Showing papers in "Disease Markers in 2009"
TL;DR: This review focuses on the molecular mechanisms of the suPAR fragments and the link to the inflammatory process, as this could lead to medical applications in infectious and pathological conditions.
Abstract: soluble urokinase Plasminogen Activator Receptor (suPAR) levels reflect inflammation and elevated suPAR levels are found in several infectious diseases and cancer. suPAR exists in three forms; suPARI-III, suPARII-III and suPARI which show different properties due to structural differences. Studies suggest that full-length suPAR is a regulator of uPAR/uPA by acting as uPA-scavenger, whereas the cleaved suPARII-III act as a chemotactic agent promoting the immune response via the SRSRY sequence in the linker-region. This review focus on the various suPAR fragments and their involvement in inflammation and pathogenic processes. We focus on the molecular mechanisms of the suPAR fragments and the link to the inflammatory process, as this could lead to medical applications in infectious and pathological conditions.
431 citations
TL;DR: ThemiR-31 overexpression may be involved in the development and progression of CRC and the miR-143 andMiR-145 may play a certain role in theDevelopment of colon and/or rectal cancers but not in progression of the disease.
Abstract: We are just beginning to understand how microRNAs (miRNAs) are involved in tumor-related processes in humans. Applying real-time RT-PCR, we investigated the miR-31, miR-143 and miR-145 expression in 98 primary CRC specimens, along with the corresponding normal mucosa specimens, and analyze the relationship of their expression with clinicopathological features. Our results showed the miR-31 expression was up-regulated in CRC compared to normal mucosa (p = 0.001). Furthermore, miR-31 expression was positively related to advanced TNM stage (p = 0.026) and deeper invasion of tumors (p = 0.024). MiR-145 was down-regulated in both colon (p = 0.001) and rectal (p = 0.012) cancer. MiR-143 was only down-regulated in colon cancer (p = 0.023) but not in rectal cancer (p = 0.351). There was no relationship of miR-143 and miR-145 expression with other clinicopathological features (p > 0.05), except that the miR-145 expression was related to cancer site (p = 0.03). In conclusion, the miR-31 overexpression may be involved in the development and progression of CRC. The miR-143 and miR-145 may play a certain role in the development of colon and/or rectal cancers but not in progression of the disease.
205 citations
TL;DR: Using miRNA microarrays and bioinformatic analysis, miRNA expression was analyzed on human MI and foetal hearts compared to healthy adult hearts to determine whether there is any similar expression pattern between MI andfoetal heart, and to identified miRNAs that have not previously been described as dysregulated in cardiovascular diseases.
Abstract: MicroRNAs (miRNAs), small non-coding RNA molecules, are negative regulators of gene expression. Recent studies have indicated their role in various forms of cardiovascular disease. In spite of the number of miRNA microarray analyses performed, little is known about the genome-wide miRNA expression pattern in human myocardial infarction (MI).Using miRNA microarrays and bioinformatic analysis, miRNA expression was analyzed on human MI and foetal hearts compared to healthy adult hearts, to determine whether there is any similar expression pattern between MI and foetal hearts, and to identified miRNAs that have not previously been described as dysregulated in cardiovascular diseases. Of 719 miRNAs analyzed, approximately 50% were expressed in human hearts, 77 miRNAs were absent from all tested tissues and 57 were confidently dysregulated in at least one tested group. Some expression patterns appeared to be similar in MI and foetal hearts. Bioinformatic analysis revealed 10 miRNAs as dysregulated in MI not yet related to cardiovascular disease, and 5 miRNAs previously described only in animal models of cardiovascular diseases. Finally, qRT-PCR analysis confirmed dysregulation of 7 miRNAs, miR-150, miR-186, miR-210, miR-451, and muscle-specific, miR-1 and miR-133a/b; all of these are believed to be involved in various physiological and pathological processes.
139 citations
TL;DR: PCOS and obesity induce an increase in serum inflammatory cardiovascular risk markers, and the precise mechanisms underlying these associations require additional studies to clarify the state of the cardiovascular system in women with PCOS compared with controls.
Abstract: Background: Women with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance (IR) and related disorders. Elevated serum levels of high sensitivity CRP (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) reflect low-grade chronic inflammation and have been associated with several insulin-resistant states; they are useful cardiovascular risk markers. The objective of this study was to investigate whether soluble inflammatory markers are altered in PCOS focusing on its relationship with obesity and indexes of insulin resistance.
Patients and methods: One hundred and eight women with PCOS and 75 healthy women were recruited. Patients were divided according to body mass index (BMI) into two groups; group I (BMI < 27 kg/m2) and group II (BMI ≥ 27 Kg/m2). Serum levels of hs-CRP, IL-6, and TNF-α, lipid and hormone profiles were measured.
Results: PCOS patients had increased levels of testosterone, luteinizing hormone (LH), androstendione, insulin level and HOMA index compared to healthy BMI matched controls. High-density lipoprotein (HDL) concentrations were significantly reduced in both patient groups compared to their controls, while triglyceride levels were significantly increased in obese group compared to controls. There were no significant difference in serum inflammatory markers hs-CRP, IL-6 and TNF-α between group I and their matched controls. On the other hand, there were significant increase in these markers between group II and their matched controls. There were highly significant positive correlation between hs-CRP and IL-6 (r = 0.702, P < 0.001) and between hs-CRP and TNF-α (r = 0.621, P <0.001), also between IL-6 and TNF-α (r = 0.543, P < 0.001). These inflammatory markers correlated significantly with BMI and HOMA index. Multiple regression analysis revealed that BMI and HOMA were predictors of IL-6 levels (b = 11.173, P < 0.001, b = 13.564, P < 0.001 respectively) and BMI was the only predictor of hs-CRP levels (b = 12.578, P < 0.001) and TNF-α levels (b = 0.134, P < 0.001).
Conclusion: PCOS and obesity induce an increase in serum inflammatory cardiovascular risk markers. The precise mechanisms underlying these associations require additional studies to clarify the state of the cardiovascular system in women with PCOS compared with controls in large numbers of patients to determine the relative contribution of different factors including insulin resistance, androgen status and BMI.
121 citations
TL;DR: A systematic review of previous studies investigating the relative expression of inflammation associated cytokines within human AAA samples suggests that TNFA and INFG are the most consistently upregulated cytokines in large AAAs.
Abstract: Objectives: Inflammation is critical in abdominal aortic aneurysm (AAA) but there is no current consensus on which inflammation related cytokines are important. The aim of this review was to systemically assess previous studies investigating the relative expression of inflammation associated cytokines within human AAA samples. Methods: The MEDLINE database was searched for studies which simultaneously examined an array of different inflammation associated cytokines in aortic samples in order to identify those associated with AAA. Focused searches were then conducted for further studies assessing relative concentrations of these cytokines in aortic samples in relation to AAA. Appropriate studies were assessed by two reviewers independently. Results: Eighteen studies were included. A number of different cytokines have been consistently found to be upregulated within AAA by comparison to aortic samples removed from patients without cardiovascular disease, however findings relative to samples of aortic athero-thrombosis were less consistent. TNFA and INFG appear to be the most consistently associated with AAA in studies using both normal and atherosclerotic controls. Cautious interpretation of these data is recommended due to a number of methodological problems. Conclusions: This systematic review suggests that TNFA and INFG are the most consistently upregulated cytokines in large AAAs. Further studies utilizing larger populations, new proteomic techniques and better patient matching are required.
74 citations
TL;DR: 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 and co-expression of CD147 with MCT 1 was associated with lymph-node and/or distant metastases in adenOCarcinomas.
Abstract: 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.
68 citations
TL;DR: The 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 ofCREB- mediated gene expression in AD hippocampus.
Abstract: 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 the in silico observations in 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.
63 citations
TL;DR: It is suggested that serum TGF-β1 levels appear to be modulated by gender, age and lifestyle factors such as obesity, cigarette smoking, and alcohol drinking in healthy Japanese adults.
