Hormone replacement therapy, mammography screening and changing age-specific incidence rates of breast cancer: an ecological study comparing two European populations

Background: In 2003, for the first time, US breast cancer incidence rates have fallen. Experts argue whether this is due to the reduced uptake of screening mammography or to lower use of Hormone Replacement Therapy (HRT). This study aims to disentangle the respective impact of screening and HRT on age-incidence rates and histology of breast cancer, by comparing two populations with comparably high levels of screening mammography, but with different prevalence of HRT. Methods: We included all invasive breast cancers recorded at the Geneva cancer registry (n=4,909) and the Netherlands Cancer Registry (n=152,428) between 1989-2003. We compared age-specific incidence rates and trends in histological subtyping between the two populations. Results: Between 1989-1991, incidence rates increased with age in both populations. In 2001-2003, women aged 60-64years showed highest incidence rates in Geneva, while in the Netherlands incidence rates continued to increase with age. The annual increase in ductal cancer incidence was similar in the Netherlands (2.3%) and Geneva (2.5%), but the annual increase in lobular cancer was sharper in Geneva (10%) than in the Netherlands (5%). Conclusion: The sharp differences in age distribution and histological subtyping of breast cancer between two European populations are not attributable to screening, since both populations have a high uptake of mammography screening. Since the prevalence of HRT use is very high in Geneva and rather low in the Netherlands, HRT may explain these discrepancies. However, other etiological factors and differences in histological assessment may also have played a rol

Constraining Ceres' interior from its Rotational Motion

Context. Ceres is the most massive body of the asteroid belt and contains about 25 wt.% (weight percent) of water. Understanding its thermal evolution and assessing its current state are major goals of the Dawn Mission. Constraints on internal structure can be inferred from various observations. Especially, detailed knowledge of the rotational motion can help constrain the mass distribution inside the body, which in turn can lead to information on its geophysical history. Aims. We investigate the signature of the interior on the rotational motion of Ceres and discuss possible future measurements performed by the spacecraft Dawn that will help to constrain Ceres' internal structure. Methods. We compute the polar motion, precession-nutation, and length-of-day variations. We estimate the amplitudes of the rigid and non-rigid response for these various motions for models of Ceres interior constrained by recent shape data and surface properties. Results. As a general result, the amplitudes of oscillations in the rotation appear to be small, and their determination from spaceborne techniques will be challenging. For example, the amplitudes of the semi-annual and annual nutations are around ~364 and ~140 milli-arcseconds, and they show little variation within the parametric space of interior models envisioned for Ceres. This, combined with the very long-period of the precession motion, requires very precise measurements. We also estimate the timescale for Ceres' orientation to relax to a generalized Cassini State, and we find that the tidal dissipation within that object was probably too small to drive any significant damping of its obliquity since formation. However, combining the shape and gravity observations by Dawn offers the prospect to identify departures of non-hydrostaticity at the global and regional scale, which will be instrumental in constraining Ceres' past and current thermal state. We also discuss the existence of a possible Chandler mode in the rotational motion of Ceres, whose potential excitation by endogenic and/or exogenic processes may help detect the presence of liquid reservoirs within the asteroid.Comment: submitted to Astronomy and Astrophysic

Diagnostic accuracy of large-core needle biopsy for nonpalpable breast disease: a meta-analysis

For the evaluation of non-palpable lesions of the breast, image-guided large-core needle biopsies are increasingly replacing needle-localized open breast biopsies. In this study, the diagnostic accuracy of this minimally invasive technique was evaluated by reviewing the available literature. Five cohort studies were included in a meta-analysis. Sensitivity rate, histological agreement between needle biopsy and subsequent surgery or long-term mammographic follow-up and clinical consequences for different disease prevalences were assessed. The sensitivity rate of large-core needle biopsy for the diagnosis of breast cancer was high (97%). The reclassified agreement rate between core biopsy and subsequent surgical biopsy or long-term mammographic follow-up was also high (94%). In case of 20% breast cancer prevalence among women referred after screening (as in the US), the risk of breast cancer despite benign large-core needle biopsy result is less than 1%. In European countries, however, prevalence of breast cancer among referred women is 60–70%. This would result in a risk of breast cancer despite benign large-core needle biopsy result of 4–6%. The results of this meta-analysis indicate that the image guided large-core needle biopsy is a promising alternative for the needle localized breast biopsy. However, additional research is needed to explore the limiting factors of the technique. Without such detailed knowledge, a benign histological diagnosis on large-core needle biopsy in countries with high prevalence of malignancy among referred women should be interpreted with caution. © 2000 Cancer Research Campaig

Accelerated in vivo proliferation of memory phenotype CD4+ T-cells in human HIV-1 infection irrespective of viral chemokine co-receptor tropism.

