A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5±1.2 years versus 77.6±2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Manifestation and parental assessment of children’s cancer pain at home: an exploratory mixed methods study

Aims and objectives To describe pain manifestation in children with cancer at home and understand how parents assess this pain. Background Pain is experienced by children with cancer throughout their cancer journey. Short‐term, and into survivorship, pain has negative physical and psychological consequences. Changes in treatment location mean children with cancer spend more time at home. Little is known about pain experienced by children at home or how parents assess this pain. Design A mixed methods convergent parallel study was reported using STROBE. Method Parents of children with cancer on active treatment were recruited from one tertiary cancer centre. Parental attitudes towards pain expression were assessed using surveys. Parents recorded their child’s pain manifestation in pain diaries kept for one month. Interviews captured a deeper understanding of pain manifestation and how parents assess this pain at home. Integration occurred after each data collection method was analysed separately. Results Predominantly children were not in pain at home. However, most children experienced at least one episode of problematic pain over the pain diary period. Surveys showed parents held misconceptions regarding children’s pain expression. Interviews diverge from surveys and suggest parents used a range of information sources to assess pain. Conclusion Children with cancer may differ from one another in the manifestation of pain at home resulting in multiple pain trajectories. Parents of children with cancer are able to adequately assess their child’s pain using information from multiple source

Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors

Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. Methods Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC(0–12), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. Results No association between dose normalized AUC(0–12) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. Conclusions Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib

Response to Lawrence DJ: The global summit on the efficacy and effectiveness of spinal manipulative therapy for the prevention and treatment of non-musculoskeletal disorders: A systematic review of the literature

Thank you for the opportunity to respond to the Letter to the Editor by Dana J. Lawrence. In his letter, Lawrence states that the results of our systematic review may be due to bias. However, he does not adequately substantiate his claims..

Solubilization and Characterization of Phosphoprotein Phosphatase(s) from Bovine Corpus-Luteum Plasma Membranes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65607/1/j.1432-1033.1975.tb02186.x.pd

Genome-wide association reveals genetic effects on human Aβ₄₂and τ protein levels in cerebrospinal fluids: a case control study

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ_1-42, T-tau, and P-tau_181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.</p> <p>Methods</p> <p>Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ_1-42, T-tau, and P-tau_181PLevels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.</p> <p>Results</p> <p>We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ_1-42levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. <it>CYP19A1 </it>'aromatase' (rs2899472), <it>NCAM2</it>, and multiple SNPs located on chromosome 10 near the <it>ARL5B </it>gene demonstrated the strongest associations with Aβ_1-42in normal subjects. Two genes found to be near the top SNPs, <it>CYP19A1 </it>(rs2899472, p = 1.90 × 10^-7) and <it>NCAM2 </it>(rs1022442, p = 2.75 × 10^-7) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau_181Plevels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ_1-42).</p> <p>Conclusions</p> <p>Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.</p