Abstract: Elevated serum or plasma Transforming Growth Factor-β1 (TGF-β1) levels have been linked to cancer and other diseases in numerous studies; however, very few studies have reported an association between circulating TGF-β1 and lifestyle factors in healthy people. We examined the association between serum TGF-β1 levels and gender, age, body mass index (BMI), smoking, and drinking in a large population-based cohort study (N = 9,142). Serum TGF-β1 levels were detected by the Quantikine enzyme-linked immunoassay kit (R&D Systems). The data indicated highly significant (p<0.0001) difference in serum TGF-β1 levels between men (mean value: 37.6 ± 0.12 ng/mL, N = 4888) and women (mean value: 35.1 ± 0.12 ng/ml, N = 4254). Serum TGF-β1 levels decreased with age (trend p < 0.0001) and were positively associated with obesity (trend p < 0.0001) in both men and women. We observed a significant trend with increased serum TGF-β1 levels corresponding to increased amount of tobacco and alcohol consumption in men (trend p < 0.0001). These findings suggest that serum TGF-β1 levels appear to be modulated by gender, age and lifestyle factors such as obesity, cigarette smoking, and alcohol drinking in healthy Japanese adults.
56 citations
TL;DR: Nitric oxide metabolites, lipid peroxidation products, and glutathione peroxidase activity were significantly increased in serum of subjects with relapsing-remitting multiple sclerosis in comparison with that of healthy controls, supporting the hypothesis that multiple sclerosis is a component closely linked to oxidative stress.
Abstract: Objective: To determine the oxidative stress markers in serum from patients with relapsing-remitting multiple sclerosis. Methods: Blood samples from healthy controls and 22 patients 15 women (7 aged from 20 to 30 and 8 were > 40 years old) and 7 men (5 aged from 20 to 30 and 2 were > 40 years old) fulfilling the McDonald Criteria and classified as having Relapsing-Remitting Multiple Sclerosis accordingly with Lublin were collected for oxidative stress markers quantification. Results: Nitric oxide metabolites (nitrates/nitrites), lipid peroxidation products (malondialdehyde plus 4-hidroxialkenals), and glutathione peroxidase activity were significantly increased in serum of subjects with relapsing-remitting multiple sclerosis in comparison with that of healthy controls. These data support the hypothesis that multiple sclerosis is a component closely linked to oxidative stress.
52 citations
TL;DR: The relatively high intraindividual variability of salivary TBARS indicates that the use of saliva TBARS will be limited to research on a population level, although some informative value might be gained by repeated samplings.
Abstract: Introduction: Salivary TBARS are a potential marker of oxidative stress in the oral cavity. Previous studies have found increased levels of salivary TBARS in various diseases. The aim of this study was to assess the variability of salivary TBARS in both genders.
Subjects & Methods: Saliva samples from thirty-eight healthy volunteers (18F & 20M) were collected every day during 30 day period. TBARS levels were measured spectrophotometrically using a high-throughput 96-well plate method. Time series analysis was performed using standard statistical methods.
Results: Repeated measures ANOVA showed a significant variation of salivary TBARS within day and subjects (p < 0.001). The dynamics did not differ between genders. Intraindividual variability was very high in both genders with coefficients of variation of more than 60%. Interindividual variability was higher in men than in women (73% vs. 46%; p < 0.01).
Discussion: The relatively high intraindividual variability indicates that the use of salivary TBARS will be limited to research on a population level, although some informative value might be gained by repeated samplings. Factors influencing the biological variability of salivary TBARS should be identified in further studies.
52 citations
TL;DR: Work on viral factors, host genetic markers and immunological determinants that have been identified in individuals with superior control of HIV infection or in subjects who remain uninfected despite frequent exposure to the viral pathogen are reviewed.
Abstract: HIV infection, if left untreated, leads in most cases to the development of wide immune deterioration, opportunistic infections and eventually AIDS and death. The identification of individuals who despite persisting infection show no or few signs of HIV disease progression has spurred hopes that an effective HIV vaccine could be attainable. The design of such a vaccine will greatly depend on the precise definition of disease markers, host genetic and immune characteristics that mediate relative in vivo control of this virus. Accordingly, a number of viral factors and host genetic characteristics have been shown to play a crucial role in the control of HIV disease by delaying progression to AIDS or even preventing infection. There is also an improved understanding of humoral and cellular immune responses in terms of specificity, functional repertoire, longevity and tissue distribution and their ability to contain HIV replication. However, the definition of good immune correlates unequivocally and causally associated with protection or disease progression remains elusive. Here we review work on viral factors, host genetic markers and immunological determinants that have been identified in individuals with superior control of HIV infection or in subjects who remain uninfected despite frequent exposure to the viral pathogen.