CD4(+) T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i) that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5(+) cells, and (ii) that X4-tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4(+) compartment. To test these hypotheses we measured in vivo turnover rates of CD4(+) T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation (p) and disappearance (d*) rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143-569 cells/ul) participated. CCR5-expression defined a CD4(+) subpopulation of predominantly CD45R0(+) memory cells with accelerated in vivo proliferation (p = 2.50 vs 1.60%/d, CCR5(+) vs CCR5(-); healthy controls; P<0.01). Conversely, CXCR4 expression defined CD4(+) T-cells (predominantly CD45RA(+) naive cells) with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5(+)CD45R0(+)CD4(+) memory T-cells (p = 5.16 vs 2.50%/d, HIV vs controls; P<0.05), naïve cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9) or X4-tropic (n = 4). Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells (p = 0.54 vs 0.72 vs 0.44%/d in control, R5-tropic, and X4-tropic groups respectively). Our data are most consistent with models in which CD4(+) T-cell loss is primarily driven by non-specific immune activation

A study of genetic and environmental influences on maternal and paternal CBCL syndrome scores in a large sample of 3-year-old Dutch twins.

Background. There is increasing evidence that behavioral problems are common in very young children, yet little is known about the etiology of individual differences in these problems. It is unclear to what degree environmental and genetic factors influence the development of early child psychopathology. In this paper, we focus on the following issues. Firstly, to what degree do genetic and environmental factors influence variation in behavioral problems? Secondly, to what degree are these underlying etiological factors moderated by sex and informant? We investigate these issues by analyzing Child Behavior Checklist (CBCL) data on 9689 3-year-old twin pairs. Methods. Rater Bias and Psychometric Models were fitted to CBCL/2-3 data obtained from mothers and fathers to determine the genetic and environmental contributions to the five CBCL syndromes:aggressive, oppositional, overactive, withdrawn, and anxious/depressed behavior. Results. Parental ratings are influenced by aspects of the child's behavior that are experienced in the same way by both parents and by aspects of the child's behavior that are experienced uniquely by each parent. There is evidence for high genetic contributions to all CBCL syndromes. Shared and non-shared environmental influences play significant roles as well. One exception is overactive behavior, which is influenced by genetic and non-shared environmental influences only. Conclusions. Variation in behavior problems in the very young shows high heritability. Individual raters offer unique perspectives that can have an impact on estimates of problem behavior and genetic architecture. Therefore, multi-informant approaches in the assessment of the very young will be useful to clinicians and researchers alike

Pre-divorce problems in 3-year-olds: a prospective study in boys and girls

Objective: We examined to what extent internalizing and externalizing problems at age 3 preceded and predicted parental divorce, and if divorce and the time lapse since divorce were related to internalizing and externalizing problems at age 12. Methods: Parental ratings of internalizing and externalizing problems were collected with the Child Behavior Checklist (CBCL) in a large sample (N = 6,426) of 3-yearold children. All these children were followed through the age of 12 years, at which parents completed the CBCL again, while teachers completed the Teacher's Report Form. Children whose parents divorced between age 3 and age 12 were compared with children whose families remained intact. Results: Girls whose parents divorced between ages 3 and 12 already showed more externalizing problems at age 3 than girls whose parents stayed married. Higher levels of externalizing problems in girls at age 3 predicted later parental divorce. Parental reports indicated that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents. Levels of teacher-reported problems were not different between children with married versus divorced parents. However, children whose parents divorced between ages 3 and 12 showed more teacher-rated internalizing problems at age 12 when the divorce was more recent than when the divorce was less recent. Parental ratings of both internalizing and externalizing problems at age 12 were not associated with the time lapse since divorce. Conclusion: Externalizing problems in girls precede and predict later parental divorce. Post-divorce problems in children vary by raters, and may depend on the time lapse since divorce

Anterior fundoplication at the time of congenital diaphragmatic hernia repair

The loss of normal anatomic barriers in neonates with congenital diaphragmatic hernia (CDH) can predispose children to gastroesophageal reflux (GER). In an attempt to improve post-operative feeding, we have added a modified anterior fundoplication to restore natural gastric and esophageal positioning. The institutional review board of both participating centers approved this study. Between 1997 and 2008, 13 neonates with high-risk anatomy underwent repair of CDH combined with an anterior fundoplication (Boix-Ochoa). The anatomic indications for concomitant fundoplication were absence of an intra-abdominal esophagus, an obtuse angle of His, and a small, vertically oriented stomach. Ten patients survived to discharge and eight were on full oral nourishment. One required partial gastrostomy feedings for an improving oral aversion and quickly progressed to full oral feedings. One patient with chromosomal anomalies and swallowing dysfunction remained on long-term bolus gastrostomy feedings. Two with progressive symptoms of GER and failure to thrive required conversion to a 360° wrap after 18 months of medical management. This was performed in conjunction with a planned, staged muscle flap reconstruction in one patient. There were no complications related to the fundoplication. Anatomic predictors of severe GER can be efficiently countered at the time of CDH repair. A modified fundoplication should be considered in the operative management of high-risk infants

Valence-dependent influence of serotonin depletion on model-based choice strategy.

Human decision-making arises from both reflective and reflexive mechanisms, which underpin goal-directed and habitual behavioural control. Computationally, these two systems of behavioural control have been described by different learning algorithms, model-based and model-free learning, respectively. Here, we investigated the effect of diminished serotonin (5-hydroxytryptamine) neurotransmission using dietary tryptophan depletion (TD) in healthy volunteers on the performance of a two-stage decision-making task, which allows discrimination between model-free and model-based behavioural strategies. A novel version of the task was used, which not only examined choice balance for monetary reward but also for punishment (monetary loss). TD impaired goal-directed (model-based) behaviour in the reward condition, but promoted it under punishment. This effect on appetitive and aversive goal-directed behaviour is likely mediated by alteration of the average reward representation produced by TD, which is consistent with previous studies. Overall, the major implication of this study is that serotonin differentially affects goal-directed learning as a function of affective valence. These findings are relevant for a further understanding of psychiatric disorders associated with breakdown of goal-directed behavioural control such as obsessive-compulsive disorders or addictions.This research was funded by Wellcome Trust Grants awarded to VV (Intermediate WT Fellowship) and Programme Grant (089589/Z/09/Z) awarded to TWR, BJE, ACR, JWD and BJS. It was conducted at the Behavioural and Clinical Neuroscience Institute, which is supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354). YW was supported by the Fyssen Foundation. SP is supported by Marie Curie Intra-European Fellowship (FP7-People-2012-IEF).This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/mp.2015.4

Prediction of Co-Receptor Usage of HIV-1 from Genotype

Human Immunodeficiency Virus 1 uses for entry into host cells a receptor (CD4) and one of two co-receptors (CCR5 or CXCR4). Recently, a new class of antiretroviral drugs has entered clinical practice that specifically bind to the co-receptor CCR5, and thus inhibit virus entry. Accurate prediction of the co-receptor used by the virus in the patient is important as it allows for personalized selection of effective drugs and prognosis of disease progression. We have investigated whether it is possible to predict co-receptor usage accurately by analyzing the amino acid sequence of the main determinant of co-receptor usage, i.e., the third variable loop V3 of the gp120 protein. We developed a two-level machine learning approach that in the first level considers two different properties important for protein-protein binding derived from structural models of V3 and V3 sequences. The second level combines the two predictions of the first level. The two-level method predicts usage of CXCR4 co-receptor for new V3 sequences within seconds, with an area under the ROC curve of 0.937±0.004. Moreover, it is relatively robust against insertions and deletions, which frequently occur in V3. The approach could help clinicians to find optimal personalized treatments, and it offers new insights into the molecular basis of co-receptor usage. For instance, it quantifies the importance for co-receptor usage of a pocket that probably is responsible for binding sulfated tyrosine

Clinical significance of HIV-1 coreceptor usage

The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage