS child (n= 102) or DS pregnancy (n= 9) and mothers with a healthy child (n= 141).MTHFRC677T and A1298C polymorphisms were assessed by PCR-RFLP. Allele/genotype frequencies differences were determined using χ2test. Odds ratio and the 95% confidence intervals were calculated to evaluate the effects of different alleles/genotypes. No statistically significant differences were found between the frequencies of allele/genotype or genotype combinations of theMTHFRC677T and A1298C polymorphisms in the case and the control groups. Additionally, the observed frequencies of the stable (677CC/1298AA, 677CC/1298AC, 677CC/1298CC) and unstable (677CT/1298AA, 677CT/1298AC, 677TT/1298AA) enzyme configurations were not significantly different. We found no evidence to support the possibility thatMTHFRpolymorphisms and the stability of the enzyme configurations were associated with risk of having a child with DS in Croatian population.
Analysis of Osteocalcin as a Candidate Gene for Type 2 Diabetes (T2D) and Intermediate Traits in Caucasians and African Americans
Authors: Das Swapan K. , Sharma Neeraj K. , Elbein Steven C.
Published: June 2013

Recent studies in mice and human identified osteocalcin (OCN) as a bone-derived hormone that modulates insulin secretion and insulin sensitivity. OCN is synthesized by the bone gamma-carboxyglutamate protein (BGLAP) gene located in the well replicated region of type 2 diabetes (T2D) linkage on chromosome 1q22. We resequencedBGLAPgene in 192 individuals with T2D and performed case-control studies in 766 Caucasian (461 T2D and 305 controls) and 563 African American individuals (371 T2D and 192 controls). Metabolic effects ofBGLAPvariants were examined in 127 nondiabetic members of Caucasian T2D families and in 498 unrelated nondiabetic African American and Caucasian individuals.BGLAPexpression was tested in transformed lymphocytes from 60 Caucasian individuals. We identified 17 single nucleotide polymorphisms (SNPs) in African Americans, but observed only the two known SNPs in Caucasians. No SNP was associated with T2D. Promoter SNP rs1800247 was not associated with metabolic traits including insulin sensitivity (SI) or fasting glucose in either population, but nonsynonymous SNP rs34702397 (R94Q) was nominally associated with SI(uncorrectedp= 0.05) and glucose-mediated glucose disposal (SG; uncorrectedp= 0.03) in African Americans. No SNP altered measures of insulin secretion or obesity, nor wasBGLAPexpression associated with rs1800247. Our study was sufficiently powered to excludeBGLAPvariants as a major risk factor (OR > 1.5) for T2D in Caucasians, but coding variants in exon 4 may alter glucose homeostasis and diabetes risk in African Americans.
Distribution of C-reactive Protein and Its Association with Cardiovascular Risk Factors in a Population-Based Sample of Chinese
Authors: Zhao Yanfang , Wang Rui , Ma Xiuqiang , Yan Xiaoyan , Zhang Zhansai , He Xiang , He Jia
Published: June 2013

C-reactive protein (CRP) levels vary remarkably with ethnic status. Its distribution and correlates should be investigated across diverse populations, and these were limited in a representative Chinese population. We investigated 3133 participants aged 18–80 years in Shanghai, which were sampled using a randomized, stratified, multi-stage sampling method. The distribution of CRP was highly skewed toward a lower level. The median CRP was 0.55 mg/L (0.61 mg/L in males, 0.51 mg/L in females). Participants living in urban region had higher CRP levels than those in rural region (0.67 vs. 0.46 mg/L). CRP levels showed significant correlation with traditional cardiovascular risk factors, and it was most strongly correlated with body mass index. Multivariate logistic regression analyses indicated that elevated CRP (being in the top 15 percentile of CRP; CRP ≥ 2.09 mg/L) was significantly associated with obesity, hypertension, diabetes, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, high triglycerides and cardiovascular disease history. In conclusion, the distribution of CRP in adult Chinese was comparable with that of many other Asian populations but different from that of Western populations. Metabolic impairment was associated with elevated CRP, and CRP levels should be interpreted in conjunction with the lipid profile.
Effect of Genetic Variant (rs11887534) inABCG8Gene in Coronary Artery Disease and Response to Atorvastatin Therapy
Authors: Srivastava Anshika , Garg Naveen , Srivastava Anvesha , Srivastava Kshitij , Mittal Balraj
Published: June 2013

Background:ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms inABCG8gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role ofABCG8D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response.

Methodology:The study included 213 CAD patients and 220 controls. Genotyping ofABCG8D19H polymorphism was done by PCR-RFLP.