TL;DR: The authors summarizes available epidemiological evidence for four emerging inflammatory markers implicated in coronary heart disease (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2 and interleukin-6) and considers their likely utility in cardiovascular risk prediction.
Abstract: Cardiovascular disease is the leading cause of global mortality, with coronary heart disease (CHD) its major manifestation. Although inflammation, the body’s response to noxious stimuli, is implicated in several stages of CHD development, the relevance of circulating levels of markers of inflammation to CHD risk remains uncertain. This review summarizes available epidemiological evidence for four emerging inflammatory markers implicated in CHD (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2 and interleukin-6); considers their likely utility in cardiovascular risk prediction; and outlines areas of outstanding uncertainty.
TL;DR: Serum SP-D levels were significantly increased in patients who experienced an acute exacerbation compared to patients with stable disease or control subjects and were found to be inversely related to various lung function parameters including FEV1/FVC% predicted.
Abstract: Background: There is a paucity of lung specific biomarkers to diagnose exacerbations of chronic obstructive pulmonary disease (COPD) and to track their progression. Surfactant protein D (SP-D) is a pulmonary collectin regulating the innate immunity of the lung and its serum expression is perturbed in COPD. However, it is not known whether serum levels change during exacerbations. We sought to determine whether serum SP-D levels are raised in COPD exacerbations. Objectives: To determine whether or not patients with exacerbations have elevated serum SP-D levels compared with asymptomatic controls, stable disease. Study design: case control study. Methods: We measured serum SP-D levels from patients with stable COPD (n = 14), patients experiencing acute exacerbations (n = 13) and in control subjects (n = 54) using a specific immunoassay and compared the levels using analysis of variance. Results: Serum SP-D levels were significantly increased in patients who experienced an acute exacerbation (227 ± 120 ng/mL) compared to patients with stable disease (151 ± 83 ng/mL) or control subjects (128 ± 65 ng/mL; p = 0.003). Serum SP-D levels were also found to be inversely related to various lung function parameters including FEV1/FVC% predicted. Conclusions: Our study suggests that serum SP-D levels are increased in patients during exacerbations and may be a potential diagnostic biomarker for COPD exacerbations.
TL;DR: It is concluded that differences in cotinine levels among smokers suggest racial variation in exposure to and/or metabolism of tobacco smoke constituents, but the findings do not support a role for menthol preference in this disparity.
Abstract: The purpose of this study was to estimate black/white differences in cotinine levels for current smokers of both sexes, and to explore the potential contribution of mentholated cigarettes to these differences. Sera from 255 current smokers sampled from Southern Community Cohort Study participants (65 black men, 65 black women, 63 white men, 62 white women) were analyzed for cotinine, and linear regression was used to model the effect of race on cotinine level, adjusting for the number of cigarettes smoked within the last 24 hours, use of menthol vs. non-menthol cigarettes, exposure to environmental tobacco smoke, and age. Black smokers smoked fewer cigarettes than white smokers, yet had crude mean cotinine levels nearly as high or higher than white smokers. After multivariate adjustment, cotinine levels were an average of 50 ng/ml higher among black than white women (p=0.008) and non-significantly 12 ng/ml higher among black than white men (p=0.52). We observed no increase in cotinine levels associated with menthol cigarette use. We conclude that differences in cotinine levels among smokers suggest racial variation in exposure to and/or metabolism of tobacco smoke constituents, but our findings do not support a role for menthol preference in this disparity.
TL;DR: In this article, the association of sICAM-1 and sVCAM1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity was investigated.
