The investigation and management of unilateral nipple discharge.

INTRODUCTION: Between 16,000 and 48,000 women are estimated to present to UK breast clinics with nipple discharge each year. The incidence of malignancy in these women is 2.7-24.2%. Currently, there is no consensus on the best way to investigate and manage these women. The aim of this study was to assess the rate of malignancy in women presenting with unilateral nipple discharge, and to evaluate the role of examination, imaging and cytology in reliably predicting outcome. METHODS: Breast units were asked to prospectively collect data on all new patients with unilateral nipple discharge. Data collected included discharge colour, whether it was uniductal or multiductal, examination and imaging findings, cytology results and outcome. RESULTS: Complete datasets were submitted by 5 units on 228 patients. The incidence of malignancy was 4.4%. Clinical examination was valuable in detecting malignancy and multiductal discharge was not related to malignancy. The positive predictive value for detecting malignancy for an abnormality found on mammography was 53.5% and for ultrasonography, it was 65.2%. The role of cytology in detecting malignancy was inconclusive with positive predictive values of the presence of red blood cells and epithelial cells at 6.1% and 10.7% respectively. CONCLUSIONS: A large number of women are investigated for nipple discharge (with huge resource implications) but there is little reliable evidence on the best way to investigate and manage these patients. A larger study is needed to evaluate the role of investigations in nipple discharge to produce guidelines on optimal management.

Neutral Hydrogen Structures Trace Dust Polarization Angle: Implications for Cosmic Microwave Background Foregrounds.

Using high-resolution data from the Galactic Arecibo L-Band Feed Array HI (GALFA-Hi) survey, we show that linear structure in Galactic neutral hydrogen (Hi) correlates with the magnetic field orientation implied by Planck 353 GHz polarized dust emission. The structure of the neutral interstellar medium is more tightly coupled to the magnetic field than previously known. At high Galactic latitudes, where the Planck data are noise dominated, the Hi data provide an independent constraint on the Galactic magnetic field orientation, and hence the local dust polarization angle. We detect strong cross-correlations between template maps constructed from estimates of dust intensity combined with either Hi-derived angles, starlight polarization angles, or Planck 353 GHz angles. The Hi data thus provide a new tool in the search for inflationary gravitational wave B-mode polarization in the cosmic microwave background, which is currently limited by dust foreground contamination.

Enhanced collisionless shock formation in a magnetized plasma containing a density gradient.

Two-dimensional hybrid simulations of super-Alfvénic expanding debris plasma interacting with an inhomogeneous ambient plasma are presented. The simulations demonstrate improved collisionless coupling of energy to the ambient ions when encountering a density gradient. Simulations of an expanding cylinder running into a step function gradient are performed and compared to a simple analytical theory. Magnetic flux probe data from a laboratory shock experiment are compared to a simulation with a more realistic debris expansion and ambient ion density. The simulation confirms that a shock is formed and propagates within the high density region of ambient plasma.

Use of the surgical Apgar score to guide postoperative care.

INTRODUCTION: The surgical Apgar score (SAS) can predict 30-day major complications or death after surgery. Studies have validated the score in different patient populations and suggest it should be used to objectively guide postoperative care. We aimed to see whether using the SAS in a decisive approach in a future randomised controlled trial (RCT) would be likely to demonstrate an effect on postoperative care and clinical outcome. METHODS: A total of 143 adults undergoing general/vascular surgery in 9 National Health Service hospitals were recruited to a pilot single blinded RCT and the data for 139 of these were analysed. Participants were randomised to a control group with standard postoperative care or to an intervention group with care influenced (but not mandated) by the SAS (decisive approach). The notional primary outcome was 30-day major complications or death. RESULTS: Incidence of major complications was similar in both groups (control: 20/69 [29%], intervention: 23/70 [33%], p=0.622). Immediate admissions to the critical care unit was higher in the intervention group, especially in the SAS 0-4 subgroup (4/6 vs 2/7) although this was not statistically significant (p=0.310). Validity was also confirmed in area under the curve (AUC) analysis (AUC: 0.77). CONCLUSIONS: This pilot study found that a future RCT to investigate the effect of using the SAS in a decisive approach may demonstrate a difference in postoperative care. However, significant changes to the design are needed if differences in clinical outcome are to be achieved reliably. These would include a wider array of postoperative interventions implemented using a quality improvement approach in a stepped wedge cluster design with blinded collection of outcome data.

Magnetic field measurements in low density plasmas using paramagnetic Faraday rotator glass.

Paramagnetic Faraday rotator glass (rare-earth doped borosilicate) with a high Verdet constant will be used to measure the magnetic field inside of low density Helium plasmas (T(e) ~ 5 eV, T(i) ~ 1 eV) with a density of n ~ 10(12) cm(-3). Linearly polarized light is sent through the glass such that the plane of polarization is rotated by an angle that depends on the strength of the magnetic field in the direction of propagation and the length of the crystal (6 mm). The light is then passed into an analyzer and photo-detector setup to determine the change in polarization angle. This setup can detect magnetic fields up to 5 kG with a resolution of <5 G and a temporal resolution on the order of a nanosecond. The diagnostic will be used to characterize the structure and evolution of laser-driven collisionless shocks in large magnetized plasmas.

Feasibility of characterizing laser-ablated carbon plasmas via planar laser induced fluorescence.

Planar laser induced fluorescence (PLIF) imaging can potentially assess ion distributions and coupling in the context of super-Alfvénic ablation plasma expansions into magnetized background plasmas. In this feasibility study, we consider the application of PLIF to rapidly expanding carbon plasmas generated via energetic laser ablation of graphite. By utilizing hydrodynamic and collisional-radiative simulations, we identify schemes accessible to commercially available tunable lasers for the C I atom, the C II ion, and the C V ion. We then estimate the signal-to-noise ratios yielded by the schemes under reasonable experimental configurations.

Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease.

BACKGROUND: Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS. METHODS: Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, ß4-integrin, ß6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase IIα and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series. RESULTS: Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases. CONCLUSION: This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

A Contralateral Complication of Extra-peritoneal Laparoscopic Inguinal Hernia Repair.

A 63 year old female underwent an uncomplicated total extraperitoneal repair of a right direct inguinal hernia. One week later she presented with a strangulated left femoral hernia. We believe the dissection of the extraperitoneal space caused bleeding which tracked down through the femoral canal resulting in a femoral hernia. To date there are no reports of such a complication following total extraperitoneal inguinal hernia repair in the literature.

Positive and negative aspects of sentinel lymph node biopsy in breast cancer.

The sentinel lymph node (SLN) is the first lymph node to receive lymphatic drainage from a tumor. SLN biopsy has become a mainstay of breast cancer management and is used when the axilla is clinically clear of disease. Staging of the axilla in breast cancer is used to predict prognosis and in planning adjuvant treatment. SLN biopsy is not used where there has been previous axillary or breast radiotherapy or surgery, locally advanced or inflammatory disease and stage IV disease. Controversies remain in several specific clinical situations, including management of the axilla following detection of a positive SLN. There are no sufficiently robust predictive tumor features to prevent completion axillary dissection in these cases. However, there is evidence that immediate axillary surgery for operable, clinically node-negative breast cancer provides no survival benefit and may be unnecessary for many women. SLN biopsy may have a role after neoadjuvant chemotherapy, sparing some women from axillary node dissection. Further work is required to ascertain SLN biopsy sensitivity prior to its routine use in the clinic for multicentric and multifocal disease.

Effect of adding and removing N-glycosylation recognition sites on the thermostability of barley alpha-glucosidase.

The thermostability of alpha-glucosidase is important because the conversion of starch to fermentable sugars during the industrial production of beer and fuel ethanol typically occurs at relatively high temperatures (60-75 degrees C). Barley (Hordeum vulgare) alpha-glucosidase is unstable at these elevated temperatures; however, the alpha-glucosidase from sugar beet (Beta vulgaris) is stable at these temperatures. An alignment of the deduced amino acid sequences of barley and sugar beet alpha-glucosidases revealed considerable differences in the number and position of N-glycosylation recognition sites (NGRS). Other researchers have shown that additions or removals of NGRS resulted in either the stabilization or destabilization of the enzymes at elevated temperatures. NGRS present in the barley sequence and absent in the sugar beet sequence were removed via site-directed mutagenesis from the barley protein. Recognition sites absent in the barley sequence and present in the sugar beet sequence were added via mutagenesis into the barley alpha-glucosidase. Two mutations significantly increased thermostability, one mutation significantly decreased thermostability and five mutations had little effect on alpha-glucosidase thermostability.

The effect of proline insertions on the thermostability of a barley alpha-glucosidase.

The thermal stability of alpha-glucosidase is important because the conversion of starch to fermentable sugars during industrial production of ethanol (e.g. brewing, fuel ethanol production) typically takes place at temperatures of 65-73 degrees C. In this study we investigate the thermostability of alpha-glucosidases from four plant species, compare their deduced amino acid sequences, and test the effect of substituting a proline for the residue present in the wild-type enzyme on the thermostability of alpha-glucosidase. The alpha-glucosidase from barley (Hordeum vulgare) was significantly less thermostable than the other three alpha-glucosidases. A comparison of the published deduced amino acid sequences of these four alpha-glucosidases revealed conserved proline residues in the three most thermostable alpha-glucosidases that were not found in the barley enzyme. Site-directed mutagenesis was done on recombinant barley alpha-glucosidase to create proteins with prolines at these conserved positions. The thermostability (T(50)) of one of these mutant enzymes, T340P, was 10 degrees C higher than the non-mutated enzyme.

Selecting lineup foils in eyewitness identification experiments: experimental control and real-world simulation.

Experimental research on eyewitness identification follows a standard principle of experimental design. Perpetrator-present and perpetrator-absent lineups are constructed with the same foils, so that the two conditions are identical except for the presence or absence ofthe trueperpetrator ofthe crime. However, this aspect of the design simulates conditions that do not correspond to those of real criminal investigations. Specifically, these conditions can create perp-absent lineups in which the foils are selected based on their similarity to an unknown person--the real perpetrator. Analysis of the similarity relations predicts that when foils for perp-absent lineups are selected based on their match to the perpetrator the false identification rate will be lower than if the foils are selected based on their match to the innocent suspect. This prediction was confirmed in an experiment that compared these two perp-absent lineup conditions. These results suggest that false identification rates in previous experiments would have been higher if the foils had been selected based on their match to the innocent suspect, rather than the absent perpetrator.

Postnatal alterations of GABA receptor profiles in the rat superior colliculus.

Midbrain sections taken from Sprague-Dawley rats of varying ages within the first four postnatal weeks were used to determine, immunocytochemically, putative changes of GABA(A) receptor beta2/3 subunits, GABA(B) receptor (R1a and R1b splice variants), and GABA(C) receptor rho1 subunit expression and distribution in the superficial, visual layers of the superior colliculus. Immunoreactivity for the GABA(A) receptor beta2/3 subunits was found in the superficial grey layer from birth. The labelling changed with age, with an overall continuous reduction in the number of cells labelled and a significant increase in the labelling intensity distribution (neuropil vs soma). Further analysis revealed an initial increase in the labelling intensity between postnatal days 0 and 7 in parallel with an overall reduction of labelled neurones. This was followed by a significant decrease in labelling intensity distribution between postnatal days 7 and 16, and a subsequent increase in intensity between postnatal days 16 and 28. The labelling profiles for GABA(B) receptors (R1a and R1b splice variants) and GABA(C) receptors (rho1 subunit) showed similar patterns. Both receptors could be found in the superficial layers of the superior colliculus from birth, and the intensity and distribution of labelling remained constant during the first postnatal month. However, the cell body count showed a significant decrease between postnatal days 7 and 16. These changes may be related to the time-point of eye opening, which occurred approximately two weeks after birth. For all three receptor types, the cell body count remained constant after postnatal day 16. By four weeks of age, there was no significant difference between the cell numbers obtained for the different receptors. Both GABA itself and neurofilament labelling were also obtained in the superficial superior colliculus at birth. Neurofilament, although found at birth, showed very little ordered arrangement until 16days after birth. When slices were double labelled for GABA(C) receptors and neurofilament, some overlap was observed. Double labelling for the presynaptic protein synaptophysin and GABA(C) receptors showed proximity in some places, indicative of a partly synaptic location of GABA(C) receptors. When GABA(C) and GABA(A) receptors were labelled simultaneously, some but not all neurones showed immunoreactivity for both receptor types. In conclusion, all three GABA receptor types were found to be present in the superior colliculus from birth, and all show some form of postnatal modification, with GABA(A) receptors demonstrating the most dramatic changes. However, GABA(B) and GABA(C) receptors are modified significantly around the onset of input-specific activity. Together, this points towards a contribution of the GABAergic system to processes of postnatal maturation in the superficial superior colliculus.

Cell signalling at the shoot meristem.

The regulation of cell differentiation at meristems is crucial to developmental patterning in plants. Rapid progress has been made in identifying the genes that regulate differentiation and the receptor-mediated signalling events that have a key role in this process. In particular, we are now learning how the CLAVATA receptor kinase signalling pathway promotes stem cell differentiation in balance with the initiation of stem cells by the transcription factor WUSCHEL.

Meristems: start your signaling.

All of the cells of the shoot apex are derived from a small number of stem cells in the center of the shoot meristem. Hence, cell lineage plays no role in establishing pattern formation or cell fate at the shoot apex. Growing evidence has implicated a number of cell signaling pathways in regulating shoot meristem development and organ formation. These signaling pathways include receptor-mediated signaling, protein movement via plasmodesmata, and potential feedback loops.

REVOLUTA regulates meristem initiation at lateral positions.

While the shoot apical meristem (SAM) is indirectly responsible for the initiation of all above-ground postembryonic organs, in most plants the vast majority of these organs are directly initiated by lateral meristems. In Arabidopsis thaliana, the lateral meristems include flower meristems (FMs), which form on the flanks of the SAM, and lateral shoot meristems (LSMs), which develop in leaf axils. While significant progress has been made on the molecular genetic basis of SAM initiation during embryo development, relatively little is known about the initiation of meristems at lateral positions. Here we have characterized the phenotypic consequences and genetic interactions of mutations in the REVOLUTA (REV) gene, with an emphasis on the role of REV in lateral meristem initiation. Our observations indicate that REV is required for initiation of both LSMs and FMs, and likely acts in the same pathway as, and upstream of, known meristem regulators. We identified the REV gene and found it encodes a predicted homeodomain/leucine zipper transcription factor that also contains a START sterol-lipid binding domain. REV is the same as the IFL gene. REV was expressed at the earliest stages of LSM and FM formation. Within the inflorescence shoot meristem, REV expression appeared to predict 3--5 incipient flower primordia on the flanks of the SAM, and REV expression at stage 1 and stage 2 matched that of WUS and STM, respectively. We propose that REV acts at lateral positions to activate the expression of known meristem regulators.

Does the Conners' Continuous Performance Test aid in ADHD diagnosis?

The performance of clinic-referred children aged 6-11 (N = 100) was examined using the Conners' Continuous Performance Test (CPT) and measures of auditory attention (Auditory Continuous Performance Test; ACPT), phonological awareness, visual processing speed, and visual-motor competence. The Conners' CPT overall index was unrelated to measures of visual processing speed or visual-motor competence. Although the Conners' CPT converged with the ACPT, the latter demonstrated age and order effects. Significant variance in Conners' CPT parameters was predicted by phonological awareness measures, suggesting that Reading Disordered (RD) children could be "false positives" on the Conners' CPT. The Conners' CPT overall index, phonological awareness, and visual-motor measures were submitted to a 2 x 2 MANCOVA (ADHD vs. RD, covarying for age and socioeconomic status): a main effect for RD status was found. Children with ADHD did not have higher Conners' CPT scores than did clinical controls; however, children with Reading Disorders did. Phonological measures distinguished RD children from ADHD children and other clinical controls. ADHD children who failed the Conners' CPT were rated by teachers as more hyperactive. Despite the strengths of the Conners' CPT, its utility for differential diagnosis of ADHD is questioned.

CLAVATA3, a multimeric ligand for the CLAVATA1 receptor-kinase.

The CLAVATA1 (CLV1) and CLAVATA3 (CLV3) proteins form a potential receptor and ligand pair that regulates the balance between cell proliferation and differentiation at the shoot meristem of Arabidopsis. CLV1 encodes a receptor-kinase, and CLV3 encodes a predicted small, secreted polypeptide. We demonstrate that the CLV3 and CLV1 proteins coimmunoprecipitate in vivo, that yeast cells expressing CLV1 and CLV2 bind to CLV3 from plant extracts, and that binding requires CLV1 kinase activity. CLV3 only associates with the presumed active CLV1 protein complex in vivo. More than 75% of CLV3 in cauliflower extracts is bound with CLV1, consistent with hypotheses of ligand sequestration. Soluble CLV3 was found in an approximately 25-kilodalton multimeric complex.

Selecting foils for identification lineups: matching suspects or descriptions?

Two experiments directly compare two methods of selecting foils for identification lineups. The suspect-matched method selects foils based on their match to the suspect, whereas the description-matched method selects foils based on their match to the witness's description of the perpetrator. Theoretical analyses and previous results predict an advantage for description-matched lineups both in terms of correctly identifying the perpetrator and minimizing false identification of innocent suspects. The advantage for description-matched lineups should be particularly pronounced if the foils selected in suspect-matched lineups are too similar to the suspect. In Experiment 1, the lineups were created by trained police officers, and in Experiment 2, the lineups were constructed by undergraduate college students. The results of both experiments showed higher suspect-to-foil similarity for suspect-matched lineups than for description-matched lineups. However, neither experiment showed a difference in correct or false identification rates. Both experiments did, however, show that there may be an advantage for suspect-matched lineups in terms of no-pick and rejection responses. From these results, the endorsement of one method over the other seems premature.