The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel ...biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (n
=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10
. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10
. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.
The Many Faces of Facial Nerve Schwannoma Wiggins, R.H., III; Harnsberger, H.R; Salzman, K.L ...
American Journal of Neuroradiology,
03/2006, Letnik:
27, Številka:
3
Journal Article
Recenzirano
The imaging appearance of facial nerve schwannomas (FNSs) has been described as an enhancing tubular mass (using T1-enhanced MR) within an enlarged facial nerve canal (using CT). The purpose of this ...study is to identify how often the FNS imaging findings conform to this description and determine whether there are underlying anatomic explanations for the discrepant imaging appearances identified.
The clinical, pathologic, and radiologic records of 24 FNS in 23 patients were retrospectively reviewed. Each FNS was evaluated for location along the facial nerve. The lesions were cataloged by facial nerve segment with the imaging characteristics of each segment described.
The average age at time of first imaging was 39 years (age range, 10-70 years). Eighteen (71%) of the 24 FNSs were pathologically confirmed, while the others were determined intraoperatively or diagnostically by the presence of both enlargement of the facial nerve canal and enhancement on contrast-enhanced T1 MR examination. The most common location was in the geniculate fossa (83%), followed by the labyrinthine and tympanic segments of the facial nerve (both 54%). The most common clinical presentation was facial neuropathy (42%).
The classic description of FNS on enhanced T1 MR is that of a well-circumscribed fusiform enhancing mass along the course of the intratemporal facial nerve with bone algorithm CT showing sharply defined bony canal enlargement. Modern imaging techniques, however, demonstrate the importance of the surrounding anatomic landscape, leading to various imaging appearances. Lesions traversing the labyrinthine segment can demonstrate a dumbbell appearance. When FNSs track along the greater superficial petrosal nerve, they may present as a round mass projecting up into the middle cranial fossa. FNS of the tympanic segment of the facial nerve preferentially pedunculate into the middle ear cavity, clinically presenting as a middle ear mass. When the mastoid segment of the facial nerve is involved, irregular and "invasive" tumor margins seen on MR can be explained on CT as tumor breaking into surrounding mastoid air cells.
An analysis of a case–control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important ...drug–drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998–2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1–143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2–infinity). Several medications were tested in vitro for their potential to cause drug–drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose‐dependent drug–drug interactions with other medications metabolized by CYP2C8.
Clinical Pharmacology & Therapeutics (2012); 91 5, 896–904. doi:10.1038/clpt.2011.295
Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. ...Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism
Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with nonuse, was associated with a clinically relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT.
The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A(1), A(2) or B alleles is not well defined.
To examine the ...association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT).
We used data from two ongoing population-based case-control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non-fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non-fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single-nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O(1), O(2), A(11), A(2) and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome.
As compared with the O(1)O(1) group, the A(11) allele was associated with an increased risk of VT odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41-2.26 and MI (OR 1.23; 95% CI 1.05-1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI 1.29-2.57) and ischemic stroke (OR 1.59; 95% CI 1.17-2.17). The AB diplotype category was associated with a 2.7-fold risk of VT (OR 2.70; 95% CI 1.73-4.21). No other associations reached significance.
The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.
Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in ...postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation.
Background Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval CI: -0.35, -0.12) and 1 μg mL
higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.
We evaluate the sensitivity of the size calibrations of
two commercially available, high-resolution optical particle sizers to
changes in aerosol composition and complex refractive index (RI). The
...Droplet Measurement Technologies Ultra-High Sensitivity Aerosol Spectrometer (UHSAS) and the TSI, Inc. Laser Aerosol Spectrometer (LAS) are
two commonly used instruments for measuring the portion of the aerosol size
distribution with diameters larger than nominally 60–90 nm. Both instruments
illuminate particles with a laser and relate the single-particle light
scattering intensity and count rate measured over a wide range of angles to
the size-dependent particle concentration. While the optical block geometry
and flow system are similar for each instrument, a significant difference
between the two models is the laser wavelength (1054 nm for the UHSAS and
633 nm for the LAS) and intensity (about 100 times higher for the UHSAS), which
may affect the way each instrument sizes non-spherical or absorbing
aerosols. Here, we challenge the UHSAS and LAS with laboratory-generated,
mobility-size-classified aerosols of known chemical composition to quantify
changes in the optical size response relative to that of ammonium sulfate
(RI of 1.52+0i at 532 nm) and NIST-traceable polystyrene latex spheres
(PSLs with RI of 1.59+0i at 589 nm). Aerosol inorganic salt species are
chosen to cover the real refractive index range of 1.32 to 1.78, while
chosen light-absorbing carbonaceous aerosols include fullerene soot,
nigrosine dye, humic acid, and fulvic acid standards. The instrument
response is generally in good agreement with the electrical mobility
diameter. However, large undersizing deviations are observed for the
low-refractive-index fluoride salts and the strongly absorbing nigrosine dye and fullerene soot particles. Polydisperse size distributions for both fresh
and aged wildfire smoke aerosols from the recent Fire Influence on Regional
to Global Environments Experiment and Air Quality (FIREX-AQ) and the Cloud,
Aerosol, and Monsoon Processes Philippines Experiment (CAMP2Ex)
airborne campaigns show good agreement between both optical sizers and
contemporaneous electrical mobility sizing and particle time-of-flight mass
spectrometric measurements. We assess the instrument uncertainties by
interpolating the laboratory response curves using previously reported RIs
and size distributions for multiple aerosol type classifications. These
results suggest that, while the optical sizers may underperform for strongly
absorbing laboratory compounds and fresh tailpipe emissions measurements,
sampling aerosols within the atmospherically relevant range of refractive
indices are likely to be sized to better than ±10 %–20 % uncertainty over the submicron aerosol size range when using instruments calibrated with
ammonium sulfate.
