Expression pattern of Nogo‐A,MAG, and NgR in regenerating urodele spinal cord

Background: The mammalian central nervous system is incapable of substantial axon regeneration after injury partially due to the presence of myelin‐associated inhibitory molecules including Nogo‐A and myelin associated glycoprotein (MAG). In contrast, axolotl salamanders are capable of considerable axon regrowth during spinal cord regeneration. Results: Here, we show that Nogo‐A and MAG, and their receptor, Nogo receptor (NgR), are present in the axolotl genome and are broadly expressed in the central nervous system (CNS) during development, adulthood, and importantly, during regeneration. Furthermore, we show that Nogo‐A and NgR are co‐expressed in Sox2 positive neural progenitor cells. Conclusions: These expression patterns suggest myelin‐associated proteins are permissive for neural development and regeneration in axolotls. Developmental Dynamics 242:847–860, 2013. © 2013 Wiley Periodicals, Inc.     

Polymorphisms in IL‐1A are associated with endometrial cancer susceptibility among Chinese Han population: A case–control study

Endometrial cancer (EC) is one of the most common malignant tumours of the female genital tract, and it has become a serious malignant disease of the female genital tract in China. Existing researches have revealed the association between polymorphisms of IL‐1A and several gynaecological diseases. In this research, we analysed the association between IL‐1A gene polymorphisms and endometrial cancer susceptibility in Chinese female population. A total of 81 patients and 198 healthy people were selected. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression. Genetic models and analyses showed that IL‐1A rs3783550 TT and rs3783546 CC increased the risk of endometrial cancer under the recessive model, respectively (rs3783550: OR = 2.80, 95%CI: 1.32–5.92, p = .008; rs3783546: OR = 2.79, 95%CI: 1.32–5.89, p = .008). In the recessive model, we also found that both IL‐1A rs1609682 and IL‐1A rs3783521 increased the risk of endometrial cancer, respectively (rs1609682: OR = 2.79, 95%CI: 1.32–5.89, p = .0081; rs3783521: OR = 2.80, 95%CI: 1.32–5.92, p = .008). Haplotype analysis was performed that did not reveal any significant results. In summary, IL‐1A rs3783550, rs3783546, rs1609682 and rs3783521 polymorphisms may be associated with an increased risk of endometrial cancer in Chinese female populations.     

A follow‐up case–control association study of tractable (druggable) genes in recurrent major depression

The High‐Throughput Disease‐specific target Identification Program (HiTDIP) aimed to study case–control association samples for 18 common diseases. Here we present the results of a follow‐up case–control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max‐Planck Institute (MP‐GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow‐up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator‐Activated Receptor‐Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow‐up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP‐GSK sample. Performing Cochran–Mantel–Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP‐GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis. © 2011 Wiley‐Liss, Inc.     

Cerebrospinal fluid γδ T cell frequency is age‐related: a case–control study of 435 children with inflammatory and non‐inflammatory neurological disorders

Studies of cerebrospinal fluid (CSF) γδ T cells in children are limited, due especially to the lack of control data. In adults, gamma/delta T cells (TCR‐γδ) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of γδ T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case–control study of 100 children with non‐inflammatory neurological disorders (NIND), 312 with opsoclonus–myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF γδ T cell frequency and patient age was striking: median frequency of 27% in infants and 3·3% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for γδ T cell activation [human leucocyte antigen D‐related (HLA‐DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)‐4, interferon (IFN)‐γ] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies/combinations, none altered the frequency of total CSF γδ T cells or subsets significantly. In OIND, the CSF γδ T cell frequency was < 10% for single samples of other paraneoplastic disorders [anti‐neuronal nuclear antibody (ANNA)‐1, PCA‐1, teratoma‐associated syndrome], cerebellar ataxia (post‐infectious, ataxia‐telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF γδ T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut‐off references for NIND are important findings for the design of future paediatric studies.     

Polymorphisms of inflammation‐related genes and colorectal cancer risk: a population‐based case–control study in China

The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation‐related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population‐based case–control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation‐related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene–gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation‐related genes on CRC risk.     

