Therkildsen C.,Copenhagen University |
Therkildsen C.,Institute of Clinical science |
Ladelund S.,Copenhagen University |
Rambech E.,Institute of Clinical science |
And 4 more authors.
European Journal of Neurology | Year: 2015
Background and purpose: Brain tumors represent a rare and relatively uncharacterized tumor type in Lynch syndrome. Methods: The national Danish Hereditary Nonpolyposis Colorectal Cancer Register was utilized to estimate the cumulative life-time risk for brain tumors in Lynch syndrome, and the mismatch repair (MMR) status in all tumors available was evaluated. Results: Primary brain tumors developed in 41/288 families at a median age of 41.5 (range 2-73) years. Biallelic MMR gene mutations were linked to brain tumor development in childhood. The risk of brain tumors was significantly higher (2.5%) in MSH2 gene mutation carriers compared to patients with mutations in MLH1 or MSH6. Glioblastomas predominated (56%), followed by astrocytomas (22%) and oligodendrogliomas (9%). MMR status was assessed in 10 tumors, eight of which showed MMR defects. None of these tumors showed immunohistochemical staining suggestive of the IDH1 R132H mutation. Conclusion: In Lynch syndrome brain tumors occurred in 14% of the families with significantly higher risks for individuals with MSH2 gene mutations and development of childhood brain tumors in individuals with constitutional MMR defects. © 2015 EAN.
Minas C.,Institute of Clinical science |
Curry E.,Imperial College London |
Montana G.,Statistics Section
Bioinformatics | Year: 2013
Motivation: Due to rapid technological advances, a wide range of different measurements can be obtained from a given biological sample including single nucleotide polymorphisms, copy number variation, gene expression levels, DNA methylation and proteomic profiles. Each of these distinct measurements provides the means to characterize a certain aspect of biological diversity, and a fundamental problem of broad interest concerns the discovery of shared patterns of variation across different data types. Such data types are heterogeneous in the sense that they represent measurements taken at different scales or represented by different data structures. Results:We propose a distance-based statistical test, the generalized RV (GRV) test, to assess whether there is a common and non-random pattern of variability between paired biological measurements obtained from the same random sample. The measurements enter the test through the use of two distance measures, which can be chosen to capture a particular aspect of the data. An approximate null distribution is proposed to compute P-values in closed-form and without the need to perform costly Monte Carlo permutation procedures. Compared with the classical Mantel test for association between distance matrices, the GRV test has been found to be more powerful in a number of simulation settings. We also demonstrate how the GRV test can be used to detect biological pathways in which genetic variability is associated to variation in gene expression levels in an ovarian cancer sample, and present results obtained from two independent cohorts. Availability: R code to compute the GRV test is freely available from http://www2.imperial.ac.uk/ ~gmontanaContact: firstname.lastname@example.org Supplementary data: Supplementary data are available at Bioinformatics online. © The Author 2013. Published by Oxford University Press.
Omerov P.,Karolinska University Hospital |
Omerov P.,Karolinska Institutet |
Steineck G.,Karolinska Institutet |
Steineck G.,Institute of Clinical science |
And 5 more authors.
Psychological Medicine | Year: 2014
Background. Valuable trauma-related research may be hindered when the risks of asking participants about traumatic events are not carefully weighed against the benefits of their participation in the research.Method. The overall aim of our population-based survey was to improve the professional care of suicide-bereaved parents by identifying aspects of care that would be amenable to change. The study population included 666 suicide-bereaved and 377 matched (2:1) non-bereaved parents. In this article we describe the parents' perceptions of their contacts with us as well as their participation in the survey. We also present our ethical-protocol for epidemiological surveys in the aftermath of a traumatic loss.Results. We were able to contact 1410 of the 1423 eligible parents; eight of these parents expressed resentment towards the contact. Several participants and non-participants described their psychological suffering and received help because of the contact. A total of 666 suicide-bereaved and 377 non-bereaved parents returned the questionnaire. Just two out of the 1043 answered that they might, in the long term, be negatively affected by participation in the study; one was bereaved, the other was not. A significant minority of the parents reported being temporarily negatively affected at the end of their participation, most of them referring to feelings of sadness and painful memories. In parallel, positive experiences were widely expressed and most parents found the study valuable.Conclusions. Our findings suggest, given that the study design is ethically sound, that suicide-bereaved parents should be included in research since the benefits clearly outweigh the risks. Copyright © 2013 Cambridge University Press.
Redfors Y.D.,Institute of Clinical science |
Grondahl H.G.,Institute for Postgraduate Dental Education |
Grondahl H.G.,Gothenburg University |
Hellgren J.,Institute of Clinical science |
And 4 more authors.
Otology and Neurotology | Year: 2012
Objective: To assess the use of cone beam computed tomography (CBCT) compared with multi-slice computed tomography (MSCT) in otosclerosis, with special emphasis on middle- and inner-ear anatomy. Study Design: Prospective study. Patients: Twenty patients who underwent a stapedectomy 30 years ago were selected on the basis of bone conduction threshold values. Their mean age was 65 years (range, 48-76 yr). Intervention: All patients underwent CBCT and MSCT with a slice thickness of 0.5 to 0.6 mm. Main Outcome Measures: Sixteen middle- and inner-ear anatomic structures and stapedial prostheses were analyzed by visual grading analysis. To assess critical reproduction and thereby the clinical applicability of CBCT, a dichotomization was made. Assessment of otosclerotic foci was performed using a grading system dividing the lesions in; 1) sole fenestral lesions, 2) retrofenestral lesions with or without fenestral lesions and 3) severe retrofenestral lesions. Results: The 16 anatomic structures were clearly reproduced by both imaging techniques. However, there was an interobserver variation in judging the superiority of 1 method in favor of the other. Otosclerotic lesions were diagnosed in 80/95% using MSCT and 50/85% using CBCT (evaluators 1 and 2, respectively). Retrofenestral lesions were diagnosed in 5 of 10 of ears with severe-to-profound hearing loss, whereas no retrofenestral lesions were diagnosed in the 10 ears with mild-to-moderate hearing loss. The stapedial prostheses were adequately or very well reproduced by both methods. Conclusion: CBCT is a new imaging technique with a considerably lower radiation dose than conventional MSCT. Our study indicates that CBCT is suitable and, in many ways, equivalent to MSCT, for temporal bone imaging in otosclerosis. © 2012, Otology & Neurotology, Inc.
Yang M.,China Japan Friendship Hospital Health Ministry of China |
Li X.,Institute of Clinical Science |
Pang C.-H.,China Japan Friendship Hospital |
Huang L.-P.,China Japan Friendship Hospital Health Ministry of China
Breast Care | Year: 2013
Background: Pure mucinous breast carcinoma is a relatively rare subtype of breast malignancy. This study is to investigate the clinical and pathologic features of pure mucinous breast carcinoma. Patients andMethods: A retrospective review of our database of patients who presented with breast cancer was performed. The medical records of 1,060 patients with invasive breast cancer who underwent surgery were reviewed. Results: 28 patients with pure mucinous breast cancer were identified. The mean age was 55.28 ± 15.73 years. 17 patients underwent modified radical mastectomy; 11 underwent breast-conserving therapy. The tumor size was T1 in 19 patients, T2 in 8 patients, and T3 in 1 patient. None of the patients had lymph node metastasis. There was no distant metastasis. 18 were stage I, and 10 were stage II. Estrogen receptor, progesterone receptor, HER-2, and P53 were positive in 96, 93, 0, and 28%, respectively. Median follow-up was 42 months (range 1-84 months). 1 patient had local recurrence. The overall survival rate was 100%. Conclusion: Pure mucinous breast carcinoma has a favorable prognosis. Less invasive treatment might be optional. Larger data samples with longer follow-up would be necessary to gain a better understanding of this disease. © 2013 S. Karger AG, Basel.
Block L.,Institute of Clinical science |
Lundborg C.,Institute of Clinical science |
Bjersing J.,Institute of Clinical science |
Dahm P.,Institute of Clinical science |
And 2 more authors.
Clinical Journal of Pain | Year: 2015
Introduction: This randomized, cross-over, double-blind, controlled study of continuous intrathecal morphine administration in patients with severe, long-term pain addresses whether the supplementation of low doses of naloxone in this setting is associated with beneficial clinical effects. Methods: All of the study subjects (n=11) provided informed consent and were recruited from a subset of patients who were already undergoing long-term treatment with continuous intrathecal morphine because of difficult-to-treat pain. The patients were (in a randomized order) also given intrathecal naloxone (40 ng/24 h or 400 ng/24 h). As control, the patients' ordinary dose of morphine without any additions was used. The pain (Numeric Rating Scale, NRS) during activity, perceived quality of sleep, level of activity, and quality of life as well as the levels of several proinflammatory and anti-inflammatory cytokines in the blood were assessed. The prestudy pain (NRS during activity) in the study group ranged from 3 to 10. Results: A total of 64% of the subjects reported improved quality of sleep during treatment with naloxone at a dose of 40 ng per 24 hours as compared with 9% with sham treatment (P=0.024). Although not statistically significant, pain was reduced by 2 NRS steps or more during supplemental treatment with naloxone in 36% of subjects when using the 40 ng per 24 hours dose and in 18% of the subjects when using naloxone 400 ng per 24 hours dose. The corresponding percentage among patients receiving unaltered treatment was 27%. Conclusions: To conclude, the addition of an ultralow dose of intrathecal naloxone (40 ng/24 h) to intrathecal morphine infusion in patients with severe, persistent pain improved perceived quality of sleep. We were not able to show any statistically significant effects of naloxone on pain relief, level of activity, or quality of life. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Sheffield N.C.,Duke University |
Thurman R.E.,University of Washington |
Song L.,Duke University |
Safi A.,Duke University |
And 6 more authors.
Genome Research | Year: 2013
Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types. © 2013, Published by Cold Spring Harbor Laboratory Press.
Panda S.,Umeå University |
Nilsson J.A.,Institute of Clinical science |
Gekara N.O.,Umeå University
Immunity | Year: 2015
Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response. © 2015 Elsevier Inc.
Muth A.,Institute of Clinical science |
Ragnarsson O.,Gothenburg University |
Johannsson G.,Gothenburg University |
Wangberg B.,Institute of Clinical science
British Journal of Surgery | Year: 2015
Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The main aims of this paper were to review outcome after surgical versus medical treatment of PA and partial versus total adrenalectomy in patients with PA. Methods: Relevant medical literature from PubMed, the Cochrane Library and Embase OvidSP from 1985 to June 2014 was reviewed. Results: Of 2036 records, 43 articles were included in the final analysis. Twenty-one addressed surgical versus medical treatment of PA, four considered partial versus total adrenalectomy for unilateral PA, and 18 series reported on surgical outcomes. Owing to the heterogeneity of protocols and reported outcomes, only a qualitative analysis was performed. In six studies, surgical and medical treatment had comparable outcomes concerning blood pressure, whereas six showed better outcome after surgery. No differences were seen in cardiovascular complications, but surgery was associated with the use of fewer antihypertensive medications after surgery, improved quality of life, and (possibly) lower all-cause mortality compared with medical treatment. Randomized studies indicate a role for partial adrenalectomy in PA, but the high rate of multiple adenomas or adenoma combined with hyperplasia in localized disease is disconcerting. Surgery for unilateral dominant PA normalized BP in a mean of 42 (range 20-72) per cent and the biochemical profile in 96-100 per cent of patients. The mean complication rate in 1056 patients was 4.7 per cent. Conclusion: Recommendations for treatment of PA are hampered by the lack of randomized trials, but support surgical resection of unilateral disease. Partial adrenalectomy may be an option in selected patients. © 2015 BJS Society Ltd.
Spence D.,Queen's University of Belfast |
Stewart M.C.,Institute of Clinical Science |
Alderdice F.A.,Queen's University of Belfast |
Patterson C.C.,Queen's University of Belfast |
Halliday H.L.,Royal Maternity Hospital
Public Health | Year: 2012
Objective: To compare blood pressure between 50-year-old adults who were born at term (37-42 weeks of gestation) with intra-uterine growth restriction (IUGR; birth weight <10th centile) and a control group of similar age born at term without IUGR (birth weight ≥10th centile). Study design: Controlled comparative study. Methods: Participants included 232 men and women who were born at the Royal Maternity Hospital, Belfast, a large regional maternity hospital in Northern Ireland, between 1954 and 1956. One hundred and eight subjects who were born with IUGR were compared with 124 controls with normal birth weight for gestation. The main outcome measures were systolic and diastolic blood pressure at approximately 50 years of age, measured according to European recommendations. Results: The IUGR group had higher systolic and diastolic blood pressure than the control group: 131.5 [95% confidence interval (CI) 127.9-135.1] vs 127.1 (95% CI 124.3-129.2) mmHg and 82.3 (95% CI 79.6-85.0) vs 79.0 (95% CI 77.0-81.0) mmHg, respectively. After adjustment for gender, the differences between the groups were statistically significant: systolic blood pressure 4.5 (95% CI 0.3-8.7) mmHg and diastolic blood pressure 3.4 (95% CI 0.2-6.5) mmHg (both . P < 0.05). More participants in the IUGR group were receiving treatment for high blood pressure compared with the control group [16 (15%) vs 11 (9%)], although this was not statistically significant. The proportion of subjects with blood pressure >140/90 mmHg or currently receiving antihypertensive treatment was 45% (. n = 49) for the IUGR group, and 31% (. n = 38) for the control group (odds ratio 1.9, 95% CI 1.1-3.3). Adjustment for potential confounders made little difference. Conclusions: IUGR is associated with higher blood pressure at 50 years of age. Individuals born with IUGR should have regular blood pressure screening and early treatment as required. Hypertension remains underdiagnosed and undertreated in adult life. © 2012 The Royal Society for Public Health.