Disease-free Control Subjects Research Articles

Automated in-depth cerebral arterial labelling using cerebrovascular vasculature reframing and deep neural networks

Identifying the cerebral arterial branches is essential for undertaking a computational approach to cerebrovascular imaging. However, the complexity and inter-individual differences involved in this process have not been thoroughly studied. We used machine learning to examine the anatomical profile of the cerebral arterial tree. The method is less sensitive to inter-subject and cohort-wise anatomical variations and exhibits robust performance with an unprecedented in-depth vessel range. We applied machine learning algorithms to disease-free healthy control subjects (n = 42), patients with stroke with intracranial atherosclerosis (ICAS) (n = 46), and patients with stroke mixed with the existing controls (n = 69). We trained and tested 70% and 30% of each study cohort, respectively, incorporating spatial coordinates and geometric vessel feature vectors. Cerebral arterial images were analyzed based on the ‘segmentation-stacking’ method using magnetic resonance angiography. We precisely classified the cerebral arteries across the exhaustive scope of vessel components using advanced geometric characterization, redefinition of vessel unit conception, and post-processing algorithms. We verified that the neural network ensemble, with multiple joint models as the combined predictor, classified all vessel component types independent of inter-subject variations in cerebral arterial anatomy. The validity of the categorization performance of the model was tested, considering the control, ICAS, and control-blended stroke cohorts, using the area under the receiver operating characteristic (ROC) curve and precision-recall curve. The classification accuracy rarely fell outside each image’s 90–99% scope, independent of cohort-dependent cerebrovascular structural variations. The classification ensemble was calibrated with high overall area rates under the ROC curve of 0.99–1.00 [0.97–1.00] in the test set across various study cohorts. Identifying an all-inclusive range of vessel components across controls, ICAS, and stroke patients, the accuracy rates of the prediction were: internal carotid arteries, 91–100%; middle cerebral arteries, 82–98%; anterior cerebral arteries, 88–100%; posterior cerebral arteries, 87–100%; and collections of superior, anterior inferior, and posterior inferior cerebellar arteries, 90–99% in the chunk-level classification. Using a voting algorithm on the queued classified vessel factors and anatomically post-processing the automatically classified results intensified quantitative prediction performance. We employed stochastic clustering and deep neural network ensembles. Ma-chine intelligence-assisted prediction of vessel structure allowed us to personalize quantitative predictions of various types of cerebral arterial structures, contributing to precise and efficient decisions regarding the cerebrovascular disease.

Association of CTLA-4 gene polymorphisms and alopecia areata: a systematic review and meta-analysis

Objective To provide evidence of the association between CLTA-4 gene polymorphisms and alopecia areata (AA). Methods PubMed, EMBASE, Web of Science, Cochrane, Wanfang, and CNKI databases were searched until 30 April 2021. The selection was completed according to the inclusion and exclusion criteria. The study quality assessment was based on Newcastle-Ottawa Scale. The assessment of the association was measured by ORs and 95%CIs. Results Nine studies, containing 2858 AA cases and 5444 disease-free control subjects were included. For rs231775 polymorphism, no significant association with AA was found, which was A vs. a, OR = 1.02 [0.81, 1.30], p = 0.85; AA vs. aa, OR = 1.26 [0.81, 1.97], p = 0.31; Aa vs. aa, OR = 1.04 [0.54, 2.01], p = 0.91; AA + Aa vs. aa, OR = 1.04 [0.71, 1.53], p = 0.82; AA vs. Aa + aa, OR = 1.31 [0.97, 1.78], p = 0.08. For rs3087243 polymorphism, also no significant association was found, which was A vs. a, OR = 0.93 [0.78, 1.11]; p = 0.40, AA vs. aa, OR = 0.68 [0.44, 1.06]; p = 0.09; Aa vs. aa, OR = 0.87 [0.45, 1.68], p = 0.68; AA + Aa vs. aa, OR = 0.93 [0.68, 1.28], p = 0.66; AA vs. Aa + aa, OR = 0.78 [0.34, 1.81], p = 0.57. For rs231726 polymorphism, a significant correlation was found, which was A vs. a, OR = 0.76 [0.70, 0.82], p < 0.05. Conclusions A significant correlation between CTLA-4 rs231726 polymorphism and AA susceptibility was found, but no significant association of CTLA-4 gene rs231775 and rs3087243 polymorphisms and AA susceptibility was found.