Imaging characteristics of temporal bone meningioma have not been previously reported in the literature. CT and MR imaging findings in 13 cases of temporal bone meningioma are reviewed to define ...specific imaging features.
A retrospective review of our institutional case archive revealed 13 cases of histologically confirmed temporal bone meningioma. CT and MR imaging studies were reviewed to characterize mass location, vector of spread, bone changes, enhancement characteristics, and intracranial patterns of involvement. Clinical presenting signs and symptoms were correlated with imaging findings.
Thirteen temporal bone meningiomas were reviewed in 8 women and 5 men, aged 18-65 years. Meningiomas were stratified into 3 groups on the basis of location and tumor vector of spread. There were 6 tegmen tympani, 5 jugular foramen (JF), and 2 internal auditory canal (IAC) meningiomas. Tegmen tympani and JF meningiomas were characterized by spread to the middle ear cavity. IAC meningiomas, by contrast, spread to the cochlea and vestibule. Hearing loss was the most common clinical presenting feature in all cases of temporal bone meningioma (10/13). The presence of tumor adjacent to the ossicles strongly correlated with conductive hearing loss (7/9).
Meningioma involving the temporal bone is rare. Three subgroups of meningioma exist in this location: tegmen tympani, JF, and IAC meningioma. Tegmen tympani and JF meningiomas spread to the middle ear cavity. IAC meningiomas spread to intralabyrinthine structures. Conductive hearing loss is commonly seen in these patients and can be surgically correctable.
Marine biogenic particle contributions to atmospheric aerosol concentrations are not well understood though they are important for determining cloud optical and cloud-nucleating properties. Here we ...examine the relationship between marine aerosol measurements (with satellites and model fields of ocean biology) and meteorological variables during the North Atlantic Aerosols and Marine Ecosystems Study (NAAMES). NAAMES consisted of four field campaigns between November 2015 and April 2018 that aligned with the four major phases of the annual phytoplankton bloom cycle. The FLEXible PARTicle (FLEXPART) Lagrangian particle dispersion model is used to spatiotemporally connect these variables to ship-based aerosol and dimethyl sulfide (DMS) observations. We find that correlations between some aerosol measurements with satellite-measured and modeled variables increase with increasing trajectory length, indicating that biological and meteorological processes over the air mass history are influential for measured particle properties and that using only spatially coincident data would miss correlative connections that are lagged in time. In particular, the marine non-refractory organic aerosol mass correlates with modeled marine net primary production when weighted by 5 d air mass trajectory residence time (r=0.62). This result indicates that non-refractory organic aerosol mass is influenced by biogenic volatile organic compound (VOC) emissions that are typically produced through bacterial degradation of dissolved organic matter, zooplankton grazing on marine phytoplankton, and as a by-product of photosynthesis by phytoplankton stocks during advection into the region. This is further supported by the correlation of non-refractory organic mass with 2 d residence-time-weighted chlorophyll a (r=0.39), a proxy for phytoplankton abundance, and 5 d residence-time-weighted downward shortwave forcing (r=0.58), a requirement for photosynthesis. In contrast, DMS (formed through biological processes in the seawater) and primary marine aerosol (PMA) concentrations showed better correlations with explanatory biological and meteorological variables weighted with shorter air mass residence times, which reflects their localized origin as primary emissions. Aerosol submicron number and mass negatively correlate with sea surface wind speed. The negative correlation is attributed to enhanced PMA concentrations under higher wind speed conditions. We hypothesized that the elevated total particle surface area associated with high PMA concentrations leads to enhanced rates of condensation of VOC oxidation products onto PMA. Given the high deposition velocity of PMA relative to submicron aerosol, PMA can limit the accumulation of secondary aerosol mass. This study provides observational evidence for connections between marine aerosols and underlying ocean biology through complex secondary formation processes, emphasizing the need to consider air mass history in future analyses.
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