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- Namavar, Yasmin, et al.
(författare)
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Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.
- 2011
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 134:Pt 1, s. 143-56
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Tidskriftsartikel (refereegranskat)abstract
- Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
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| 2. |
- Chowdhury, Fahima, et al.
(författare)
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Concomitant enterotoxigenic Escherichia coli infection induces increased immune responses to Vibrio cholerae O1 antigens in patients with cholera in Bangladesh.
- 2010
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Ingår i: Infection and immunity. - 1098-5522. ; 78:5, s. 2117-24
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Tidskriftsartikel (refereegranskat)abstract
- Vibrio cholerae O1 and enterotoxigenic Escherichia coli (ETEC) are major bacterial pathogens that cause dehydrating disease requiring hospitalization of children and adults. The cholera toxin (CT) produced by V. cholerae O1 and the heat-labile toxin (LT) and/or heat-stable toxin (ST) of ETEC are responsible for secretory diarrhea. We have observed that about 13% of hospitalized diarrheal patients are concomitantly infected with V. cholerae O1 and ETEC. In order to understand the outcome of such dual infections on the clinical and immunological responses in cholera patients, we studied patients infected with V. cholerae O1 (group VC; n = 25), those infected with both V. cholerae O1 and ETEC (group VCET; n = 25), and those infected with ETEC only (group ET; n = 25). The VCET group showed more severe dehydration and had a higher intake of intravenous fluid and more vomiting than the ETEC group (P = 0.01 to 0.003). The VCET patients showed higher vibriocidal responses and increased antibody titers to cholera toxin and lipopolysaccharide (LPS) in plasma than did the V. cholerae O1 patients (P = 0.02 to <0.001). All responses in the V. cholerae O1 and in the VCET groups were more robust than those seen in the group infected with ETEC only (P = 0.01 to <0.001). We thus show that concomitant colonization with ETEC induces immune responses to V. cholerae antigens that are more robust than those seen with V. cholerae O1 infection alone. It is possible that LT or other factors expressed by ETEC may play a role as a mucosal adjuvant in enhancing the immune responses to V. cholerae O1.
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| 3. |
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| 4. |
- Hailer, Yasmin D., et al.
(författare)
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Legg-Calvé-Perthes disease and the risk of injuries requiring hospitalization : a register study involving 2579 patients
- 2012
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Ingår i: Acta Orthopaedica. - New York, USA : Informa Healthcare. - 1745-3674 .- 1745-3682. ; 83:6, s. 572-576
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Previous studies have suggested that Legg-Calvé-Perthes disease (LCPD) is associated with repetitive trauma, coagulation problems and anatomical abnormalities of the blood supply to the femoral head. The hypothesis that repetitive trauma can affect the blood supply of the femoral head, leading to LCPD, is supported by an animal model. For evidence of an increased risk of repetitive trauma, we investigated whether patients with LCPD have a higher risk for severe injuries requiring hospitalization.Patients and methods: We identified 2579 patients with LCPD in Sweden during the period 1964-2005. 13,748 individuals without LCPD were randomly selected from the Swedish general population, matched by year of birth, sex and region (control group). Cox proportional hazard regression estimated the risks.Results: Compared to the control group, patients with LCPD had a modestly raised hazard ratio (HR) of 1.2 (95% CI 1.1-1.3) for injury requiring hospitalization. The risks were slightly higher for soft tissue injuries (HR = 1.3, 95% CI:1.1-1.4) than for fractures (HR = 1.1, 95% CI: 1.0-1.3) and more pronounced among females. Compared to the control group, the higher risk for injury only applied to the lower extremities (HR = 1.2, 95% CI: 1.0-1.4) in patients with LCPD.Interpretation: Patients with LCPD are vulnerable to injuries which could be interpreted as a marker of hyperactive behavior. It could also implicate that anatomical changes in the bone formation or blood supply of the femoral head - increasing its sensibility for trauma - contribute to the etiology of LCPD.
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| 5. |
- Poulin, Lionel F., et al.
(författare)
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DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 119:25, s. 6052-6062
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Tidskriftsartikel (refereegranskat)abstract
- Mouse CD8 alpha(+) dendritic cells (DCs) in lymphoid organs and CD103(+) CD11b(-) DCs in nonlymphoid tissues share phenotypic and functional similarities, as well as a unique shared developmental dependence on the transcription factor Batf3. Human DCs resembling mouse CD8 alpha(+) DCs in phenotype and function have been identified in human blood, spleen, and tonsil. However, it is not clear whether such cells are also present in human nonlymphoid organs, and their equivalence to mouse CD8 alpha(+) DC has recently b een questioned. Furthermore, the identification of "CD8 alpha(+) DC-like" cells across different tissues and species remains problematic because of the lack of a unique marker that can be used to unambiguously define lineage members. Here we show that mouse CD8 alpha(+) DCs and CD103(+) CD11b(-) DCs can be defined by shared high expression of DNGR-1 (CLEC9A). We further show that DNGR-1 uniquely marks a CD11b(-) human DC population present in both lymphoid and nonlymphoid tissues of humans and humanized mice. Finally, we demonstrate that knockdown of Batf3 selectively prevents the development of DNGR-1(+) human DCs in vitro. Thus, high expression of DNGR-1 specifically and universally identifies a unique DC subset in mouse and humans. Evolutionarily conserved Batf3 dependence justifies classification of DNGR-1(hi) DCs as a distinct DC lineage. (Blood. 2012; 119(25): 6052-6062)
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| 6. |
- Sillivan, Stephanie E., et al.
(författare)
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ELK1 Transcription Factor Linked to Dysregulated Striatal Mu Opioid Receptor Signaling Network and OPRM1 Polymorphism in Human Heroin Abusers
- 2013
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 74:7, s. 511-519
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Tidskriftsartikel (refereegranskat)abstract
- Background: Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders. Methods: We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history. Results: A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed similar to 20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1. Conclusions: ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.
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