In this work, we study the behavior of saturation fronts for two‐phase flow through a long homogeneous porous column . In particular, the model includes hysteresis and dynamic effects in the ...capillary pressure and hysteresis in the permeabilities. The analysis uses traveling wave approximation. Entropy solutions are derived for Riemann problems that are arising in this context. These solutions belong to a much broader class compared to the standard Oleinik solutions, where hysteresis and dynamic effects are neglected. The relevant cases are examined and the corresponding solutions are categorized. They include nonmonotone profiles, multiple shocks, and self‐developing stable saturation plateaus. Numerical results are presented that illustrate the mathematical analysis. Finally, we discuss the implication of our findings in the context of available experimental results.
Two closely related genes, the presenilins (PS), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile ...AD). We performed a systematic mutation analysis of all coding and 5′-non-coding exons of PS-1 and PS-2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene (APP) had previously been excluded. Four different PS-1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50–78 years). One PS-2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS-1 and PS-2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS-1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5′-non-coding region of PS-1 and in intronic and exonic sequences of PS-2 that will be useful in genetic association studies.
Flooding of coastal areas with seawater often leads to density stratification. The stability of the density-depth profile in a porous medium initially saturated with a fluid of density
ρ
f
after ...flooding with a salt solution of higher density
ρ
s
is analyzed. The standard convection/diffusion equation subject to the so-called Boussinesq approximation is used. The depth of the porous medium is assumed to be infinite in the analytical approaches and finite in the numerical simulations. Two cases are distinguished: the laterally unbounded
CASE
A
and the laterally bounded
CASE
B
. The ratio of the diffusivity and the density difference
(
ρ
s
-
ρ
f
)
induced gravitational shear flow is an intrinsic length scale of the problem. In the unbounded
CASE
A
, this geometric length scale is the only length scale and using it to write the problem in dimensionless form results in a formulation with Rayleigh number
R
=
1
. In the bounded
CASE
B
, the lateral geometry provides another length scale. Using this geometrical length scale to write the problem in dimensionless form results in a formulation with a Rayleigh number
R
given by the ratio of the geometric and intrinsic length scales. For both
CASE
A
and
CASE
B
, the well-known Boltzmann similarity solution provides the ground state. Three analytical approaches are used to study the stability of this ground state, the first two based on the linearized perturbation equation for the concentration and the third based on the full nonlinear equation. For the first linear approach, the surface spatial density gradient is used as an approximation of the entire background density profile. This results in a crude estimate of the
L
2
-norm of the concentration showing that the perturbation at first grows, but eventually decays in time. For the other two approaches, the full ground-state solution is used, although for the second linear approach subject to the restriction that the ground state slowly evolves in time (the so-called frozen profile approximation). Just like the ground state, the resulting eigenvalue problems can be written in terms of the Boltzmann variable. The linearized stability approach holds only for infinitesimal small perturbations, whereas the nonlinear, variational energy approach is not subject to such a restriction. The results for all three approaches can be expressed in terms of Boltzmann
t
transformed relationships between the system Rayleigh number and perturbation wave number. The results of the linear and nonlinear approaches are surprisingly close to each other. Based on the system Rayleigh number, this allows delineation of systems that are unconditionally stable, marginally stable, or transiently unstable. These analytical predictions are confirmed by direct two-dimensional numerical simulations, which also show the details of the transient instabilities as function of the wave number for
CASE
A
and the wave number and Rayleigh number for
CASE
B
. A numerical example of the effect of a layer with low permeability is also shown. Using typical values of the physical parameters, the analytical and numerical results are interpreted in terms of dimensional length and time scales. In particular, an explicit stability criterion is given for vertical column experiments.
The epsilon4 allele of the APOE gene increases the risk for AD, whereas the epsilon2 allele may be protective. The authors assessed the impact of APOE genotype on hippocampal, amygdalar, and global ...brain atrophy as putative markers of preclinical AD in a nondemented population. Carriers of epsilon4 had significantly more hippocampal and amygdalar atrophy than epsilon3epsilon3 subjects, but not more global brain atrophy. Carriers of epsilon2 did not have less brain atrophy than epsilon3epsilon3 subjects.
Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid-femoral pulse ...wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score.
PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography.
All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (P<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained &12% of the total variability for each of the phenotypes.
To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.
The role of genetics in the pathogenesis of Parkinson’s disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important ...insight into its molecular aetiology. Some Parkinson’s disease genes possibly cause Parkinson’s disease by protein aggregation. The presence of Lewy bodies in carriers of mutations in one gene and their absence in carriers of another, however, still point towards a complex pathogenic network, with Parkinson’s disease as a common clinical end point. The recent identification of the fourth and fifth Parkinson’s disease genes suggests multiple pathways—an impaired oxidative stress defence for mutations in DJ‐1, and a defect in another signalling pathway for mutations in NR4A2. Despite knowledge of genetics in familial Parkinson’s disease, our knowledge of the common, late‐onset form of Parkinson’s disease remains limited. In non‐familial Parkinson’s disease, genes and environment probably interact to give rise to the disease. We review advances in the genetics of Parkinson’s disease, focusing on the monogenic forms and their clinical and population‐genetic consequences.
There is a public health demand to prevent health conditions which lead to increased morbidity and mortality among the rapidly-increasing elderly population. Data for the incidence of such conditions ...exist in cohort studies worldwide, which, however, differ in various aspects. The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project aims at harmonizing data from existing major longitudinal studies for the elderly whilst focussing on cardiovascular diseases, diabetes mellitus, cancer, fractures and cognitive impairment in order to estimate their prevalence, incidence and cause-specific mortality, and identify lifestyle, socioeconomic, and genetic determinants and biomarkers for the incidence of and mortality from these conditions. A survey instrument assessing ageing-related conditions of the elderly will be also developed. Fourteen cohort studies participate in CHANCES with 683,228 elderly (and 150,210 deaths), from 23 European and three non-European countries. So far, 287 variables on health conditions and a variety of exposures, including biomarkers and genetic data have been harmonized. Different research hypotheses are investigated with meta-analyses. The results which will be produced can help international organizations, governments and policy-makers to better understand the broader implications and consequences of ageing and thus make informed decisions.
Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, ...and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD).
Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age.
After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD.
Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.
Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and ...genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.
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