Impact of monthly headache days on migraine-related quality of life: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Allodynia; Anxiety; DepressionAl·lodínia; Ansietat; DepressióAlodinia; Ansiedad; DepresiónObjective To characterize the direct impact of monthly headache days (MHDs) on health-related quality of life (HRQoL) in people with migraine and the potential mediating effects of anxiety, depression, and allodynia. Background Although the general relationship between increased migraine frequency (i.e., MHDs) and reduced HRQoL is well established, the degree to which reduced HRQoL is due to a direct effect of increased MHDs or attributable to mediating factors remains uncertain. Methods Cross-sectional baseline data from participants with migraine who completed the Core and Comorbidities/Endophenotypes modules in the 2012–2013 US Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a longitudinal web-based survey study, were analyzed. The potential contribution of depression, anxiety, and/or allodynia to the observed effects of MHDs on HRQoL as measured by the Migraine-Specific Quality-of-Life Questionnaire version 2.1 (MSQ) was evaluated. Results A total of 12,715 respondents were included in the analyses. The MSQ domain scores demonstrated progressive declines with increasing MHD categories (B = −1.23 to −0.60; p < 0.001). The observed HRQoL decrements associated with increasing MHDs were partially mediated by the presence of depression, anxiety, and allodynia. The MHD values predicted 24.0%–32.4% of the observed variation in the MSQ domains. Depression mediated 15.2%–24.3%, allodynia mediated 9.6%–16.1%, and anxiety mediated 2.3%–6.0% of the observed MHD effects on the MSQ. Conclusions Increased MHD values were associated with lower MSQ scores; the impact of MHDs on the MSQ domain scores was partially mediated by the presence of depression, anxiety, and allodynia. MHDs remain the predominant driver of the MSQ variation; moreover, most of the variation in the MSQ remains unexplained by the variables we analyzed. Future longitudinal analyses and studies may help clarify the contribution of MHDs, comorbidities, and other factors to changes in HRQoL

Performance of plate-based cytokine flow cytometry with automated data analysis

BACKGROUND: Cytokine flow cytometry (CFC) provides a multiparameter alternative to ELISPOT assays for rapid quantitation of antigen-specific T cells. To increase the throughput of CFC assays, we have optimized methods for stimulating, staining, and acquiring whole blood or PBMC samples in 96-well or 24-well plates. RESULTS: We have developed a protocol for whole blood stimulation and processing in deep-well 24- or 96-well plates, and fresh or cryopreserved peripheral blood mononuclear cell (PBMC) stimulation and processing in conventional 96-well round-bottom plates. Samples from both HIV-1-seronegative and HIV-1-seropositive donors were tested. We show that the percent response, staining intensity, and cell recovery are comparable to stimulation and processing in tubes using traditional methods. We also show the equivalence of automated gating templates to manual gating for CFC data analysis. CONCLUSION: When combined with flow cytometry analysis using an automated plate loader and an automated analysis algorithm, these plate-based methods provide a higher throughput platform for CFC, as well as reducing operator-induced variability. These factors will be important for processing the numbers of samples required in large clinical trials, and for epitope mapping of patient responses

Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency

PURPOSE: Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published. METHODS: We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55–200 CGG repeats) and intermediate (45–54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881). RESULTS: The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7–17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8–5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02–5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency. CONCLUSION: FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause

Evidence of amygdala hypersensitivity to signals of threat

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n = 70) of 14-year olds with a history of cannabis use to a group (n = 70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at- risk for mood disorders in adulthood

Inattention and reaction time variability are linked to ventromedial prefrontal volume in adolescents

Background Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have most commonly reported volumetric abnormalities in the basal ganglia, cerebellum, and prefrontal cortices. Few studies have examined the relationship between ADHD symptomatology and brain structure in population-based samples. We investigated the relationship between dimensional measures of ADHD symptomatology, brain structure, and reaction time variability—an index of lapses in attention. We also tested for associations between brain structural correlates of ADHD symptomatology and maps of dopaminergic gene expression. Methods Psychopathology and imaging data were available for 1538 youths. Parent ratings of ADHD symptoms were obtained using the Development and Well-Being Assessment and the Strengths and Difficulties Questionnaire (SDQ). Self-reports of ADHD symptoms were assessed using the youth version of the SDQ. Reaction time variability was available in a subset of participants. For each measure, whole-brain voxelwise regressions with gray matter volume were calculated. Results Parent ratings of ADHD symptoms (Development and Well-Being Assessment and SDQ), adolescent self-reports of ADHD symptoms on the SDQ, and reaction time variability were each negatively associated with gray matter volume in an overlapping region of the ventromedial prefrontal cortex. Maps of DRD1 and DRD2 gene expression were associated with brain structural correlates of ADHD symptomatology. Conclusions This is the first study to reveal relationships between ventromedial prefrontal cortex structure and multi-informant measures of ADHD symptoms in a large population-based sample of adolescents. Our results indicate that ventromedial prefrontal cortex structure is a biomarker for ADHD symptomatology. These findings extend previous research implicating the default mode network and dopaminergic dysfunction in ADHD

Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast

A comprehensive analysis of autocorrelation and bias in home range estimation

Home range estimation is routine practice in ecological research. While advances in animal tracking technology have increased our capacity to collect data to support home range analysis, these same advances have also resulted in increasingly autocorrelated data. Consequently, the question of which home range estimator to use on modern, highly autocorrelated tracking data remains open. This question is particularly relevant given that most estimators assume independently sampled data. Here, we provide a comprehensive evaluation of the effects of autocorrelation on home range estimation. We base our study on an extensive data set of GPS locations from 369 individuals representing 27 species distributed across five continents. We first assemble a broad array of home range estimators, including Kernel Density Estimation (KDE) with four bandwidth optimizers (Gaussian reference function, autocorrelated-Gaussian reference function [AKDE], Silverman´s rule of thumb, and least squares cross-validation), Minimum Convex Polygon, and Local Convex Hull methods. Notably, all of these estimators except AKDE assume independent and identically distributed (IID) data. We then employ half-sample cross-validation to objectively quantify estimator performance, and the recently introduced effective sample size for home range area estimation ((Formula presented.)) to quantify the information content of each data set. We found that AKDE 95% area estimates were larger than conventional IID-based estimates by a mean factor of 2. The median number of cross-validated locations included in the hold-out sets by AKDE 95% (or 50%) estimates was 95.3% (or 50.1%), confirming the larger AKDE ranges were appropriately selective at the specified quantile. Conversely, conventional estimates exhibited negative bias that increased with decreasing (Formula presented.). To contextualize our empirical results, we performed a detailed simulation study to tease apart how sampling frequency, sampling duration, and the focal animal´s movement conspire to affect range estimates. Paralleling our empirical results, the simulation study demonstrated that AKDE was generally more accurate than conventional methods, particularly for small (Formula presented.). While 72% of the 369 empirical data sets had >1,000 total observations, only 4% had an (Formula presented.) >1,000, where 30% had an (Formula presented.) <30. In this frequently encountered scenario of small (Formula presented.), AKDE was the only estimator capable of producing an accurate home range estimate on autocorrelated data.Fil: Noonan, Michael J.. National Zoological Park; Estados Unidos. University of Maryland; Estados UnidosFil: Tucker, Marlee A.. Senckenberg Gesellschaft Für Naturforschung; . Goethe Universitat Frankfurt; AlemaniaFil: Fleming, Christen H.. University of Maryland; Estados Unidos. National Zoological Park; Estados UnidosFil: Akre, Thomas S.. National Zoological Park; Estados UnidosFil: Alberts, Susan C.. University of Duke; Estados UnidosFil: Ali, Abdullahi H.. Hirola Conservation Programme. Garissa; KeniaFil: Altmann, Jeanne. University of Princeton; Estados UnidosFil: Antunes, Pamela Castro. Universidade Federal do Mato Grosso do Sul; BrasilFil: Belant, Jerrold L.. State University of New York; Estados UnidosFil: Beyer, Dean. Universitat Phillips; AlemaniaFil: Blaum, Niels. Universitat Potsdam; AlemaniaFil: Böhning Gaese, Katrin. Senckenberg Gesellschaft Für Naturforschung; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Cullen Jr., Laury. Instituto de Pesquisas Ecológicas; BrasilFil: de Paula, Rogerio Cunha. National Research Center For Carnivores Conservation; BrasilFil: Dekker, Jasja. Jasja Dekker Dierecologie; Países BajosFil: Drescher Lehman, Jonathan. George Mason University; Estados Unidos. National Zoological Park; Estados UnidosFil: Farwig, Nina. Michigan State University; Estados UnidosFil: Fichtel, Claudia. German Primate Center; AlemaniaFil: Fischer, Christina. Universitat Technical Zu Munich; AlemaniaFil: Ford, Adam T.. University of British Columbia; CanadáFil: Goheen, Jacob R.. University of Wyoming; Estados UnidosFil: Janssen, René. Bionet Natuuronderzoek; Países BajosFil: Jeltsch, Florian. Universitat Potsdam; AlemaniaFil: Kauffman, Matthew. University Of Wyoming; Estados UnidosFil: Kappeler, Peter M.. German Primate Center; AlemaniaFil: Koch, Flávia. German Primate Center; AlemaniaFil: LaPoint, Scott. Max Planck Institute für Ornithologie; Alemania. Columbia University; Estados UnidosFil: Markham, A. Catherine. Stony Brook University; Estados UnidosFil: Medici, Emilia Patricia. Instituto de Pesquisas Ecológicas (IPE) ; BrasilFil: Morato, Ronaldo G.. Institute For Conservation of The Neotropical Carnivores; Brasil. National Research Center For Carnivores Conservation; BrasilFil: Nathan, Ran. The Hebrew University of Jerusalem; IsraelFil: Oliveira Santos, Luiz Gustavo R.. Universidade Federal do Mato Grosso do Sul; BrasilFil: Olson, Kirk A.. Wildlife Conservation Society; Estados Unidos. National Zoological Park; Estados UnidosFil: Patterson, Bruce. Field Museum of National History; Estados UnidosFil: Paviolo, Agustin Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Ramalho, Emiliano Esterci. Institute For Conservation of The Neotropical Carnivores; Brasil. Instituto de Desenvolvimento Sustentavel Mamirauá; BrasilFil: Rösner, Sascha. Michigan State University; Estados UnidosFil: Schabo, Dana G.. Michigan State University; Estados UnidosFil: Selva, Nuria. Institute of Nature Conservation of The Polish Academy of Sciences; PoloniaFil: Sergiel, Agnieszka. Institute of Nature Conservation of The Polish Academy of Sciences; PoloniaFil: Xavier da Silva, Marina. Parque Nacional do Iguaçu; BrasilFil: Spiegel, Orr. Universitat Tel Aviv; IsraelFil: Thompson, Peter. University of Maryland; Estados UnidosFil: Ullmann, Wiebke. Universitat Potsdam; AlemaniaFil: Ziḝba, Filip. Tatra National Park; PoloniaFil: Zwijacz Kozica, Tomasz. Tatra National Park; PoloniaFil: Fagan, William F.. University of Maryland; Estados UnidosFil: Mueller, Thomas. Senckenberg Gesellschaft Für Naturforschung; . Goethe Universitat Frankfurt; AlemaniaFil: Calabrese, Justin M.. National Zoological Park; Estados Unidos. University of Maryland; Estados Unido

Shelled pteropods in peril: Assessing vulnerability in a high CO2 ocean

The impact of anthropogenic ocean acidification (OA) on marine ecosystems is a vital concern facing marine scientists and managers of ocean resources. Euthecosomatous pteropods (holoplanktonic gastropods) represent an excellent sentinel for indicating exposure to anthropogenic OA because of the sensitivity of their aragonite shells to the OA conditions less favorable for calcification. However, an integration of observations, experiments and modelling efforts is needed to make accurate predictions of how these organisms will respond to future changes to their environment. Our understanding of the underlying organismal biology and life history is far from complete and must be improved if we are to comprehend fully the responses of these organisms to the multitude of stressors in their environment beyond OA. This review considers the present state of research and understanding of euthecosomatous pteropod biology and ecology of these organisms and considers promising new laboratory methods, advances in instrumentation (such as molecular, trace elements, stable isotopes, palaeobiology alongside autonomous sampling platforms, CT scanning and high-quality video recording) and novel field-based approaches (i.e. studies of upwelling and CO2 vent regions) that may allow us to improve our predictive capacity of their vulnerability and/or resilience. In addition to playing a critical ecological and biogeochemical role, pteropods can offer a significant value as an early-indicator of anthropogenic OA. This role as a sentinel species should be developed further to consolidate their potential use within marine environmental management policy making

Genetic predisposition to ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

cited By 0Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.Peer reviewe