Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Niemann‐Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post‐mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C‐X‐C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL‐3, IL‐10 and IL‐13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147148/1/jimd0083.pd

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Mobilized Peripheral Blood Stem Cells (PBSC) Compared with Bone Marrow (BM) as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced Intensity Conditioning (RIC-alloSCT) in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR): a Retrospective Analysis From the ALWP of EBMT

Of all the grave crises in Northern Ireland's history, the events of Bloody Sunday are perhaps the most notorious. The subject of an independent inquiry that is the longest and most expensive the British government has ever undertaken, this yet to be resolved issue continues to be one of the most significant events in the recent history of the Troubles. This book tackles the subject from a new angle that covers both the political and psychological aspects of what happened. Based on extensive interviews with families whose relatives were killed by British soldiers, it is a record of the trauma that they have suffered. Setting Bloody Sunday in social, political and historical contexts, the authors examine the events of the day itself, the aftermath, and the relationship between post-traumatic stress disorder, grief, mourning and storytelling. The authors conclude with accounts of state and community responses to the trauma, and the impact and implications of the Saville Inquiry, which has allowed family members to express publicly their stories about the events of Bloody Sunday

Toxicokinetics of selenium in the slider turtle, Trachemys scripta

peer reviewedSelenium (Se) is an essential element that can be harmful for wildlife. However, its toxicity in poikilothermic amniotes, including turtles, remains poorly investigated. The present study aims at identifying selenium toxicokinetics and toxicity in juvenile slider turtles (age: 7 months), Trachemys scripta, dietary exposed to selenium, as selenomethionine SeMet, for eight weeks. Non-destructive tissues (i.e. carapace, scutes, skin and blood) were further tested for their suitability to predict selenium levels in target tissues (i.e. kidney, liver and muscle) From conservation perspective. 130 juvenile yellow-bellied slider turtles were assigned in three groups of 42 individuals each (i.e. control, SeMet1 and SeMet2). These groups were subjected to a feeding trial including an eight-week supplementation period SP8 and a following four-week elimination period EP4. During the SP8, turtles fed on diet containing 1.1 ± 0.04, 22.1 ± 1.0 and 45.0 ± 2.0 µg.g-1 of selenium (control, SeMet1 and SeMet2, respectively). During the EP4, turtles fed on non-supplemented diet. At different time during the trial, six individuals per group were sacrificed and tissues collected (i.e. carapace, scutes, skin, blood, liver, kidney, muscle) for analyses. During the SP8 (Figure 1), both SeMet1 and SeMet2 turtles efficiently accumulated selenium from a SeMet dietary source. The more selenium was concentrated in the food, the more it was in the turtle body but the less it was removed from their tissues. Moreover, SeMet was found to be the more abundant selenium species in turtles’ tissues. Body condition (i.e. growth in mass and size, feeding behaviour and activity) and survival of the SeMet1 and SeMet2 turtles seemed to be unaffected by the selenium exposure. There were clear evidences that reptilian species are differently affected by and sensitive to selenium exposure but the lack of any adverse effects was quite unexpected