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1.
  • Deshpande, J, et al. (författare)
  • Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death.
  • 1992
  • Ingår i: Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. - 0014-4819. ; 88:1, s. 91-105
  • Tidskriftsartikel (refereegranskat)abstract
    • The ultrastructural changes in the pyramidal neurons of the CA1 region of the hippocampus were studied 6 h, 24 h, 48 h, and 72 h following a transient 10 min period of cerebral ischemia induced by common carotid occlusion combined with hypotension. The pyramidal neurons showed delayed neuronal death (DND), i.e. at 24 h and 48 h postischemia few structural alterations were noted in the light microscope, while at 72 h extensive neuronal degeneration was apparent. The most prominent early ultrastructural changes were polysome disaggregation, and the appearance of electron-dense fluffy dark material associated with tubular saccules. Mitochondria and nuclear elements appeared intact until frank neuronal degeneration. The dark material accumulated with extended periods of recirculation in soma and in the main trunks of proximal dendrites, often beneath the plasma membrane, less frequently in the distal dendrites and seldom in spines. Protein synthesis inhibitors (anisomycin, cycloheximide) and an RNA synthesis inhibitor (actinomycin D), administered by intrahippocampal injections or subcutanously, did not mitigate neuronal damage. Therefore, DND is probably not apoptosis or a form of programmed cell death. We propose that the dark material accumulating in the postischemic period represents protein complexes, possibly aggregates of proteins or internalized plasma membrane fragments, which may disrupt vital cellular structure and functions, leading to cell death.
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2.
  • Mondal, Tanmoy, et al. (författare)
  • Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
  • 2018
  • Ingår i: Cancer Cell. - 1535-6108. ; 33:3, s. 417-434.e7
  • Tidskriftsartikel (refereegranskat)abstract
    • Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies. Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.
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3.
  • Rostami, Elham, 1979- (författare)
  • Traumatic brain injury in humans and animal models
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Traumatic brain injuries (TBI) are receiving increasing attention due to a combination of injuries related to war and sports, as well as to an increasing number of traffic accident survivors. Today the leading cause of death in young adults in industrialized nations is traumatic brain injury and in the population under 35 years, the death rate is 3.5 times that of cancer and heart disease combined. Despite a major improvement in the outcome of TBI in the acute setting, the assessment, therapeutic interventions and prevention of long-term complications remain a challenge. The challenges today are primarily related to a rapid diagnosis, identification of patient’s pathophysiological heterogeneity and to limit the secondary injuries. TBI is a complex condition that can be caused by focal or diffuse primary impacts that may initiate complex secondary neurochemical processes that proceeds over hours and days. The major secondary events include neuronal death, ischemia, excitotoxicity, mitochondrial failure, oxidative stress, oedema and inflammation. In addition, the brain’s restorative capacity involving neurotrophins, in particular brain derived neurotrophic factor (BDNF), is triggered. Animal models are necessary to gain a deeper insight into the events that follow a TBI, and to ultimately apply the findings to the clinical setting. The aim of this thesis was to identify distinct pathological processes in different types of TBI by using animal models that mimic distinct types of TBI found in patients. We investigated alterations in gene expression, serum biomarkers and secondary processes such as inflammatory response involving the complement cascade. In addition we aimed to assess the effects of heterogeneity of TBI patients, based on their genetic background, on the outcome of TBI, with specific focus on BDNF. We used animal models to mimic three major types of TBI; blast wave, penetrating and rotational acceleration TBI. We found distinct profiles of alteration in gene expression in these models. The histological findings in blast and rotational TBI indicated these injuries to be mild. The hallmark of the rotational TBI was axonal injuries found in anatomical locations comparable with clinical findings in diffuse axonal injuries (DAI) in humans. Despite the mild type of injury displayed in the histology and behavioural outcome, significant increases in the serum biomarkers Tau, S100B, NF-H and MBP were observed up to 2 weeks following the injury. The complement cascade was initiated in both penetrating and rotational TBI, detected by C1q and C3. However, the terminal pathway that generates cell death, detected by C5b9, was only activated in the penetrating TBI. This suggests that axonal injuries and secondary axotomy found in the rotational TBI are not complement mediated. In order to investigate whether genetic heterogeneity can be used to predict injury outcome and brain plasticity following TBI, we targeted the ApoE ε4 allele and the BDNF gene. We investigated whether there was an association between the presence of the ApoE ε4 allele and BDNF polymorphisms and cognitive outcome in veterans who had suffered penetrating head injury. We found that the genetic polymorphisms of BDNF predict general intelligence following penetrating TBI. Subsequently we investigated the expression of BDNF and its receptors TrkB-full length, TrkB-truncated and p75NTR, in animals exposed to penetrating TBI. The expression of TrkB truncated and p75NTR was altered in the chronic phase. In summary, these results show the importance of categorizing the different types of TBI, not only through the use of animal models but also in the clinical setting. Each type of TBI shows distinct patterns of gene expression, behavioural outcome, and morphological changes that may be reflected in the release of serum biomarkers. In the clinical setting, the situation is further complicated by the coexistence of different types of injuries. In addition to this, the genetic background of each patient contributes to the heterogeneity of TBI pathology as well as their ability to recover. The use of distinct types of TBI models will provide essential information about the underlying pathology, which can then be applied to the clinical setting. This will contribute to the establishment of better diagnostic tools as well as more individualized treatment approaches.
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4.
  • Giddaluru, Sudheer, et al. (författare)
  • Genetics of structural connectivity and information processing in the brain
  • 2016
  • Ingår i: Brain Structure and Function. - 1863-2653. ; 221:9, s. 4643-4661
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.
