Role of the Perigenual Anterior Cingulate and Orbitofrontal Cortex in Contingency Learning in the Marmoset.

Two learning mechanisms contribute to decision-making: goal-directed actions and the "habit" system, by which action-outcome and stimulus-response associations are formed, respectively. Rodent lesion studies and human neuroimaging have implicated both the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC) in the neural basis of contingency learning, a critical component of goal-directed actions, though some published findings are conflicting. We sought to reconcile the existing literature by comparing the effects of excitotoxic lesions of the perigenual anterior cingulate cortex (pgACC), a region of the mPFC, and OFC on contingency learning in the marmoset monkey using a touchscreen-based paradigm, in which the contingent relationship between one of a pair of actions and its outcome was degraded selectively. Both the pgACC and OFC lesion groups were insensitive to the contingency degradation, whereas the control group demonstrated selectively higher performance of the nondegraded action when compared with the degraded action. These findings suggest the pgACC and OFC are both necessary for normal contingency learning and therefore goal-directed behavior.This research was supported by a Programme Grant [G0901884] from the Medical Research Council UK (MRC) to ACR, and a Wellcome Trust Senior Investigator Award [104631 /Z/14/Z] to TWR. SAWJ was supported by a BCNI-MRC studentship. The authors wish to thank C. H Parkinson and R. Underwood for preparation of the histological material. T.W.R. consults for Cambridge Cognition, Lilly, Lundbeck, Teva, Shire Pharmaceuticals and Merck, Sharp and Dohme. He has received research grants from Lilly, Lundbeck and GSK. The remaining authors have no potential competing financial interests to disclose.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/cercor/bhw06

Incidence of Retinoblastoma Has Increased : Results from 40 European Countries

Funding Information: Obtained funding: N/A; Study was performed as part of the regular employment duties of all authors at their institutions. No additional funding was provided.Non peer reviewe

Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets

BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition. METHODS Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations. RESULTS Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10−8), including rs12700667 on 7p15.2 (P = 1.6 × 10−9), rs7521902 near WNT4 (P = 1.8 × 10−15), rs10859871 near VEZT (P = 4.7 × 10−15), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10−8), rs7739264 near ID4 (P = 6.2 × 10−10) and rs13394619 in GREB1 (P = 4.5 × 10−8). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10−8) and rs4141819 on 2p14 (P = 9.2 × 10−8). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis. CONCLUSIONS Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways

Sex, gender, and retinoblastoma : analysis of 4351 patients from 153 countries

Objective To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. Methods A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. Results For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (chi(2) = 6.925, corrected p = 0.025) and for Asia (chi(2) = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (chi(2) = 2.205, p = 0.14). Conclusions No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.Peer reviewe

A complete view of galaxy evolution: panchromatic luminosity functions and the generation of metals

When and how did galaxies form and their metals accumulate? Over the last decade, this has moved from an archeological question to a live investigation: there is now a broad picture of the evolution of galaxies in dark matter halos: their masses, stars, metals and supermassive blackholes. Galaxies have been found and studied in which these formation processes are taking place most vigorously, all the way back in cosmic time to when the intergalactic medium (IGM) was still largely neutral. However, the details of how and why the interstellar medium (ISM) in distant galaxies cools, is processed, recycled and enriched in metals by stars, and fuels active galactic nuclei (AGNs) remain uncertain. In particular, the cooling of gas to fuel star formation, and the chemistry and physics of the most intensely active regions is hidden from view at optical wavelengths, but can be seen and diagnosed at mid- & far-infrared (IR) wavelengths. Rest-frame IR observations are important first to identify the most luminous, interesting and important galaxies, secondly to quantify accurately their total luminosity, and finally to use spectroscopy to trace the conditions in the molecular and atomic gas out of which stars form. In order to map out these processes over the full range of environments and large-scale structures found in the universe - from the densest clusters of galaxies to the emptiest voids - we require tools for deep, large area surveys, of millions of galaxies out to z~5, and for detailed follow-up spectroscopy. The necessary tools can be realized technically. Here, we outline the requirements for gathering the crucial information to build, validate and challenge models of galaxy evolution.Comment: A whitepaper submitted on 15th February 2009 in response to the call from the Astro2010 panel: astro2010.org; uploaded as an 8-page pdf fil

Endometriosis and the Coronavirus (COVID-19) Pandemic: Clinical Advice and Future Considerations

The COVID-19 pandemic has led to a dramatic shift in the clinical practice of women’s health and routine care for endometriosis has been severely disrupted. Endometriosis is defined as an inflammatory disease characterized by lesions of endometrial-like tissue outside the uterus that is associated with pelvic pain and/or infertility (1). It affects ∼10% of reproductive age women worldwide, is diagnosed by surgical visualization or by radiological imaging, and is managed with hormone treatments or by laparoscopic removal of lesions (2–4). At the time of writing, under the guidance of international gynecological organizations (5–7), many centers temporarily ceased offering outpatient appointments, diagnostic imaging for nonacute pelvic pain, surgery for endometriosis, and fertility treatments. In the absence of routine care pathways and uncertainty about when health services will be available again, endometriosis sufferers are likely to feel vulnerable and that resultant stress and anxiety may contribute to a worsening of symptoms. The pandemic poses several important questions for healthcare providers on how best to deliver care within these restrictions. Herein, we present clinical advice on the management of endometriosis during the COVID-19 pandemic and future considerations

MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients