Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies

Objective: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. Study Design: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. Results: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4-337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. Conclusions: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort

Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

<p>Abstract</p> <p>Background</p> <p>Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development.</p> <p>Methods</p> <p>A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death.</p> <p>Results</p> <p>The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90).</p> <p>Conclusions</p> <p>This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.</p

Amount of Information Needed for Model Choice in Approximate Bayesian Computation

Approximate Bayesian Computation (ABC) has become a popular technique in evolutionary genetics for elucidating population structure and history due to its flexibility. The statistical inference framework has benefited from significant progress in recent years. In population genetics, however, its outcome depends heavily on the amount of information in the dataset, whether that be the level of genetic variation or the number of samples and loci. Here we look at the power to reject a simple constant population size coalescent model in favor of a bottleneck model in datasets of varying quality. Not only is this power dependent on the number of samples and loci, but it also depends strongly on the level of nucleotide diversity in the observed dataset. Whilst overall model choice in an ABC setting is fairly powerful and quite conservative with regard to false positives, detecting weaker bottlenecks is problematic in smaller or less genetically diverse datasets and limits the inferences possible in non-model organism where the amount of information regarding the two models is often limited. Our results show it is important to consider these limitations when performing an ABC analysis and that studies should perform simulations based on the size and nature of the dataset in order to fully assess the power of the study

LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the ε-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism.Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Aβ-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of γ- and α-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.These data suggest that increased APP expression and Aβ exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Chemical tagging with APOGEE: discovery of a large population of N-rich stars in the inner Galaxy

Formation of globular clusters (GCs), the Galactic bulge, or galaxy bulges in general is an important unsolved problem in Galactic astronomy. Homogeneous infrared observations of large samples of stars belonging to GCs and the Galactic bulge field are one of the best ways to study these problems. We report the discovery by APOGEE (Apache Point Observatory Galactic Evolution Experiment) of a population of field stars in the inner Galaxy with abundances of N, C, and Al that are typically found in GC stars. The newly discovered stars have high [N/Fe], which is correlated with [Al/Fe] and anticorrelated with [C/Fe]. They are homogeneously distributed across, and kinematically indistinguishable from, other field stars within the same volume. Their metallicity distribution is seemingly unimodal, peaking at [Fe/H] ∼ −1, thus being in disagreement with that of the Galactic GC system. Our results can be understood in terms of different scenarios. N-rich stars could be former members of dissolved GCs, in which case the mass in destroyed GCs exceeds that of the surviving GC system by a factor of ∼8. In that scenario, the total mass contained in so-called ‘first-generation’ stars cannot be larger than that in ‘second-generation’ stars by more than a factor of ∼9 and was certainly smaller. Conversely, our results may imply the absence of a mandatory genetic link between ‘second-generation’ stars and GCs. Last, but not least, N-rich stars could be the oldest stars in the Galaxy, the by-products of chemical enrichment by the first stellar generations formed in the heart of the Galaxy

Comparative structural and functional analysis of Bunyavirus and Arenavirus cap-snatching Endonucleases

Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5′ end by an endonuclease (EN) domain located in the N-terminal region of the viral polymerase. We present the structure of the cap-snatching EN of Hantaan virus, a bunyavirus belonging to hantavirus genus. Hantaan EN has an active site configuration, including a metal co-ordinating histidine, and nuclease activity similar to the previously reported La Crosse virus and Influenza virus ENs (orthobunyavirus and orthomyxovirus respectively), but is more active in cleaving a double stranded RNA substrate. In contrast, Lassa arenavirus EN has only acidic metal co-ordinating residues. We present three high resolution structures of Lassa virus EN with different bound ion configurations and show in comparative biophysical and biochemical experiments with Hantaan, La Crosse and influenza ENs that the isolated Lassa EN is essentially inactive. The results are discussed in the light of EN activation mechanisms revealed by recent structures of full-length influenza virus polymerase

Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

BACKGROUND: The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP) transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1) in four CNS-relevant human cell lines. RESULTS: There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines) displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. CONCLUSION: Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs

A New (Old), Invasive Ant in the Hardwood Forests of Eastern North America and Its Potentially Widespread Impacts

Biological invasions represent a serious threat for the conservation of biodiversity in many ecosystems. While many social insect species and in particular ant species have been introduced outside their native ranges, few species have been successful at invading temperate forests. In this study, we document for the first time the relationship between the abundance of the introduced ant, Pachycondyla chinensis, in mature forests of North Carolina and the composition, abundance and diversity of native ant species using both a matched pair approach and generalized linear models. Where present, P. chinensis was more abundant than all native species combined. The diversity and abundance of native ants in general and many individual species were negatively associated with the presence and abundance of P. chinensis. These patterns held regardless of our statistical approach and across spatial scales. Interestingly, while the majority of ant species was strongly and negatively correlated with the abundance and presence of P. chinensis, a small subset of ant species larger than P. chinensis was either as abundant or even more abundant in invaded than in uninvaded sites. The large geographic range of this ant species combined with its apparent impact on native species make it likely to have cascading consequences on eastern forests in years to come, effects mediated by the specifics of its life history which is very different from those of other invasive ants. The apparent ecological impacts of P. chinensis are in addition to public health concerns associated with this species due to its sometimes, deadly sting

Psychiatry out-of-hours: a focus group study of GPs' experiences in Norwegian casualty clinics

Background: For Norwegian general practitioners (GPs), acute treatment of mental illness and substance abuse are among the most commonly experienced emergency situations in out-of-hours primary healthcare. The largest share of acute referrals to emergency psychiatric wards occurs out-of-hours, and out-of-hours services are responsible for a disproportionately high share of compulsory referrals. Concerns exist regarding the quality of mental healthcare provided in the out-of-hours setting. The aim of this study was to explore which challenges GPs experience when providing emergency care out-of-hours to patients presenting problems related to mental illness or substance abuse. Methods: We conducted a qualitative study based on two individual interviews and six focus groups with purposively sampled GPs (totally 45 participants). The interviews were analysed successively in an editing style, using a thematic approach based on methodological descriptions by Charmaz and Malterud. Results: Safety and uncertainty were the dominating themes in the discussions. The threat to personal safety due to unpredictable patient behaviour was a central concern, and present security precautions in the out-of-hours services were questioned. The GPs expressed high levels of uncertainty in their work with patients presenting problems related to mental illness or substance abuse. The complexity of the problems presented, shortage of time, limited access to reliable information and limited range of interventions available during out-of-hours contributed to this uncertainty. Perceived access to second opinion seemed to have a major impact on subjectively experienced work stress. Conclusions: The GPs experienced out-of-hours psychiatry as a field with high levels of uncertainty and limited support to help them meet the experienced challenges. This might influence the quality of care provided. If the current organisation of emergency mental healthcare is to be kept, we need to provide GPs with a better support framework out-of-hours