5.
  • Munthe, Christian, 1962-, et al. (författare)
  • The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening
  • 2015
  • Ingår i: Public Health Ethics. - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283
  • Tidskriftsartikel (refereegranskat)abstract
    • The vision of legendary criminologist Cesare Lombroso to use scientific theories of individual causes of crime as a basis for screening and prevention programmes targeting individuals at risk for future criminal behaviour has resurfaced, following advances in genetics, neuroscience and psychiatric epidemiology. This article analyses this idea and maps its ethical implications from a public health ethical standpoint. Twenty-seven variants of the new Lombrosian vision of forensic screening and prevention are distinguished, and some scientific and technical limitations are noted. Some lures, biases and structural factors, making the application of the Lombrosian idea likely in spite of weak evidence are pointed out and noted as a specific type of ethical aspect. Many classic and complex ethical challenges for health screening programmes are shown to apply to the identified variants and the choice between them, albeit with peculiar and often provoking variations. These variations are shown to actualize an underlying theoretical conundrum in need of further study, pertaining to the relationship between public health ethics and the ethics and values of criminal law policy.
6.
  • Rostami, Elham, 1979-, et al. (författare)
  • Mechanisms of Blast Induced Brain Injuries, Experimental Studies in Rats.
  • 2011
  • Ingår i: NeuroImage. - 1053-8119. ; 54S1 2011/Epub 2010:54 suplement 1, s. S89-S97
  • Tidskriftsartikel (refereegranskat)abstract
    • Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2 mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects.
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7.
  • Sjöberg, Rickard L., et al. (författare)
  • Development of depression: : sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene
  • 2006
  • Ingår i: International Journal of Neuropsychopharmacology. - 1461-1457 .- 1469-5111. ; 9:4, s. 443-449
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous research has demonstrated that a polymorphism in the serotonin transporter gene (5-HTTLPR) and adverse psychosocial circumstances interact to predict depression. The purpose of the present study was to explore the extent to which sex modulates these effects. Eighty-one boys and 119 girls (16-19 years old) were interviewed about psychosocial background variables and genotyped for the 5-HTT promoter polymorphism. There were two main results. First, boys and girls carrying the short 5-HTTLPR allele react to different kinds of environmental factors. Whereas males were affected by living in public housing rather than in own owned homes and by living with separated parents, females were affected by traumatic conflicts within the family. Second, the responses of males and females carrying the short 5-HTTLPR allele to environmental stress factors go in opposite directions. Thus, whereas females tend to develop depressive symptoms, males seem to be protected from depression. The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls.
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8.
  • Eklund, Erik, et al. (författare)
  • Proteoglycan production in disomic and trisomy 7-carrying human synovial cells.
  • 2002
  • Ingår i: Matrix Biology. - Elsevier. - 1569-1802. ; 21:4, s. 325-335
  • Tidskriftsartikel (refereegranskat)abstract
    • To gain further insight into the synthesis and structure of the synovial matrix of joints, we have established cell cultures from synovial specimens and elaborated their production of hyaluronan and proteoglycans. The cultures secreted mainly the small proteoglycan decorin, but also considerable amounts of the related biglycan and the large proteoglycan versican. Only minor amounts of heparan sulfate proteoglycans were found. All cultures also had a high production of hyaluronan, which highlights the important role for normal joint function of these cells. In joint diseases, a common feature is the presence of an extra chromosome 7 (trisomy 7) in the synovial cells. To study the possible consequences of trisomy 7 on the synovial cell function, we extended our study to cultures that had been sub-cloned to contain high amounts of trisomy 7-carrying cells. These cell cultures had approximately four times more versican than their disomic counterparts in the cell culture medium, indicating that versican may be a mediator in the processes of joint destructive disorders. To find an explanation for this increase in versican, we investigated the expression/secretion of PDGF-AA and IL-6, cytokines with their genes located to chromosome 7. Indeed, both these cytokines were increased in the cultures with high frequencies of trisomy 7. We then added the two cytokines to cell cultures of disomic synovial cells, but only cells treated with IL-6 displayed an increased amount of versican. Thus, we suggest that the increased amount of versican in cultures of trisomy 7-carrying cells relates to an autocrine loop involving an increased IL-6 production.
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9.
  • Moens, Lotte N. J., et al. (författare)
  • HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples
  • 2015
  • Ingår i: Journal of Molecular Diagnostics. - 1525-1578 .- 1943-7811. ; 17:6, s. 729-739
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.
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10.
  • Persson, N, et al. (författare)
  • Synergy effects of HbA(1c) and variants of APOE and BDNFVal(66)Met explains individual differences in memory performance
  • 2013
  • Ingår i: Neurobiology of Learning and Memory. - 1074-7427. ; 106, s. 274-282
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed at exploring if synergy effects of Brain-Derived Neurotrophic Factor (BDNF) Val66Met, Apolipoprotein E (APOE) and HbA1c (glycated haemoglobin) could explain individual differences in memory performance over 10 years in a population based sample of nondemented adults (N = 888, 35–85 years at baseline). Episodic memory was affected by such agents, wheras semantic memory was spared. Both age and HbA1c were associated with episodic memory decline. BDNF66Met carriers with higher HbA1c levels evidenced slope decline in episodic recall. We found support for joint effects ofBDNFVal66Met × APOE × HbA1c and BDNFVal66Met × APOE × age on rates of episodic memory change over ten years, after controlling for age, sex, education and cardiovascular diseases. We conclude that variants of genetic polymorphisms act in synergy with long-term blood glucose control in shaping patterns of cognitive aging.
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