Population-based study of the sensitivity of axillary ultrasound imaging in the preoperative staging of node-positive invasive lobular carcinoma of the breast.

BACKGROUND: Preoperative staging of the axilla is important to allow decisions regarding neoadjuvant treatment and the management of the axilla. Invasive lobular carcinoma metastases are difficult to detect because of the infiltrative pattern of the nodal spread. In this study the sensitivity of preoperative axillary staging between invasive lobular (ILC) and ductal (IDC) carcinoma was compared. METHODS: All women diagnosed with pure ILC or IDC in the West of Scotland in 2012-2014 were identified from a database maintained prospectively within the Managed Clinical Network. Pretreatment axillary ultrasound imaging (AUS), core biopsy and fine-needle aspiration cytology (FNAC) results were compared between ILC and IDC. RESULTS: Some 602 women with ILC and 4199 with IDC had undergone axillary surgery, of whom 209 and 1402 respectively had nodal metastases. Pretreatment AUS sensitivity was significantly lower in ILC than in IDC (32·1 versus 50·1 per cent respectively, P < 0·001; OR 0·47, 95 per cent c.i. 0·34 to 0·64). Core biopsy had equally high sensitivity of 86 per cent in both subtypes; however, FNAC was significantly less sensitive in both ILC (55 per cent; P = 0·003) and IDC (75·6 per cent; P = 0·006). Multivariable analysis revealed that cT3-4 status and symptomatic presentation were both significant in predicting nodal metastasis in patients with ILC and false-negative AUS findings (OR 3·77, 95 per cent c.i. 1·69 to 8·42, P = 0·001; and OR 1·92, 1·24 to 2·98, P = 0·003, respectively). CONCLUSION: AUS is inferior in detecting axillary node metastasis in ILC compared with IDC. Women with cT3-4 lobular carcinoma may benefit from ultrasound-guided axillary biopsy regardless of the ultrasonographic appearance of the nodes.

Between-sex genetic covariance constrains the evolution of sexual dimorphism in Drosophila melanogaster.

Males and females share much of their genome, and as a result, intralocus sexual conflict is generated when selection on a shared trait differs between the sexes. This conflict can be partially or entirely resolved via the evolution of sex-specific genetic variation that allows each sex to approach, or possibly achieve, its optimum phenotype, thereby generating sexual dimorphism. However, shared genetic variation between the sexes can impose constraints on the independent expression of a shared trait in males and females, hindering the evolution of sexual dimorphism. Here, we examine genetic constraints on the evolution of sexual dimorphism in Drosophila melanogaster cuticular hydrocarbon (CHC) expression. We use the extended G matrix, which includes the between-sex genetic covariances that constitute the B matrix, to compare genetic constraints on two sets of CHC traits that differ in the extent of their sexual dimorphism. We find significant genetic constraints on the evolution of further dimorphism in the least dimorphic traits, but no such constraints for the most dimorphic traits. We also show that the genetic constraints on the least dimorphic CHCs are asymmetrical between the sexes. Our results suggest that there is evidence both for resolved and ongoing sexual conflict in D. melanogaster CHC profiles.

Retinopathy and attenuated circadian entrainment in Crx-deficient mice.

Crx, an Otx-like homeobox gene, is expressed specifically in the photoreceptors of the retina and the pinealocytes of the pineal gland. Crx has been proposed to have a role in the regulation of photoreceptor-specific genes in the eye and of pineal-specific genes in the pineal gland. Mutations in human CRX are associated with the retinal diseases, cone-rod dystrophy-2 (adCRD2; refs 3, 4, 5), retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), which all lead to loss of vision. We generated mice carrying a targeted disruption of Crx. Crx-/- mice do not elaborate photoreceptor outer segments and lacked rod and cone activity as assayed by electroretinogram (ERG). Expression of several photoreceptor- and pineal-specific genes was reduced in Crx mutants. Circadian entrainment was also affected in Crx-/- mice.

Routine four-quadrant cavity shaving at the time of wide local excision for breast cancer reduces re-excision rate.

INTRODUCTION: Breast conservation therapy (BCT) has been shown to have comparable long-term survival outcomes when compared with mastectomy. Clearance of excision margin is one of the mainstays of the surgical treatment, which if not achieved at the first operation of BCT results in the need for subsequent surgery. METHODS: This study evaluated the impact of routinely taken cavity shavings on re-excision rates. This retrospective two-centre study describes the use of routine four-quadrant cavity shaving in 449 patients with consecutively treated with wide local excision for invasive cancer or ductal carcinoma in situ. RESULTS: The overall incomplete excision rate was 10.6%. Routine cavity shaving prevented the need for re-excision in 84 patients (18.7%) and identified the need for further re-excision in 33 patients (7.3%). Median time from surgery to radiotherapy was 50 days (range 13-209) for non-re-excised patients versus 78 days (range 47-260) for re-excised patients (p<0.001). Median time to chemotherapy (n=75) was 44 days (range 14-106) for non-re-excised patients versus 56 days (range 35-116) for re-excised patients (p=0.017). CONCLUSIONS: This study demonstrates that routine cavity shaving decreases re-excision rate in patients treated with wide local excision and prevents delays to adjuvant treatment due to incomplete excision.

Perioperative considerations when operating on the very obese: tricks of the trade.

Obesity is the leading public health concern in the industrialized world with the advent of the very obese or "super obese" increasing exponentially. Bariatric surgery remains the only effective and enduring treatment for morbid obesity and can be safely accomplished in experienced centers. Surgery in the very obese may be considered high-risk: however, this risk may be managed with an experienced bariatric surgery team, appropriate anesthetic consideration, preoperative risk assessment, employment of venothrombotic event prevention, preoperative weight loss, and understanding of particular anatomic considerations. With appropriate preparation, the very obese surgical patient can achieve safe and effective surgical outcomes.

Vertebrate photoreceptor cell development and disease.

Photoreceptors provide an excellent model for studies of vertebrate neuronal differentiation, and many human diseases resulting in blindness primarily affect photoreceptors. There is therefore great interest in studying the cellular and molecular mechanisms of photoreceptor development. This article discusses our current understanding of this process, including the recent discovery of the homeodomain transcription factor Crx and its potential role in diseases affecting human vision.

Immunogenic males: a genome-wide analysis of reproduction and the cost of mating in Drosophila melanogaster females.

In Drosophila melanogaster, mating radically transforms female physiology and behaviour. Post-mating responses include an increase in the oviposition rate, a reduction in female receptivity and an activation of the immune system. The fitness consequences of mating are similarly dramatic--females must mate once in order to produce fertile eggs, but additional matings have a clear negative effect. Previously, microarrays have been used to examine gene expression of females differing in their reproductive status with the aim of identifying genes influenced by mating. However, as only virgin and single mated females were compared, transcriptional changes associated with reproduction (under natural selection) and male-induced effects (possibly under sexually antagonistic selection) cannot be disentangled. We partitioned these fundamentally different effects by instead examining the expression profiles of virgin, single mated and double mated females. We found substantial effects relating to reproduction and further effects that are only attributable to mating itself. Immune response genes dominate this male-induced effect indicating that the cost of mating may be due partly to this system's activation. We propose that both sexually antagonistic and natural selection have been important in the evolution of the innate immunity genes, thereby contributing to the sexual dimorphism and rapid evolution at these loci.

rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells.

We are interested in the mechanisms of glial cell development in the vertebrate central nervous system. We have identified genes that can direct the formation of glia in the retina. rax, a homeobox gene, Hes1, a basic helix-loop-helix gene, and notch1, a transmembrane receptor gene, are expressed in retinal progenitor cells, downregulated in differentiated neurons, and expressed in Müller glia. Retroviral transduction of any of these genes resulted in expression of glial markers. In contrast, misexpression of a dominant-negative Hes1 gene reduced the number of glia. Cotransfection of rax with reporter constructs containing the Hes1 or notch1 regulatory regions led to the upregulation of reporter transcription. These data suggest a regulatory heirarchy that controls the formation of glia at the expense of neurons.

Hemiclonal analysis reveals significant genetic, environmental and genotype x environment effects on sperm size in Drosophila melanogaster.

Spermatozoa are the most diverse of all animal cells. Variation in size alone is enormous and yet there are still no clear evolutionary explanations that can account for such diversity. The basic genetics of sperm form is also poorly understood, although sperm size is known to have a strong genetic component. Here, using hemiclonal analysis of Drosophila melanogaster, we demonstrate that there is not only a significant additive genetic component contributing to phenotypic variation in sperm length but also a significant environmental effect. Furthermore, the plasticity of sperm size has a significant genetic component to it (a genotype x environment interaction). A genotype x environment interaction could contribute to the maintenance of the substantial genetic variation in this trait and thereby explain the persistent inter-male differences in sperm size seen in numerous taxa. We suggest that the low conditional dependence and high heritability but low evolvability (the coefficient of additive genetic variation) of sperm length is more consistent with a history of stabilizing selection rather than either sexual selection or strong directional selection.

Assessing the extent of genome-wide intralocus sexual conflict via experimentally enforced gender-limited selection.

Intralocus sexual conflict, which occurs when a trait is selected in opposite directions in the two sexes, is a taxonomically widespread phenomenon. The strongest genetic evidence for a gender load due to intralocus sexual conflict comes from the Drosophila melanogaster laboratory model system, in which a negative genetic correlation between male and female lifetime fitness has been observed. Here, using a D. melanogaster model system, we utilize a novel modification of the 'middle class neighbourhood' design to relax selection in one sex, while maintaining selection in the other. After 26 generations of asymmetrical selection, we observed the expected drop in fitness of the non-selected sex compared to that of the selected sex, consistent with previous studies of intralocus sexual conflict in this species. However, the fitness of the selected sex also dropped compared to the base population. The overall decline in fitness of both the selected and the unselected sex indicates that most new mutations are harmful to both sexes, causing recurrent mutation to build a positive genetic correlation for fitness between the sexes. However, the steeper decay in the fitness of the unselected sex indicates that a substantial number of mutations are gender-limited in expression or sexually antagonistic. Our experiment cannot definitively resolve these two possibilities, but we use recent genomic data and results from previous studies to argue that sexually antagonistic alleles are the more likely explanation.

Structure-property relationships from universal signatures of plasticity in disordered solids.

When deformed beyond their elastic limits, crystalline solids flow plastically via particle rearrangements localized around structural defects. Disordered solids also flow, but without obvious structural defects. We link structure to plasticity in disordered solids via a microscopic structural quantity, "softness," designed by machine learning to be maximally predictive of rearrangements. Experimental results and computations enabled us to measure the spatial correlations and strain response of softness, as well as two measures of plasticity: the size of rearrangements and the yield strain. All four quantities maintained remarkable commonality in their values for disordered packings of objects ranging from atoms to grains, spanning seven orders of magnitude in diameter and 13 orders of magnitude in elastic modulus. These commonalities link the spatial correlations and strain response of softness to rearrangement size and yield strain, respectively.

Venn diagrams and neuronal vulnerability.

Greenamyre and Young note that there is poor correlation between which hippocampal regions are damaged in Alzheimer's disease and which have the highest concentrations of NMDA receptors. They conclude that EAAs can thus only be necessary, but not sufficient to explain Alzheimer's damage. We note that this is in fact probably the rule rather than the exception: some of the most credible agents which damage neurons are merely necessary, but not sufficient to explain selective neuronal vulnerability.

Sperm competition experiments between lines of crickets producing different sperm lengths.

Sperm numbers can be important determinants of fertilization success in sperm competition. However, the importance of variation in sperm size is less well understood. Sperm size varies significantly both between and within species and comparative studies have suggested that some of this variance can be explained by sperm competition. In this study we examine whether variation in sperm length has consequences for fertilization precedence using controlled sperm competition experiments in the field cricket Gryllus bimaculatus. This species is an ideal model for such investigations because the mechanism of sperm competition generates complete mixing of different males' spermatozoa in the female (thereby allowing individual sperm to express their own competitive abilities). We successfully bred lines of crickets, the males of which produced short, medium and long sperm types with narrow and non-overlapping distributions. Males of different lines were then sequentially mated with control females in order to create two-male sperm competitions. The paternity outcomes of these competitions were measured after matings using an irradiated male technique (with a full reciprocal design that controls for natural fertility and any irradiation effects on gamete competitiveness) over a 12 day oviposition period. However, having successfully bred diverging sperm length lines and competing males that differed in sperm length, we found no evidence that a male's sperm size explained any of the variation in their relative fertilization success. Males from lines producing longer sperm showed no fertilization advantage over males producing shorter sperm across 97 double matings. There was also no advantage for males producing a sperm length close to the population mean over those competitors whose sperm length had been selectively diverged across 63 matings.

The evolution of sperm length in moths.

Sperm form and function remain poorly understood despite being of fundamental biological importance. An instructive approach has been to examine evolutionary associations across comparable taxa between sperm characters and other, potentially selective reproductive traits. We adopt this approach here in a comparative study examining how sperm lengths are associated with male and female reproductive characters across moths. Primary data have revealed Lepidoptera to be an ideal order for examination: there is profound variation in the dimensions (but not organization) of the reproductive traits between closely related species which all share a monophyletic ancestry, for example, eupyrene sperm length varies from 110 to 12,675 microm. Eupyrene (normal fertilizing) and apyrene (anucleate and non-fertile) sperm lengths are positively correlated across taxa and both sperm types show positive associations with mating pattern (as measured by the residual testis size). At fertilization, eupyrene sperm must migrate down the often elongated female spermathecal duct from storage to unite with the ovum. Across taxa, the elongation of this duct is associated with increased eupyrene sperm length, suggesting a positive female influence on sperm size since longer, more powerful sperm may be selected to migrate and/or compete successfully down greater ductal lengths. Apyrene sperm length is not associated with female reproductive tract dimensions. However, we found a positive relationship between the residual testis volume and spermathecal volume, suggesting coevolution between male investment in spermatogenesis and the extent of the female sperm storage capacity. Within males, there is a positive association between the two organs which form the ejaculate-containing spermatophore: the testes and the accessory gland. The 'trade-up' in investment to these components is discussed in relation to paternal investment and mating patterns.

Resource allocation in on-line reading by younger and older adults.

Younger and older adults read a series of expository passages for immediate recall by self-pacing the presentation sector-by-sector on a computer screen. Regression analysis of sector reading times (RT) was used to estimate the time allocated by individuals to word-level (i.e., syllable length and mean word frequency), text-level (i.e., number of propositions, number of new concepts introduced, and total Yngve depth), and discourse-level (i.e., serial position) features. Age differences were found in the pattern of reading time allocation that engendered high levels of recall. Specifically, younger adults who achieved high recall were more responsive to word frequency and the introduction of new concepts. By contrast, high recall among the old was related to a greater degree of on-line contextual facilitation (i.e., a steeper serial position effect). These data suggest that there is an age difference in how the allocation of resources at encoding optimizes subsequent memory performance.

Patterns of resource allocation are reliable among younger and older readers.

Younger and older adults read short expository passages across 2 times of measurement for subsequent comprehension or recall. Regression analysis was used to decompose word-by-word reading times into resources allocated to word- and textbase-level processes. Readers were more sensitive to these demands when reading for recall than when reading for comprehension. Patterns of resource allocation showed good test-retest reliabilities and were predictive of memory performance. Within age group, resource allocation parameters were not systematically correlated with other individual-difference measures, suggesting that strategies of on-line resource allocation may be a unique source of individual differences in determining comprehension of and memory for text. Age differences in allocation patterns appeared to reflect general slowing among the older adults. Because older adults showed equivalent memory performance to that of younger readers, the reading time data may represent the on-line resource allocation needed for comparable outcomes among older and younger readers.

The influence of expertise and task factors on age differences in pilot communication.

The influence of expertise and task factors on age differences in a simulated pilot-Air Traffic Control (ATC) communication task was examined. Young, middle-aged, and older pilots and nonpilots listened to ATC messages that described a route through an airspace, during which they referred to a chart of this airspace. Participants read back each message and then answered a probe question about the route. It was found that pilots read back messages more accurately than nonpilots, and younger participants were more accurate than older participants. Age differences were not reduced for pilots. Pilots and younger participants also answered probes more accurately, suggesting that they were better able to interpret the ATC messages in terms of the chart in order to create a situation model of the flight. The findings suggest that expertise benefits occur for adults of all ages. High levels of flying experience among older pilots (as compared with younger pilots) helped to buffer age-related declines in cognitive resources, thus providing evidence for the mediating effects of experience on age differences.

Calcium influence on neuronal sensitivity to ethanol in selectively bred mouse lines.

Sensitivity to ethanol, as measured by blood ethanol concentration at loss of righting reflex, was increased significantly in SS but not LS mice following intracerebroventricular (ICV) administration of calcium chloride or A23187, a calcium ionophore. Magnesium chloride or lanthanum chloride, ICV, did not alter sensitivity to ethanol in either SS or LS mice, further indicating a specificity for calcium cation. Calcium was without effect on sensitivity to halothane narcosis in LS or SS mice. Endogenous brain calcium content was similar in these mouse lines, and ethanol administration either in vivo or in vitro did not alter brain calcium concentration. These results indicate that differences in brain sensitivity to ethanol are mediated, in part, by genetic differences in calcium-related processes and support the hypothesis that ethanol-induced narcosis may be due to alterations in calcium metabolism in the CNS.

Effects of ethanol and pentobarbital on neuronal hexose uptake in inbred mice.

The effect of ethanol and pentobarbital narcosis on 2-deoxyglucose uptake into brain synaptosomes prepared from inbred C57BL/6J and DBA/2J mice which exhibit differential central sensitivity to ethanol and heterogeneous ICR mice was examined. A reversible depression of synaptosomal uptake was exhibited in all strains administered ethanol acutely, occurring at 2 min in ICR and C57BL/6J mice and 15 min in DBA/2J. Uptake returned to control values in all strains at 30 min although the mice remained intoxicated. Brain glucose concentration was significantly elevated at this time. Pentobarbital administration was without effect on synaptosomal hexose transport in DBA/2J and C57BL/6J mice but increased it significantly in ICR mice at 30 min. Pentobarbital anesthesia did not alter brain glucose concentration. No correlation was apparent between synaptosomal 2-deoxyglucose uptake and differential CNS sensitivity to ethanol and pentobarbital. The effects of ethanol and pentobarbital on neuronal hexose transport is discussed with respect to reported changes in glycolytic metabolism produced by these agents.