Abstract: To investigate the association of sICAM-1 and sVCAM-1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity, sixty RA patients and 60 healthy non-related subjects (HS) matched for age and sex were recruited. Soluble adhesion molecules were determined by ELISA technique. Rheumatoid factor (RF), C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured by routine methods. Disability and clinical activity was measured with Spanish-HAQ-DI and DAS28 scores, respectively. The ICAM1 and VCAM1 polymorphism were identified using the PCR-RFLP procedure. Inter-group comparison showed increased levels of sICAM-1 and sVCAM-1 in RA patients (284 and 481 ng/mL) versus HS (132 and 280 ng/mL); in the RA group, significant correlations between sVCAM-1 and RF (r = 0.402), ESR (r = 0.426), Spanish-HAQ-DI (r = 0.276), and DAS28 (r = 0.342) were found, whereas sICAM-1 only correlated with RF (r = 0.445). In RA patients, a significant association with the 721A allele of ICAM1 polymorphism (p = 0.04), was found. In addition, the allele impact (G/A+A/A) of this polymorphism was confirmed, (p = 0.038, OR = 2.3, C.I. 1.1-5.0). sVCAM-1 and sICAM-1 serum levels reflected the clinical status in RA, independently of the ICAM1 and VCAM1 polymorphism. However, the ICAM1 721A allele could be a genetic marker to RA susceptibility.
TL;DR: Assessment of ER α T/C polymorphism in endometriosis and fibroid patients from Asian Indian population indicates a significant association of C allele with both endometrization and fibroids, and further studies are warranted in this area.
Abstract: Endometriosis and fibroids are estrogen-dependent benign pathologies of the uterus, which account for infertility and pelvic pain along with dysmenorrhea in women. Suppression of the disease and recurrence after discontinuing hormone therapy strongly suggests that these are responsive to hormones, especially estrogen, which acts via its receptor. A T/C SNP in intron 1 and exon 2 boundary of estrogen receptor (ER) α gene recognized by PvuII enzyme has been associated with several female pathologies like breast cancer, osteoporosis, endometriosis and fibroids in various ethnic groups. The aim of the present study was to assess this ER α T/C polymorphism in endometriosis and fibroid patients from Asian Indian population. Genomic DNA was isolated from 367 women, who included 110 cases of endometriosis, 142 cases of uterine fibroids and 115 healthy age matched women volunteers. PCR was carried out to amplify ER α gene followed by restriction digestion with Pvu II. Results indicate a significant association of C allele with both endometriosis [OR = 2.6667, 95% CI = 1.4166 to 5.0199; p < 0.05] and fibroids [2.0833, 95% CI = 1.1327 to 3.8319; p < 0.05]. Further studies are needed in larger population to establish ER α C allele as a risk marker for endometriosis and fibroids in Asian Indian women. Ethnicity, race, diet etc may play a role in susceptibility to endometriosis and fibroids and further studies are warranted in this area.
TL;DR: The results suggest that CAT and TNFA polymorphisms alone and in combination influence the activity of RA.
Abstract: Reactive oxygen and nitrogen species are involved in the pathology of rheumatoid arthritis (RA). Polymorphisms in genes coding for superoxide dismutases (SOD2 and SOD3), catalase (CAT), tumor necrosis factor-alpha (TNFA) and inducible NO synthase (NOS2A) may influence RA activity. We determined SOD2 Ala-9Val, SOD3 Arg213Gly, CAT C-262T, TNFA G-308A, TNFA C-857T and NOS2A (CCTTT)n polymorphisms in 327 RA patients. Carriers of CAT -262T and TNFA -308A allele had lower mean disease activity score of 28 joint count (DAS28) values than patients with CAT -262CC and TNFA -308GG genotypes (p = 0.014 and p = 0.046, respectively). Patients with the combination of CAT -262T and TNFA -308A allele had lower mean DAS28 values and a higher probability for low disease activity than non-carriers (p = 0.003, OR = 3.585, 95% CI = 1.538–8.357). Our results suggest that CAT and TNFA polymorphisms alone and in combination influence the activity of RA.
TL;DR: The serum adiponectin concentration was correlated with conventional clinical variables, but the most powerfully associated factor was the serum ferritin level.
Abstract: Background: The serum concentrations of ferritin and adiponectin are associated with several metabolic disorders and have been used as predictors of insulin resistance and metabolic syndrome. But there have been no reports demonstrating a direct correlation between serum ferritin and adiponectin levels. We performed this study to evaluate the association between serum ferritin and adiponectin concentrations.
TL;DR: Higher expression of survivin and cortactin correlates significantly with tumor stages and shorter survival time, and may be good biomarkers of aggressiveness of colorectal adenocarcinomas.
Abstract: Objective: Survivin and cortactin are factors that promote tumor progression. We tested the hypothesis that survivin and cortactin expressions correlate with the clinico-pathological parameters of colorectal adenocarcinomas and survival time. Methods: Immunohistochemical analysis of survivin and cortactin were performed using tissue microarrays of 119 specimens from 18 well, 50 moderately, and 27 poorly differentiated colorectal adenocarcinomas and 24 colorectal adenomas with dysplasia. As control, 10 specimens of normal colorectal epithelia were included.
TL;DR: Pro-BNP levels higher than 360 pg/mL are associated with cardioembolic stroke and may be useful to reclassify undetermined strokes as of cardioembolics origin.
Abstract: Background: Stroke subtype diagnosis leads to specific therapies to reduce recurrences. Because nearly one third of patients remain with unknown etiology after a complete screening workup, we aim to investigate whether molecular markers of myocardial damage were associated with cardioembolic stroke and if they were useful to reclassify strokes of undetermined etiology. Methods: We included 262 patients with first ischemic stroke within the first 12 hours. Stroke subtype was evaluated by TOAST criteria. Stroke of undetermined origin were reclassified into likely atherothrombotic or likely cardioembolic according to a predefined non-validated algorithm. Blood samples were obtained on admission to determine serum levels of molecular markers (pro-BNP, pro-ANP and CK-MB) of myocardial damage. Results: Patients with cardioembolic infarct showed higher levels of pro-BNP, pro-ANP and CK-MB. Pro-BNP > 360 pg/mL was independently associated with cardioembolic stroke (OR: 28.51, CI95%: 5.90-136.75, p 360 pg/mL was the only factor independently associated with likely cardioembolic stroke. Conclusions: Pro-BNP levels higher than 360 pg/mL are associated with cardioembolic stroke and may be useful to reclassify undetermined strokes as of cardioembolic origin.
TL;DR: Basic concepts of genetics and epidemiology are discussed as a departure to evaluate and review every step that should be followed to design, conduct, analyze, interpret and present data from studies, using particularities of infectious diseases, especially leprosy and tuberculosis as models.
Abstract: In the past decade, genetic epidemiological analyses in infectious diseases have increased drastically since the publication of human genome and all the subsequent projects analyzing human diversity at molecular level. The great majority of studies use classical epidemiological designs applied to genetic data, and more than 80% of published studies use population-based case-control designs with widely spread genetic markers in human genome, like short tandem repeats (STR) or single nucleotide polymorphisms (SNP), in genes chosen by their physiological association with the disease (candidate genes). Even though genetic data is less prone to several bias issues inherent to case-control studies, some care has to be taken when designing, performing, analyzing and interpreting results from such studies. Here we discuss some basic concepts of genetics and epidemiology as a departure to evaluate and review every step that should be followed to design, conduct, analyze, interpret and present data from those studies, using particularities of infectious diseases, especially leprosy and tuberculosis as models.
TL;DR: It is demonstrated that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.
Abstract: Background: Glatiramer acetate (GA, Copaxone ) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood. Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC). Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS. Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation. Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.
TL;DR: The results suggest that maternal folate-related polymorphisms studied here have no influence on trisomy 21 susceptibility in subjects of Brazilian population.
Abstract: Recent evidence shows that almost 92% of the DS children are born from young mothers, suggesting that other risk factors than advanced maternal age must be involved In this context, some studies demonstrated a possible link between DS and maternal polymorphisms in genes involved in folate metabolism These polymorphisms, as well as low intake of folate could generate genomic instability, DNA hypomethylation and abnormal segregation, leading to trisomy 21 We compared the frequency of CBS 844ins68, MTR 2756A>G, RFC-1 80G> A and TC 776C>G polymorphisms among 114 case mothers and 110 matched controls, in order to observe whether these variants act as risk factors for DS The genotype distributions revealed that there were not significant differences between both samples However, when we proceed the multiplicative interaction analyses between the four polymorphisms described above together with the previously studied MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G polymorphisms, our results show that the combined genotype TC 776CC / MTHFR 677TT and TC 776CC / MTR 2756AG were significantly higher in the control sample Nevertheless, there was no significant association after Bonferroni correction Our results suggest that maternal folate-related polymorphisms studied here have no influence on trisomy 21 susceptibility in subjects of Brazilian population
TL;DR: The role of some of the most promising obesity biomarkers in cardiovascular epidemiology, including inflammatory markers, adiponectin, resistin, and fetuin-A are discussed.
Abstract: Obesity is an established risk factor for cardiovascular disease (CVD), yet, the underlying mechanisms are only poorly understood. The adipose tissue produces a variety of hormones and cytokines and thereby actively participates in a network of biomarkers that may be relevant for the development of CVD. Such obesity biomarkers have a great potential to better characterize the obesity phenotype that may be relevant for the risk of CVD beyond anthropometric parameters. They may be used to support mechanistic studies, to help identify individuals at risk for CVD, and to evaluate the effect of preventive measures. The present article discusses the role of some of the most promising obesity biomarkers in cardiovascular epidemiology, including inflammatory markers, adiponectin, resistin, and fetuin-A. Importantly, some of these markers have been related to cardiovascular risk even after accounting for anthropometric parameters. Further, the potential ability to manipulate blood levels of some of these biomarkers through medication, diet and lifestyle make them attractive markers for cardiovascular risk. However, many open questions remain – especially with regard to the causal role of the factors as well as with regard to the extent of improvement in CVD prediction by these markers – before measurement of these biomarkers may be recommended on a public health level.
TL;DR: The characteristics of promising biomarkers are described which have shown an important additive value in the assessment of cardiovascular risk and the prognostic value of multimarker models in the settings of primary prevention of cardiovascular disease and secondary prevention for patients with acute coronary syndromes.
Abstract: Various biomarkers express different pathways and pathophysiologic mechanisms of cardiovascular disease, such as inflammation, oxidative stress, myocardial injury, activation of the neurohormonal pathways, myocardial stress and renal function. Current thinking supports the notion that the combination of these biomarkers could increase their diagnostic and prognostic value. The multimarker approach offers benefits since it increases the diagnostic and prognostic information and may help in the design of a strategy for prevention or management of cardiovascular diseases. The purpose of the current review is to describe the characteristics of promising biomarkers which have shown an important additive value in the assessment of cardiovascular risk. Also, an extended reference is made regarding studies that address the prognostic value of multimarker models in the settings of primary prevention of cardiovascular disease and secondary prevention for patients with acute coronary syndromes, chronic coronary artery disease and heart failure.
TL;DR: The data suggest that genetic variation in UG and NF-κB2 pathways could have effects in connective tissue disease susceptibility.
Abstract: Immune and inflammatory response activation is a common feature of connective tissue diseases and systemic vasculitis. The aim of our study was to evaluate the possible involvement of TNFα c.-308A > G, IL-10 c.-1082A > G, uteroglobin c.38A > G, TGFβ 1 c.869C > T and NFκB2 c.-1837T > C gene polymorphisms in susceptibility to connective tissue diseases. Our study cohort included 68 unrelated patients affected by rheumatoid arthritis (RA) (37 patients) and ANCA-positive [micropolyangiitis (mPA) 17 patients] or ANCA-negative systemic vasculitis [including 8 patients with Henoch-Schonlein purpura (HSP) and 6 patients with mixed cryoglobulinaemia (MC)] as well as 98 control subjects. Allele frequency analysis of uteroglobin c.38G > A polymorphism showed a significant increase in the c.38A allele in patients (p= 0.002). Genotype frequency analysis of uteroglobin and NF-κB2 gene polymorphisms in patients showed an increase in c.38GA and c.38AA genotypes in the uteroglobin gene (p=0.02) coupled with an increase in homozygous c.-1837CC in the NF-κB2 gene (p=0.02). Our data suggest that genetic variation in UG and NF-κB2 pathways could have effects in connective tissue disease susceptibility.
TL;DR: It is demonstrated that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.
Abstract: Cytochrome P450 1B1 (CYP1B1) and catechol-$O$-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu432Val and/or COMT Val158Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val158Val) in combination with CYP1B1 heterozygous variant (Leu432Val) [OR: 0.21; 95% CI (0.05–0.82), p value; 0.021] and COMT heterozygous variant (Val158Met) in combination with CYP1B1 wild type (Leu432Leu) [OR: 0.29; 95% CI (0.08–0.96), p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.
TL;DR: It is concluded that the common MTHFR 677C>T polymorphism is not likely to be a maternal risk factor for DS in the Danish population and that the difference to previous studies can probably be explained by small sample size or geographic variation in gene polymorphisms involving gene-nutritional or gene-gene or gene -nutritional-environmental factors.
Abstract: Chromosomal aneuploidy consists the leading cause of fetal death in our species. Around 50% of spontaneous abortions until 15 weeks of gestational age are chromosomally aneuploid, with trisomies accounting for 50% of the abnormal abortions. Trisomy 21 is the most common chromosome abnormality in liveborns and is usually the result of nondisjunction of chromosome 21 in meiosis in either oogenesis or spermatogenesis. To investigate the relationship between folate metabolism and Down syndrome (DS) in a Danish population, we analyzed the common 677C>T genetic polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Our cohort consisted of 181 mothers of children with DS versus 1,084 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to examine the MTHFR 677C>T polymorphism. No significant association between the polymorphism and the risk for DS was found. We conclude that the common MTHFR 677C>T polymorphism is not likely to be a maternal risk factor for DS in our cohort and that the difference to previous studies can probably be explained by small sample size or geographic variation in gene polymorphisms involving gene-nutritional or gene-gene or gene-nutritional-environmental factors.
TL;DR: There is no solid association of polymorphisms related to MTHFR and ACE genes with non-complicated overweight or obesity among Saudi subjects from Qassim Region.
Abstract: Background: This work was planned to check for the association of polymorphisms related to methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) genes with overweight/obesity among Saudi subjects from Qassim region. Methods: This work included 130 subjects having overweight or obesity and 111 normal controls. Their age mean ± SD was 27 ± 9.8 and 24 ± 8.8 years respectively. Their DNA was analyzed for polymorphisms of MTHFR; 677C/T and 1298 A/C and ACE; I/D genes using real-time PCR. Results: Genotype and allele frequencies of studied polymorphisms in cases of overweight/obesity showed no significant statistical difference compared to that of controls. However, on analysis of body mass index (BMI), cases showed slightly higher but statistically nonsignificant mean ± SD values among those carrying the mutant MTHFR 677 T allele (CT + TT vs. CC, 30.7 ± 4.5 vs. 29.9 ± 4.9), 1298 C allele (AC + CC vs. AA, 29.9 ± 4.1 vs. 29.7 ± 5.5) and ACE D allele (ID + DD vs. II, 30.0 ± 5.1 vs. 29.1 ± 2.8). In addition controls having the DD and ID genotypes showed higher statistically significant values of BMI than those of the II genotype (22.0 ± 1.9, 21.7 ± 2.6 and 19.5 ± 2.3 respectively, p< 0.05). Conclusion: There is no solid association of polymorphisms related to MTHFR and ACE genes with non-complicated overweight or obesity among Saudi subjects from Qassim Region.
TL;DR: Elevated levels of CRP and fibrinogen and reduced level of adiponectin can be used for early diagnosis of T2DM and can predict diabetic complications.
Abstract: Objectives: To study the interrelationships of adiponectin, C-reactive protein (CRP) and fibrinogen with each other in T2DM patients with (T2DM-C) and without complications (T2DM-NC) among healthy individuals. Design and methods: The study comprised of 120 T2DM-C, 59 T2DM-NC patients and 40 healthy volunteers. Biochemical markers were determined in the serum. Results: Positivity rates of CRP and fibrinogen were significantly increased in T2DM-C as compared to T2DM-NC or controls, whereas adiponectin showed highest level in healthy individuals. Inflammatory biomarkers were inversely correlated with adiponectin ( P< 0.01). Lipid profiles, kidney functions and BMI, showed positive significant correlation with CRP and fibrinogen but negative correlation with adiponectin. For better detection of T2DM, the combined sensitivity (98.9%) and specificity (92.5%) of fibrinogen and adiponectin was higher than the combined sensitivity and specificity of fibrinogen and CRP or adiponectin and CRP or than that of the biomarkers alone. Conclusion: Elevated levels of CRP and fibrinogen and reduced level of adiponectin can be used for early diagnosis of T2DM and can predict diabetic complications.