Neuronal Nogo‐A in New‐born Retinal Ganglion Cells: Implication for the Formation of the Age‐related Fiber Order in the Optic Tract

Nogo‐A is highly expressed in oligodendrocytes in the adult central nervous system (CNS). Recently it was found that Nogo‐A is also expressed in some neuronal types during development. Here, we examined the expression pattern of Nogo‐A in both the retina and optic tract (OT) of mouse embryos from E12 to E15. After perturbation of its function in the OT for 5 hr in the brain slice culture system using a Nogo‐A specific antibody or antagonist of its receptor (NEP1‐40), the optic nerve fibers and growth cones were traced with DiI. We showed that most Tuj‐1 positive new‐born neurons at E12 were Nogo‐A positive. At E15, retinal neurons reduced the Nogo‐A expression. It was worth noting that some projecting axons expressed Nogo‐A along the retinofugal pathway. On the basis of their specific locations within the superficial half of the OT and the colocalization with GAP‐43 (a marker for the newly born growth cones and axons), we concluded that those Nogo‐A positive axons were the newly arrived retinal fibers. Blocking the function of Nogo‐A with Nogo‐A antibody or NEP1‐40 resulted in the shift of DiI labeled axons and growth cones from the superficial half to the whole depth of the OT. These results indicate that Nogo‐A in the newly born retinal ganglion cells (RGCs) and their axons are involved in sorting out the newly arrived axons to the subpial region of the OT. Anat Rec, 299:1027–1036, 2016. © 2016 Wiley Periodicals, Inc.     

Narcolepsy with cataplexy and pregnancy: a case–control study

This was a retrospective case–control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich‐Horvat et al. (J. Sleep Res., 2013, 22: 496–512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27.1%), a disease before pregnancy was present compared with eight cases (4.9%) in the control group (P < 0.001); among them, extrinsic asthma was reported 11 times in the narcolepsy with cataplexy group (P < 0.005). Patients with narcolepsy with cataplexy more often had a single pregnancy compared with controls (P < 0.05). Gestational diabetes was more frequent in patients with narcolepsy with cataplexy (P < 0.05). Induced deliveries were higher in controls (P < 0.009). No differences were found between the groups in terms of duration of pregnancies and complications during and after delivery, as during the puerperium. Neonates from patients had heavier birth weight (P < 0.015). The breastfeeding period was longer in patients (P < 0.01). Modafinil and methylphenidate were the drugs administered in six pregnancies. No significant differences in depression during pregnancy and during puerperium were found between patients and controls. This is the first case–control study in women with narcolepsy with cataplexy related to pregnancy, delivery, childbirth and puerperium. Data suggest that patients have pregnancy outcomes similar to controls. The prevalence of gestational diabetes was higher in women with narcolepsy with cataplexy. Caesarean sections, complications during delivery and normal perinatal period for infants were similar in both groups. Breastfeeding was longer in patients.     

Activating the AKT2–nuclear factor‐κB–lipocalin‐2 axis elicits an inflammatory response in age‐related macular degeneration

Age‐related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome‐mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome‐mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin‐2 (LCN‐2) and the inflammatory responses induced in this mouse model. We show that nuclear factor‐κB (NF‐κB) and STAT‐1 may function as a complex in our animal model system, together controlling the upregulation of LCN‐2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN‐2‐positive neutrophils in the choroid and retina of early AMD patients as compared with age‐matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2–NF‐κB–LCN‐2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Parent‐of‐origin‐environment interactions in case‐parent triads with or without independent controls

With case–parent triad data, one can frequently deduce parent of origin of the child's alleles. This allows a parent‐of‐origin (PoO) effect to be estimated as the ratio of relative risks associated with the alleles inherited from the mother and the father, respectively. A possible cause of PoO effects is DNA methylation, leading to genomic imprinting. Because environmental exposures may influence methylation patterns, gene–environment interaction studies should be extended to allow for interactions between PoO effects and environmental exposures (i.e., PoOxE). One should thus search for loci where the environmental exposure modifies the PoO effect. We have developed an extensive framework to analyze PoOxE effects in genome‐wide association studies (GWAS), based on complete or incomplete case–parent triads with or without independent control triads. The interaction approach is based on analyzing triads in each exposure stratum using maximum likelihood estimation in a log‐linear model. Interactions are then tested applying a Wald‐based posttest of parameters across strata. Our framework includes a complete setup for power calculations. We have implemented the models in the R software package Haplin. To illustrate our PoOxE test, we applied the new methodology to top hits from our previous GWAS, assessing whether smoking during the periconceptional period modifies PoO effects on cleft palate only.     

HIF‐1α triggers long‐lasting glutamate excitotoxicity via system xc− in cerebral ischaemia–reperfusion

Hypoxia‐inducible factor 1α (HIF ‐1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF ‐1α might contribute to glutamate‐mediated excitotoxicity during cerebral ischaemia–reperfusion (CIR ) and investigated its molecular mechanism. We showed that an HIF ‐1α conditional knockout mouse displayed an inhibition in CIR ‐induced elevation of extracellular glutamate and N ‐methyl‐d ‐aspartate receptor (NMDAR ) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF ‐1α mainly regulates the cystine–glutamate transporter (system x_c^?) subunit xCT by directly binding to its promoter; xCT and its function are up‐regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR ) or CIR ‐mediated glutamate excitotoxicity in vitro and in vivo . Pharmaceutical inhibition of system x_c^? by a clinically approved anti‐cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF ‐1α plays a role in CIR ‐induced glutamate excitotoxicity via the long‐lasting activation of system x_c^?‐dependent glutamate outflow and suggest that system x_c^? is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Detection of SV40 in colon cancer: A molecular case–control study from Northeast Italy

To explore the involvement of the simian polyomavirus SV40 in human colon cancer, a molecular case–control study was undertaken in patients and in their relatives living in an area where the spread of SV40 has already been documented. From 2006 to 2008, 94 colon cancer patients (age: 37–90 years) and 91 subjects (age: 32–70 years) relatives of each index case were enrolled. A blood sample and a specimen of cancer tissue or biopsy were collected, from each patient or control, respectively. Samples were analyzed twice for Polyomavirus (i.e., SV40, JCV, and BKV) by PCR and by quantitative real‐time PCR (RT‐qPCR) with reproducible results. No BKV/JCV was detected either in normal or pathological tissues. SV40 was not present in control subjects, either normal tissue or in biopsies from adenomas or polyps. All blood samples were negative. Conversely, six adenocarcinoma specimens were positive for SV40 sequences (overall prevalence 6.4%, P = 0.03 in comparison with controls). Nevertheless, the SV40‐associated colon cancer risk proved statistically not significant (OR = 3.91; P = 0.115) when adjusted for age. Quantitation of SV40 DNA performed by RT‐qPCR showed a low viral load ranging from 6.2 × 10¹ to 9 × 10³ copies per reaction. This molecular case–control survey showed, for the first time in fresh samples and by RT‐qPCR, that SV40 can be detected in colon cancer tissue. However, the finding was not statistically significant when compared with a well‐structured community control group. Thus, the role of SV40 and other polyomavirus in colon cancer genesis deserves further investigation. J. Med. Virol. 82: 1197–1200, 2010. © 2010 Wiley‐Liss, Inc.     

Lack of association of a single‐nucleotide polymorphism of the μ‐opioid receptor gene with anxiety‐related traits: Results from a cross‐sectional study of adults and a longitudinal study of children

There is evidence from animal experiments that the μ‐ and δ‐opioid receptors may play a role in anxiety and depression. It might therefore be expected that functional polymorphisms of these genes in humans are associated with anxiety and depression. We investigated a single‐nucleotide polymorphism (Asn40Asp) of the μ‐opioid receptor gene (OPRM1). This association was investigated in two samples: 1) a cross‐sectional survey of 867 community‐living adults aged 18–79 years who were assessed for anxiety and depression symptoms and related personality traits; and 2) a longitudinal study of childhood temperament in which 660 children were followed from infancy to the mid‐teens and assessed for anxiety‐related temperament and behavior problems. The data did not support a role for the Asn40Asp polymorphism in anxiety and depression, despite adequate statistical power to detect small effects. © 2002 Wiley‐Liss, Inc.