Gamma-Synuclein Levels Are Elevated in Peritoneal Fluid of Patients with Endometriosis.

BackgroundThe role of gamma-synuclein (SNCG) has been widely examined in malignant conditions due to its possible role in disease progression, but very little information is available on its theoretical function on endometriosis formation.Material/MethodsBetween January 2016 and December 2016, we collected peritoneal fluid and plasma samples from 45 consecutive female patients, of which 15 were without endometriosis, 15 had minimal to mild endometriosis, and 15 had moderate to severe endometriosis. The statistical power was 0.98. We evaluated SNCG levels in the peritoneal fluid and plasma of patients diagnosed with endometriosis, and we compared them with the levels obtained from disease-free control subjects by using enzyme-linked immunosorbent assay.ResultsSNCG levels were statistically significantly (1.2-fold) higher in the peritoneal fluid of patients with endometriosis compared to controls (p=0.04). We did not find a significant difference between SNCG levels in the plasma of our endometriosis patients and the control group (p=0.086). However, despite previous data showing very limited expression of SNCG in healthy tissues, we found SNCG in the peritoneal fluid of all of the patients in our healthy control group.ConclusionsLevels of SNCG were statistically significantly higher in the peritoneal fluid of patients with endometriosis compared to disease-free controls, which may indicate its possible role the formation and progression of the disease. Moreover, its biological function should be further investigated due to the conflicting results concerning its expression in healthy tissues.

IL-13-regulated Macrophage Polarization during Granuloma Formation in an In Vitro Human Sarcoidosis Model.

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free control subjects were incubated for 7 days with purified protein derivative-coated polystyrene beads. Molecular responses, as reflected by differential expression of genes, extracellular cytokine patterns, and cell surface receptor expression, were analyzed. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared with human lung and mediastinal lymph node gene expression profiles. Compared with identically treated PBMCs of control subjects (n = 5), purified protein derivative-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Ingenuity Pathway Analysis of differential expression gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Whole blood microRNA expression pattern differentiates patients with rheumatoid arthritis, their seropositive first-degree relatives, and healthy unrelated control subjects

BackgroundEpigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA). To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).MethodsTotal RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12). Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.ResultsWhole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs. Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups. Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart. We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs. Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks. Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.ConclusionsWe highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA. Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.

MR diffusion tensor imaging of optic radiation in chronic Leber's hereditary optic neuropathy

Objective To observe quantitatively the optic radiation alterations in chronic Leber's hereditary optic neuropathy (LHON) using MR diffusion tensor imaging at 3.0 T. Methods Twenty-five patients with chronic LHON and twenty-eight sex- and age-matched disease-free control subjects were enrolled from March 2011 to December 2014. The whole brain DTI examination and retinal optical coherence tomography were performed in all the subjects. The parameters values of optic radiation including fractional anisotropy(FA),mean diffusivity(MD),principal eigenvalue(λ//),orthogonal eigenvalue(λ⊥) and average retinal nerve fiber layer (RNFL) thickness and temporal retinal nerve fiber layer(RNFL) thickness were measured. For DTI and OCT parameters, differences between patients and controls and differences right and left of the patient group were evaluated using independent-samples t test and paired t test respectively. Results In LHON patients, the DEC maps showed that the bilateral optic radiation fibers were obviously sparse and slender. The values of FA, MD, λ// and λ⊥ in the right optic radiation were 0.523±0.050, (0.903±0.061) ×10-9 mm2/s, (4.999±0.097) ×10-9 mm2/s and (4.126±0.065) ×10-9 mm2/s respectively, and the corresponding values of left optic radiation were 0.537±0.041, (1.057±0.573)×10-9 mm2/s,(5.052±0.119)×10-9 mm2/s and (4.138±0.072)×10-9 mm2/s. Compared with optic radiation in the control group, the bilateral FA was significant reduced, the bilateral λ⊥ value and right MD value were significant increased (t=-6.524, -6.045, 6.932, 6.454, 3.471, P 0.05) .There were no significant differences in FA, MD, λ// and λ⊥ between the left and right eyes in LHON patients(P>0.05). The values of average RNFL thickness and temporal RNFL thickness in right eyes were (59.36±10.94) and (41.72±9.43) μm respectively, and the corresponding values of left eyes were (60.12±9.81), (44.72±9.43) μm. The average and temporal RNFL thickness were significantly thinned in LHON patients compared with the control group (t=-16.357, -10.398,-17.169,-9.672, P 0.05), temporal RNFL thickness between the left and right eyes was statistically significant (t=2.645, P<0.05). Conclusion The bilateral optic radiation had significant degeneration and atrophy in chronic LHON. Key words: Optic nerve diseases; Magnetic resonance imaging; Comparative study

Dietary inflammatory index and odds of colorectal cancer in a case-control study from Jordan.

Dietary components that promote inflammation of the colon have been suggested to be risk factors in the development of colorectal cancer (CRC). The possible link between inflammatory potential of diet and CRC has been investigated in several developed or Western countries. Despite the fact that dietary choices in the Middle East differ markedly from those in the West, results have not been reported from any study conducted in a Middle-Eastern population. We examined the association between dietary inflammatory index (DII) scores and CRC in a case-control study conducted in Jordan. This study included 153 histopathologically confirmed CRC cases and 202 disease-free control subjects' frequency matched on age, sex, and occupation. Data were collected between January 2010 and December 2012, using interviewer-administered questionnaires. DII scores were computed from dietary data reported using a food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, sex, education, physical activity, body mass index, smoking, and family history of CRC. Subjects with higher DII scores were at increased odds of CRC, with the DII being used both as a continuous variable (ORcontinuous = 1.45, 95% CI: 1.13-1.85; 1-unit increase corresponding to ≈20% of its range in the current study) and as a categorical variable (ORtertile 3 vs tertile 1 = 2.13, 95%CI: 1.23-3.72). Our results, based on a Jordanian population, add to the growing literature indicating that a pro-inflammatory diet is associated with increased odds of CRC.

Potential role of microRNA-10b down-regulation in cardiomyocyte apoptosis in aortic stenosis patients.

MicroRNAs have been associated with cardiomyocyte apoptosis, a process involved in myocardial remodelling in aortic valve (Av) stenosis (AS). Our aim was to analyse whether the dysregulation of myocardial microRNAs was related to cardiomyocyte apoptosis in AS patients. Endomyocardial biopsies were obtained from 28 patients with severe AS (based on pressure gradients and Av area) referred for Av replacement and from necropsies of 10 cardiovascular disease-free control subjects. AS patients showed an increased (P<0.001) cardiomyocyte apoptotic index (CMAI) compared with controls. Two clusters of patients were identified according to the CMAI: group 1 (CMAI ≤ 0.08%; n=16) and group 2 (CMAI > 0.08%; n=12). Group 2 patients presented lower cardiomyocyte density (P<0.001) and ejection fraction (P<0.05), and higher troponin T levels (P<0.05), prevalence of heart failure (HF; P<0.05) and NT-proBNP levels (P<0.05) than those from group 1. miRNA expression profile analysed in 5 patients randomly selected from each group showed 64 microRNAs down-regulated and 6 up-regulated (P<0.05) in group 2 compared with group 1. Those microRNAs with the highest fold-change were validated in the full two groups corroborating that miR-10b, miR-125b-2* and miR-338-3p were down-regulated (P<0.05) in group 2 compared with group 1 and control subjects. These three microRNAs were inversely correlated (P<0.05) with the CMAI. Inhibition of miR-10b induced an increase (P<0.05) of apoptosis and increased expression (P<0.05) of apoptosis protease-activating factor-1 (Apaf-1) in HL-1 cardiomyocytes. In conclusion, myocardial down-regulation of miR-10b may be involved in increased cardiomyocyte apoptosis in AS patients, probably through Apaf-1 up-regulation, contributing to cardiomyocyte damage and to the development of HF.

MiR-196a overexpression activates the MEK/ERK signal and represses the progesterone receptor and decidualization in eutopic endometrium from women with endometriosis.

Do microRNAs (miRNAs) contribute to aberrant progesterone receptor (PGR) expression in the eutopic endometrium of women with endometriosis? SUMMARY ANSWER: miR-196a upregulates MEK/ERK signalling, mediating a downregulation of PGR expression in the eutopic endometrium of women with minimal or mild endometriosis. Implantation failure is strongly suggested as an underlying cause for the observed infertility in minimal or mild endometriosis. Progesterone resistance, which is mainly caused by aberrantly expressed progesterone receptor in the eutopic endometrium, is considered as a key factor of decreased endometrial receptivity; thus far, epigenetics, but not miRNA, has been shown to affect PGR expression in the endometrium. Microarray analysis was used to analyse the eutopic endometrium. The differential expression of miR-196a was validated. Bioinformatics analysis predicted that miR-196a targets the 3'-untranslated region (UTR) of the PGR. The relationship between the miR-196a level and PGR expression was studied and the role of the MEK/ERK signal pathway was investigated. Total RNA was extracted from eutopic endometrium samples in three infertile women with mild/minimal endometriosis and three disease-free control subjects. The miRNA and mRNA expression levels were analysed by microarray analysis. The miR-196a expression was validated by qRT-PCR [endometriosis (n=22) and control (n=20)], while functional analysis utilised in vitro transfection of endometrial stromal cells (ESCs), induction of decidualization of ESCs, and luciferase reporter assays in 293 T cell lines. A total of 66 dysregulated miRNAs and 357 dysregulated mRNAs were screened by microarray analysis. miR-196a and P-MEK/P-ERK were both found to be significantly upregulated in the eutopic endometrium in patients with mild/minimal endometriosis. PGR and PGR-B mRNA were inhibited by miR-196a overexpression and upregulated by miR-196a inhibition. Luciferase reporter failed to confirm the target regulation of miR-196a on PGR. Transfection of ESCs with a miR-196a mimic led to an increase in the P-MEK/P-ERK protein levels, decrease in the PGR protein levels, and atypical decidualization. Following miR-196a inhibition, the P-MEK/P-ERK protein was downregulated and the PGR protein was upregulated. Inhibition of P-MEK/P-ERK also increased PGR expression. Data are presented in Supplementary Tables SI and SII. This study focused on the role of miR-196a, and therefore does not involve other miRNAs; hence, it is possible that other miRNAs may also be responsible for progestin resistance in endometriosis. Our data revealed altered miRNA expression and activated MEK/ERK signalling in the eutopic endometrium in minimal or mild endometriosis. We showed that the miR-196a level is associated with reduced expression of PGR isoforms through MEK/ERK, suggesting that miR-196a and MEK/ERK are both potential biomarkers of endometriosis. These results provide a novel approach to target the mechanisms behind progesterone resistance in endometriosis. This research was supported by the National Natural Science Foundation of China (No. 81370693). The authors have no conflicts of interest.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY EVIDENCE OF RETINAL NERVE FIBER LAYER AND GANGLION CELL LOSS IN ADULT PATIENTS WITH NEUROFIBROMATOSIS TYPE 1.

To evaluate peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer thickness and analyze their correlations in adult patients with neurofibromatosis Type 1 (NF1) and disease-free controls. This cross-sectional study was performed at the Azienda Policlinico Umberto I, University of Rome "La Sapienza." All participants underwent complete ophthalmologic examination. Spectral domain optical coherence tomography was used to evaluate peripapillary retinal nerve fiber layer and obtain retinal segmentation measurements to assess macular retinal nerve fiber layer and ganglion cell layer-inner plexiform layer at 1,000 μm nasal, temporal, superior, and inferior to the fovea. Thirty-four eyes of 17 patients with NF1 (mean age, 42.2 ± 14.3 years) and 34 eyes of 17 disease-free control subjects (mean age, 41.4 ± 12.2 years) were included. All participants had best-corrected visual acuity of 20/20. The mean thickness of peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer was lower in patients with NF1 with respect to controls (P = 0.003, P = 0.022, P < 0.001, respectively). Regression analysis showed a significant correlation (P < 0.001) between mean ganglion cell layer-inner plexiform layer thickness and mean peripapillary retinal nerve fiber layer thickness in patients with NF1. Retinal nerve fiber layer and ganglion cell loss correlate well with each other in adult patients with NF1 in comparison with a healthy control population.

Diffusion tensor imaging of optic nerve and optic radiation in primary chronic angle-closure glaucoma using 3T magnetic resonance imaging.

To evaluate the value of quantitative diffusion tensor imaging (DTI) in assessing the axonal and myelin damage of the optic nerves and optic radiations in patients with chronic primary angle-closure glaucoma (PACG) by using high-field magnetic resonance (MR) imaging (3T). Twenty patients with bilateral chronic PACG and twenty age- and sex matched disease-free control subjects were enrolled. Conventional MRI and DTI were performed on all subjects using 3T MR scanner. Mean diffusivity (MD), fractional anisotropy (FA), axial diffusivities (AD) and radial diffusivities (RD) of each optic nerve and each optic radiation were measured by using post-processing software of DTI studio 2.3, and then compared between left eyes and right eyes and between patients group and control group. The paired-sample t- test were used. There was no abnormality in the shape and signal intensity of the optic nerves and optic radiations in patients group and control group on the conventional MRI. No significant differences were observed in the FA, MD, AD and RD between the right and left optic nerves and optic radiations within patients group and control group (P>0.05). The optic nerves and optic radiations of patients with chronic PACG, as compared with control subjects, had significantly higher MD, AD, RD and significantly lower FA (P<0.05). The diffusivity of optic nerves and optic radiations in chronic PACG group showed abnormal and diffusivity parameters could be used markers of axonal and myelin injury in glaucoma.

Toll-Like Receptors 2 and 4 Polymorphisms in Age-Related Macular Degeneration

Purpose: Age-related macular degeneration (AMD) is a complex disorder with multifactorial etiology, caused by a combination of genetic and environmental factors. Innate immunity appears to play a key role in the pathogenesis of AMD. The purpose of this study was to determine whether common variation in the human toll-like receptors (TLRs) 2 and 4 alters the risk of AMD.Patients and methods: A total of 183 patients with AMD and 200 disease-free control subjects were enrolled. The genotyping of polymorphisms TLR2 (TLR2-Arg753Gln: rs5743708) and TLR4 (TLR4-Asp299Gly: rs4986790; TLR4-Thr399Ile: rs4986791) were done using real-time PCR.Results: TLR2 Arg753Gln genotype had approximately four times greater risk of AMD compared with TLR2 Arg753Arg genotype (OR = 3.88; 95% CI: 1.76–8.75, p = 0.001). TLR2 Arg753Gln genotype was significantly higher in the patients with dry-type AMD (16%) and wet-type AMD (18%) than in the control (5%) subjects (p = 0.005 and p = 0.0008, respectively). There were no significant differences in the distribution of TLR4-Asp299Gly and TLR4-Thr399Ile genotypes between AMD patients and controls (p > 0.05).Conclusion: Our results suggest that TLR2 polymorphism may contribute to the pathogenesis of AMD.

Increased miR-196a expression represses PGR in infertile women with minimal or mild endometriosis by increased activationof the MEK/ERK signal

Endometriosis-related infertility is common in women of reproductive age. Progesterone resistance, especially aberrantly expressed progesterone receptor in the eutopic endometrium, is considered as a key causal factor. Our objective is to explore microRNA-mediated mechanism controlling aberrant progesterone receptor expression in infertile women with minimal or mild endometriosis. microRNA Array, combined with Human Gene Expression microarrays, was used to screen eutopic endometrium of infertile women with minimal or mild endometriosis. Bioinformatics analysis predicted that microRNA-196a target the PGR 3′UTR. We studied the relationship between microRNA-196a level and PGR expression in endometrial stromal cells (ESCs). According to mRNAs microarray result, MAPK pathway is activated in eutopic mid-secretory endometrium. The role of MAPK pathway involved regulation of miR-196a on PGR was also investigated. The study was conducted at West China Second University Hospital of Sichuan University. 22 infertile women with r-AFSI-IIendometriosis and 20 disease-free control subjects were enrolled. MiRCURY LNATM microRNA Array(v.18.0)(Exiqon), Human 4×44K Gene Expression Microarrays v2(Agilent), qRT-PCR, cell culture, transfections, luciferase reporter assays, and western bolt were used in this study. 66 differently expressed microRNAs (fold change≥2.00 and p<0.05) were found by microRNA array in eutopic endometrium of infertile women with minimal or mild endometriosis. Among them, the expression of 54 microRNAs were increased, while 12 microRNAs were decreased. Meanwhile, mRNA array screened 357 differently expressed mRNAs (fold change≥2.00 and p<0.05).Among them, 224 mRNAs over-expressed and 133 mRNAs down-expressed. miR-196a was the highest over-expression microRNA, which was confirmed by qRT-PCR. The transfection of ESCs with miR-196a mimics significantly decreased expression of total PGR and PGR-B mRNA levels, while total PGR and PGR-B mRNA expression were up-regulated by miR-196a inhibitor. Luciferase reporter failed to confirm the target regulation of miR-196a on PGR in 293T cell line. Based on mRNA microarray, Western blot confirmed that P-MEK1/2 and P-ERK1/2, the key molecular of MAPK pathway, were upregulated in eutopic endometrium in infertile women with minimal or mild endometriosis. P-MEK1/2 and P-ERK1/2 expression were up-regulated, PGR-A and PGR-B expression were inhibited, and the ratio of PGR-A/PGR-B was up-regulated by miR-196a overexpression in eutopic ESCs. Meanwhile, a specific P-MEK/P-ERK inhibitor, U0126 resulted in upregulation of PGR-A and PGR-B protein, and the downregulation of the protein ratio of PGR-A/PGR-B in ESCs. Aberrantly expressed miR-196a represses PGR expression and upregulate the protein ratio of PGR-A/PGR-B via activation of MAPK pathway in eutopic endometrium of infertile women with minimal or mild endometriosis.

Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis.

Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.

The Association Between Visual Field Defect Severity and Fear of Falling in Primary Open-Angle Glaucoma

To determine if glaucomatous visual field defect severity is associated with fear of falling. This is a cross-sectional study. A total of 387 consecutive subjects with POAG were enrolled in this study along with 293-ocular disease-free control subjects, who were screened at the same institutions. We defined mild POAG as MD of -6 dB or better, moderate POAG as MD of -6 to -12 dB, and severe POAG as MD of -12 dB or worse in the better eye. All participants were requested to answer a questionnaire on fear of falling. Associations between POAG severity and the prevalence of fear of falling were evaluated with the Cochran-Armitage trend test. Multivariable factors including age-adjusted odds ratios (ORs) for the prevalence of fear of falling and 95% confidence intervals (CIs) were evaluated with logistic regression models. The prevalence of fear of falling was 35/293 (11.9%) in the control group, 38/313 (12.1%) in the mild POAG group, 12/48 (25.0%) in the moderate POAG group, and 6/26 (23.1%) in the severe POAG group, and the trend was statistically significant (P = 0.028 Cochran-Armitage trend test). The adjusted ORs for prevalence in the mild, moderate, and severe POAG groups compared with that in the control group were 1.44 (95% CI: 0.83-2.51), 2.33 (95% CI: 1.00-5.44), and 4.06 (95% CI: 1.39-11.90), respectively. Among patients with POAG, the severity of visual field defects is associated with fear of falling. (http://www.umin.ac.jp/ctr/index.htm number, UMIN000005574.).

Genome-wide association study of bronchial asthma in the Volga-Urals region of Russia

Bronchial asthma is a chronic inflammatory respiratory disease that is caused by the complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between SNPs within 17q12-21 genomic region and childhood bronchial asthma in individuals of European descent. Association with this genomic region was then replicated in a number of independent samples of European and Asian descent. Here we report results of the first genome-wide association study of bronchial asthma in the Volga-Ural region of Russia. The present study includes 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnic origin (Russians, Tatars and Bashkirs). Genotyping of DNA samples was carried out using the Illumina Human610 quad array as a part of GABRIEL project (contract from the EC No LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550915 SNPs genotyped in 330 cases and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed statistically significant association with bronchial asthma (p < or = 4.79 x 10(-7)). SNP rs7216389 with the strongest evidence for association (p = 1.01 x 10(-7)) is located within the first intron of the GSDMB gene. Evidence for association was stronger with childhood-onset asthma (p = 1.97 x 10(-6) for SNP rs7216389) compared to late-onset asthma (p = 1.8 x 10(-4) for SNP rs7216389). Our replication study using three SNPs within GSDMB gene confirmed association with only childhood-onset asthma. In summary, these results suggest an important role for genetic variants within 17q12-q21 region in the development of bronchial asthma in the Volga-Ural region of Russia.

Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis. Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12). A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity. Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity.

Correlation between lipid peroxidation-induced TBARS level and disease severity in obsessive–compulsive disorder

Oxidative stress is thought to play an important role in several neuropsychiatric diseases including obsessive–compulsive disorder (OCD). Thiobarbituric acid reacting substances (TBARS) are products formed as a result of free radical induced lipid peroxidation in the human body. Our study investigated the correlation between TBARS and the clinical severity of OCD as indicated by the Yale Brown Obsessive Compulsive Scale (YBOCS). Serum TBARS was estimated in thirty nine newly diagnosed drug free OCD patients and thirty three disease free control subjects. Mean values for serum TBARS were found to be significantly higher ( P < 0.001) in cases than in controls (5.85 nmol/ml and 3.90 nmol/ml with an SD of 0.56 and 0.81 respectively). A strong positive correlation ( r s = 0.757, p < 0.01) between the lipid peroxidation marker TBARS and the disease severity indicator YBOCS was found among cases. Significant positive correlation was also found between TBARS and the obsessive and compulsive subscales of YBOCS. These findings were in tune with previous studies, which suggested oxidative stress induced increased free radical generation in the OCD patients. Our findings may help in understanding the development and progress of OCD and the treatment of patients of OCD in future.

Segmentation in Ultrasonic B-Mode Images of Healthy Carotid Arteries Using Mixtures of Nakagami Distributions and Stochastic Optimization

The goal of this work is to perform a segmentation of the intimamedia thickness (IMT) of carotid arteries in view of computing various dynamical properties of that tissue, such as the elasticity distribution (elastogram). The echogenicity of a region of interest comprising the intima-media layers, the lumen, and the adventitia in an ultrasonic B-mode image is modeled by a mixture of three Nakagami distributions. In a first step, we compute the maximum a posteriori estimator of the proposed model, using the expectation maximization (EM) algorithm. We then compute the optimal segmentation based on the estimated distributions as well as a statistical prior for disease-free IMT using a variant of the exploration/selection (ES) algorithm. Convergence of the ES algorithm to the optimal solution is assured asymptotically and is independent of the initial solution. In particular, our method is well suited to a semi-automatic context that requires minimal manual initialization. Tests of the proposed method on 30 sequences of ultrasonic B-mode images of presumably disease-free control subjects are reported. They suggest that the semi-automatic segmentations obtained by the proposed method are within the variability of the manual segmentations of two experts.

Large brachial and common carotid artery diameter in postmenopausal women with carotid atherosclerosis

Background and purposeIt is recognized that arteries can enlarge to compensate atherosclerosis. The role of diameter enlargement of unaffected arteries is not well known. We hypothesized that brachial and common carotid arteries diameters were larger in subjects with carotid atherosclerosis compared to subjects without these lesions. MethodsWe measured diameters in the common carotid and brachial arteries. Intimal medial thickness (IMT) of carotid arteries and carotid atherosclerosis were also evaluated using ultrasound in 83 cases and 83 disease-free control subjects. ResultsCommon carotid and brachial diameter was greater in cases (subjects with carotid atherosclerosis) than controls (subjects without carotid atherosclerosis) after adjustment for confounding variables (P<0.02). Common carotid diameter was also larger in individuals with greater IMT (P<0.0001), whereas brachial artery diameter was not. Subjects with more than one carotid plaque had larger arterial diameters than those with one or without plaques. ConclusionsCommon carotid and brachial artery diameters are both larger in cases than controls. This result suggests that vascular remodeling is a systemic process and not only a local response to atherosclerosis. The relationship between diameters and burden of disease could also suggest a link between vascular remodeling and severity of disease. Finally, if confirmed in prospective studies, brachial artery diameter could help to identify subjects at high cardiovascular risk, at least in postmenopausal women.