Results:Our results showed that ABCG8 ‘H’ allele was conferring significant risk for CAD in a dominant model (OR = 2.54;p= 0.014). This increased risk for CAD was more pronounced in males (OR = 2.69;p= 0.030). No correlation ofABCG8genotypes with the risk factors (diabetes, hypertension and smoking) of CAD was observed. On atorvastatin treatment there was a significant decrease in the LDL-C levels (p= 0.021). However, stepwise multiple regression analysis showed that this decease was not associated withABCG8genetic variant (p= 0.845). Observed determinants of variation in interindividual response to atorvastatin therapy were pre-treatment LDL-C (p= 0.024) and TC (p= 0.017).

Conclusion:Although the genetic variant 19H ofABCG8confers risk for CAD in North Indian population, it is not associated with interindividual response to atorvastatin therapy.
Expression of MicroRNAs in the Urinary Sediment of Patients with IgA Nephropathy
Authors: Wang Gang , Kwan Bonnie Ching-Ha , Lai Fernand Mac-Moune , Chow Kai-Ming , Kam-Tao Li Philip , Szeto Cheuk-Chun
Published: June 2013

Background:Micro-RNAs (miRNAs) regulate one-third of all protein-coding genes and are fundamental in the pathophysiology of a wide range of diseases. We studied the expression of several miRNA species (miR-200 family, miR-205 and miR-192) in the urinary sediment of patients with IgA nephropathy (IgAN).

Methods:We studied 43 patients with biopsy-proven IgAN. Urinary expression of miRNAs was determined and compared to that from 13 healthy controls.

Results:The levels of urinary miR-200a, miR-200b and miR-429, but not miR-200c, miR-141, miR-205, or miR-192, were down-regulated in patients with IgAN. Proteinuria significantly correlated with urinary expression of miR-200a (r= −0.483,P< 0.001), miR-200b (r= −0.448,P= 0.001) and miR-429 (r= −0.466,P= 0.001). Baseline renal function significantly correlated with urinary expression of miR-200b (r= 0.512,P< 0.001) and miR-429 (r= 0.425, P = 0.005). Urinary gene expression of ZEB2 inversely correlated with miR-200b (r= −0.321,P= 0.017); and vimentin expression inversely correlated with that of miR-200a (r= −0.360,P= 0.007), miR-200b (r= −0.416,P= 0.002) and miR-429 (r= −0.375,P= 0.005). After 33.4 ± 12.6 months, the rate of renal function decline significantly correlated with urinary expression of miR-200b (r= 0.316,P= 0.034).

Conclusions:Urinary expression of miR-200a, miR-200b and miR-429 were down-regulated in patients with IgAN, and the degree of reduction correlated with disease severity and rate of progression. The results suggested that these miRNA species might play important roles in the pathophysiology of IgAN. Further studies are needed to clarify the role of urinary miRNA repression as a non-invasive marker of IgAN.
CXCL12/CXCR4-Axis Dysfunctions: Markers of the Rare Immunodeficiency Disorder WHIM Syndrome
Authors: Bachelerie Françoise
Published: June 2013

The WHIM syndrome features susceptibility to human Papillomavirus infection-induced warts and carcinomas, hypogammaglobulinemia, recurrent bacterial infections, B and T-cell lymphopenia, and neutropenia associated with retention of senescent neutrophils in the bone marrow (i.e. myelokathexis). This rare disorder is mostly linked to inherited heterozygous autosomal dominant mutations in the gene encodingCXCR4, a G protein coupled receptor with a unique ligand, the chemokine CXCL12/SDF-1. Some individuals who have full clinical forms of the syndrome carry a wild typeCXCR4gene. In spite of this genetic heterogeneity, leukocytes from WHIM patients share in common dysfunctions of the CXCR4-mediated signaling pathway upon exposure to CXCL12. Dysfunctions are characterized by impaired desensitization and receptor internalization, which are associated with enhanced responses to the chemokine. Our increasing understanding of the mechanisms that account for the aberrant CXCL12/CXCR4-mediated responses is beginning to provide insight into the pathogenesis of the disorder. As a result we can expect to identify markers of the WHIM syndrome, as well as other disorders with WHIM-like features that are associated with dysfunctions of the CXCL12/CXCR4 axis.
The Role ofE. coliInfection in the Pathogenesis of Primary Biliary Cirrhosis
Authors: Bogdanos Dimitrios P. , Baum Harold , Vergani Diego , Burroughs Andrew K.
Published: June 2013

Among various infectious agents possibly involved in the pathogenesis of primary biliary cirrhosis (PBC),Escherichia Coli (E. coli)has received special attention because of epidemiological and experimental evidence linking this bacterium with the disease's development. This review discusses early and more recent epidemiological studies associating recurrent urinary tract infections withE. coliand the development of PBC. We also critically review data provided over the years demonstrating disease-specific humoral and cellular immune responses againstE. coliantigens in patients with PBC. Finally, we assess the relevance of experimental findings reporting cross-reactive immunity between mimicking sequences ofE. coliand the major PBC mitochondrial antigens in the pathogenesis of the PBC. We also address the extent to which molecular mimicry and immunological cross-reactivity can be considered as a critical pathogenic process linking infection with self destruction.