802 research outputs found
sj-pdf-1-jcb-10.1177_0271678X211066299 - Supplemental material for Genome-wide association study of brain arteriolosclerosis
No full textSupplemental material, sj-pdf-1-jcb-10.1177_0271678X211066299 for Genome-wide association study of brain arteriolosclerosis by Lincoln MP Shade, Yuriko Katsumata, Timothy J Hohman, Kwangsik Nho, Andrew J Saykin, Shubhabrata Mukherjee, Kevin L Boehme, John SK Kauwe, Lindsay A Farrer, Gerard D Schellenberg, Jonathan L Haines, Richard P Mayeux, Julie A Schneider, Peter T Nelson and David W Fardo in Journal of Cerebral Blood Flow & Metabolism</p
Measuring Access and Practice: Designing a Survey Methodology for the Hygiene, Sanitation and Water Sector
No full textAccess to safe water and sanitary means of excreta disposal are essential elements of
human development and poverty alleviation. It is estimated that one in four people in
the developing world lacks access to water while over half the population has no
access to sanitation. From the Alma-Ata declaration in 1978 to the recent Millennium
Development Goals, efforts to improve this situation have been hampered by the lack
of meaningful indicators to measure hygiene, sanitation and water coverage and
establish progress towards the goals and targets set out by the international
community.
This thesis aims to determine if measuring prevalence of access to water~ sanitation
and the practice of hygienic behaviour in hous~hold surveys can be.improved. With
no indicators available in current international' laws and targets, various aspects of
access and practice were examined to design indicators for field-testing. By using
- existing data sets, the research established that there is a high geographic clustering of
the measures of interest, which results in large design effects (deff) and rates of
homogeneity (roh) in cluster surveys. Based on the calculated roh optimum numbers
ofcluster and sample size were calculated for the field trials. This requires
introducing survey costs in the sample size calculations. The high clustering of water
and sanitation indicator require large sample sizes, resulting in large amounts of data
which organisations in the four field trials in Kosovo, South Africa, Kenya and Laos
found difficult to handle. Practical problems in the implementation of the survey
method resulted in non-sampling errors and could cause reluctance in adoption the
methodology. The research improved water and sanitation indicators but found that
for individual behaviour such as hygiene the household is not a suitable sampling unit.
It also showed that observation among interviewers have to be better standardised to
reduce the inter-surveyor.variation. Representative sampling is the current bottleneck
in the development of such a survey method. Current method requires a good
understanding of sampling theory as well as reliable sample frames, which are rarely
available to implementing organisations. Alternative sampling methods are
suggested, and recommendations are made for the further development ofthe survey
method designed in this research, which to date may be too complex for widespread
use
Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation
No full textDeficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(-/-)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction
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Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
No full textGerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD
The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease
No full textBackground\ud
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls.\ud
\ud
Results\ud
We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk.\ud
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Conclusions\ud
The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response
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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
No full textSven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease
An Estimation of the Entomological Inoculation Rate for Ifakara: A Semi-Urban Area in a Region of Intense Malaria Transmission in Tanzania.
No full textAn entomological study on vectors of malaria and their relative contribution to Plasmodium falciparum transmission in the semi-urban area of Ifakara, south-eastern Tanzania, was conducted. A total of 32 houses were randomly sampled from the area and light trap catches (LTC) performed in one room in each house every 2 weeks for 1 year. A total of 147 448 mosquitoes were caught from 789 LTC; 26 134 Anopheles gambiae s.l., 615 A. funestus, 718 other anophelines and 119 981 culicines. More than 60% of the total A. gambiae s.l. were found in five (0.6%) LTCs, with a maximum of 5889 caught in a single trap. Of 505 A. gambiae s.l. speciated by polymerase chain reaction, 91.5% were found to be A. arabiensis. Plasmodium falciparum sporozoite enzyme-linked immunosorbent assay tests were performed on 10 108 anopheles mosquitoes and 39 (0.38%) were positive. Entomological inoculation rate (EIR) estimates were generated using a standard method and an alternative method that allows the calculation of confidence intervals based on a negative binomial distribution of sporozoite positive mosquitoes. Overall EIR estimates were similar; 31 vs. 29 [95% confidence interval (CI): 19, 44] infectious bites per annum, respectively. The EIR ranged from 4 (95% CI: 1, 17) in the cool season to 108 (95% CI: 69, 170) in the wet season and from 54 (95% CI: 30, 97) in the east of the town to 15 (95% CI: 8, 30) in the town centre. These estimates show large variations over short distances in time and space. They are all markedly lower than those reported from nearby rural areas and for other parts of Tanzania
The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ
No full textBackground
The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer’s disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.
Results
Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.
Conclusions
In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction
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