Many Paths to Alzheimer's Disease: A Unifying Hypothesis Integrating Biological, Chemical, and Physical Risk Factors

Sporadic Alzheimer's disease (AD) is a complex, multifactorial disease. We should therefore expect to find many factors involved in its causation. The known neuropathology seen at autopsy in patients dying with AD is not consistently seen in all patients with AD and is sometimes seen in patients without dementia. This suggests that patients follow different paths to AD, with different people having slightly different combinations of predisposing physical, chemical and biologic risk factors, and varying neuropathology. This review summarizes what is known of the biologic and chemical predisposing factors and features in AD. We postulate that, underlying the neuropathology of AD is a progressive failure of neurons, with advancing age or other morbidity, to rid themselves of entropy, i.e., the disordered state resulting from brain metabolism. Understanding the diverse causes of AD may allow the development of new therapies targeted at blocking the paths that lead to dementia in each subset of patients

The synergy factor: a statistic to measure interactions in complex diseases

<p>Abstract</p> <p>Background</p> <p>One challenge in understanding complex diseases lies in revealing the interactions between susceptibility factors, such as genetic polymorphisms and environmental exposures. There is thus a need to examine such interactions explicitly. A corollary is the need for an accessible method of measuring both the size and the significance of interactions, which can be used by non-statisticians and with summarised, e.g. published data. The lack of such a readily available method has contributed to confusion in the field.</p> <p>Findings</p> <p>The synergy factor (<it>SF</it>) allows assessment of binary interactions in case-control studies. In this paper we describe its properties and its novel characteristics, e.g. in calculating the power to detect a synergistic effect and in its application to meta-analyses. We illustrate these functions with real examples in Alzheimer's disease, e.g. a meta-analysis of the potential interaction between a <it>BACE1 </it>polymorphism and <it>APOE</it>4: <it>SF </it>= 2.5, 95% confidence interval: 1.5–4.2; <it>p </it>= 0.0001.</p> <p>Conclusion</p> <p>Synergy factors are easy to use and clear to interpret. Calculations may be performed through the Excel programmes provided within this article. Unlike logistic regression analysis, the method can be applied to datasets of any size, however small. It can be applied to primary or summarised data, e.g. published data. It can be used with any type of susceptibility factor, provided the data are dichotomised. Novel features include power estimation and meta-analysis.</p

Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?

BACKGROUND: There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study. METHODS: We studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date. RESULTS: We replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4–3.7, p = 0.001), but not the previously suggested interaction with the ε4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD. CONCLUSION: HLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk

Hyponatremia in a Cold Weather Ultraendurance Race

We assessed the incidence and etiology of hyponatremia in the 100-mile (161 km) Iditasport ultramarathon. Subjects (8 cyclists, 8 runners) were weighed and serum sodium was measured pre- and post-race. Race diets were analyzed to determine fluid and sodium consumption. Subjects were split by post-race serum sodium concentration into hyponatremic and normonatremic groups for statistical analyses. Seven of 16 subjects (44%) were hyponatremic. The hyponatremic group exhibited a significant decrease in serum sodium concentration (137.0 to 132.9 mmol/L, and the normonatremic group experienced a significant decrease in weight (82.1 to 80.2 kg) pre- to post-race. The hypornatremic group drank more friud per hour (0.5 versus 0.4 L/h) and consumed less sodium per hour (235 versus 298 mg/h) compared to the normonatremic group. In conclusion, hyponatremia is common in an ultraendurance race held in the extreme cold, and may be caused by excessive fluid consumption and/or inadequate sodium intake

KIC 4768731: a bright long-period roAp star in theKeplerfield

We report the identification of 61.45 d−1 (711.2 μHz) oscillations, with amplitudes of 62.6 μmag, in KIC 4768731 (HD 225914) using Kepler photometry. This relatively bright (V = 9.17) chemically peculiar star with spectral type A5 Vp SrCr(Eu) has previously been found to exhibit rotational modulation with a period of 5.21 d. Fourier analysis reveals a simple dipole pulsator with an amplitude that has remained stable over a 4-yr time span, but with a frequency that is variable. Analysis of high-resolution spectra yields stellar parameters of Teff = 8100 ± 200 K, log g = 4.0 ± 0.2, [Fe/H] = +0.31 ± 0.24 and v sin i = 14.8 ± 1.6 km s−1. Line profile variations caused by rotation are also evident. Lines of Sr, Cr, Eu, Mg and Si are strongest when the star is brightest, while Y and Ba vary in antiphase with the other elements. The abundances of rare earth elements are only modestly enhanced compared to other roAp stars of similar Teff and log g. Radial velocities in the literature suggest a significant change over the past 30 yr, but the radial velocities presented here show no significant change over a period of 4 yr

Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease

Background: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10).Methods: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls.Results: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon 4 (APOE epsilon 4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded.Conclusion: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD

X-ray induced electron and ion fragmentation dynamics in IBr

Characterization of the inner-shell decay processes in molecules containing heavy elements is key to understanding x-ray damage of molecules and materials and for medical applications with Auger-electron-emitting radionuclides. The 1s hole states of heavy atoms can be produced by absorption of tunable x-rays and the resulting vacancy decays characterized by recording emitted photons, electrons, and ions. The 1s hole states in heavy elements have large x-ray fluorescence yields that transfer the hole to intermediate electron shells that then decay by sequential Auger-electron transitions that increase the ion's charge state until the final state is reached. In molecules the charge is spread across the atomic sites, resulting in dissociation to energetic atomic ions. We have used x-ray/ion coincidence spectroscopy to measure charge states and energies of I$^{q+}$ and Br$^{q'+}$ atomic ions following 1s ionization at the I and Br \textit{K}-edges of IBr. We present the charge states and kinetic energies of the two correlated fragment ions associated with core-excited states produced during the various steps of the cascades. To understand the dynamics leading to the ion data, we develop a computational model that combines Monte-Carlo/Molecular Dynamics simulations with a classical over-the-barrier model to track inner-shell cascades and redistribution of electrons in valence orbitals and nuclear motion of fragments

HD 24355 observed by the Kepler K2 mission: a rapidly oscillating Ap star pulsating in a distorted quadrupole mode

We present an analysis of the first Kepler K2 mission observations of a rapidly oscillating Ap (roAp) star, HD 24355 (V = 9.65). The star was discovered in SuperWASP broad-band photometry with a frequency of 224.31 d−1 (2596.18 μHz; P = 6.4 min) and an amplitude of 1.51 mmag, with later spectroscopic analysis of low-resolution spectra showing HD 24355 to be an A5 Vp SrEu star. The high-precision K2 data allow us to identify 13 rotationally split sidelobes to the main pulsation frequency of HD 24355. This number of sidelobes combined with an unusual rotational phase variation show this star to be the most distorted quadrupole roAp pulsator yet observed. In modelling this star, we are able to reproduce well the amplitude modulation of the pulsation, and find a close match to the unusual phase variations. We show this star to have a pulsation frequency higher than the critical cut-off frequency. This is currently the only roAp star observed with the Kepler spacecraft in short cadence mode that has a photometric amplitude detectable from the ground, thus allowing comparison between the mmag amplitude ground-based targets and the μmag spaced-based discoveries. No further pulsation modes are identified in the K2 data, showing this star to be a single-mode pulsator

HD 24355 observed by the Kepler K2 mission: A rapidly oscillating Ap star pulsating in a distorted quadrupole mode

We present an analysis of the first Kepler K2 mission observations of a rapidly oscillating Ap (roAp) star, HD 24355 ($V=9.65$). The star was discovered in SuperWASP broadband photometry with a frequency of 224.31 d$^{-1}$, (2596.18 $\mu$Hz; $P = 6.4$ min) and an amplitude of 1.51 mmag, with later spectroscopic analysis of low-resolution spectra showing HD 24355 to be an A5 Vp SrEu star. The high precision K2 data allow us to identify 13 rotationally split sidelobes to the main pulsation frequency of HD 24355. This number of sidelobes combined with an unusual rotational phase variation show this star to be the most distorted quadrupole roAp pulsator yet observed. In modelling this star, we are able to reproduce well the amplitude modulation of the pulsation, and find a close match to the unusual phase variations. We show this star to have a pulsation frequency higher than the critical cut-off frequency. This is currently the only roAp star observed with the Kepler spacecraft in Short Cadence mode that has a photometric amplitude detectable from the ground, thus allowing comparison between the mmag amplitude ground-based targets and the $\mu$mag spaced-based discoveries. No further pulsation modes are identified in the K2 data, showing this star to be a single-mode pulsator

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson