METHYLATION STATUS OF BCL6 DISTINGUISHES DNA SAMPLES FROM BENIGN AND MALIGNANT LYMPHOPROLIFERATIVE DISORDERS

INTRODUCTION: Core biopsy of the breast has become the method of choice for tissue diagnosis of screen detected microcalcifications and some mass lesions in many breast assessment centres. Biopsy results are not available until the following day. Imprint cytology of fresh breast core samples allows same-day reporting and patient counselling.
AIM: To determine the accuracy of core imprint cytology when compared with core biopsy diagnosis when used in a breast assessment centre setting.
METHODS: Core imprints (CI) were prepared and reported on all fresh core biopsies (CB) performed at the Sir Charles Gairdner Hospital Breast Centre from May to December 2000. Fresh core samples were placed on a glass microscope slide. Core radiographs were taken for microcalcification lesions (MC). A laboratory technician gently and quickly rolled the cores on the slide with fine forceps. The cores were fixed in formalin, processed and reported next day. The imprint slide was air dried and stained with DiffQuik. CI were reported using four categories: Insufficient, Benign, Indeterminate and Malignant. Counselling and planning for management were possible on the same day in women with malignant diagnoses. Clinicians were advised not to discuss negative or indeterminate CI results with women and to defer to the final CB report.
RESULTS: Cores were performed on 381 lesions. There were 83 carcinomas (38 in MC and 45 in masses) and 56 were called malignant on CI (absolute sensitivity 67.5%; 78.9% for MC and 57.8% for masses). 3 malignancies on CB were negative on CI giving a false negative rate of 3.6%. There were no false positive diagnoses. The predictive value of a benign diagnosis was 95.3%. There were no adverse effects in the histology of CB.
CONCLUSION: CI was an accurate method of providing an immediate diagnosis of malignancy in two thirds of malignancies confirmed on CB.     

Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.     

Prediction of response to antiretroviral therapy by human experts and by the EuResist data‐driven expert system (the EVE study)

Objectives

The EuResist expert system is a novel data‐driven online system for computing the probability of 8‐week success for any given pair of HIV‐1 genotype and combination antiretroviral therapy regimen plus optional patient information. The objective of this study was to compare the EuResist system vs. human experts (EVE) for the ability to predict response to treatment.

Methods

The EuResist system was compared with 10 HIV‐1 drug resistance experts for the ability to predict 8‐week response to 25 treatment cases derived from the EuResist database validation data set. All current and past patient data were made available to simulate clinical practice. The experts were asked to provide a qualitative and quantitative estimate of the probability of treatment success.

Results

There were 15 treatment successes and 10 treatment failures. In the classification task, the number of mislabelled cases was six for EuResist and 6–13 for the human experts [mean±standard deviation (SD) 9.1±1.9]. The accuracy of EuResist was higher than the average for the experts (0.76 vs. 0.64, respectively). The quantitative estimates computed by EuResist were significantly correlated (Pearson r=0.695, P<0.0001) with the mean quantitative estimates provided by the experts. However, the agreement among experts was only moderate (for the classification task, inter‐rater κ=0.355; for the quantitative estimation, mean±SD coefficient of variation=55.9±22.4%).

Conclusions

With this limited data set, the EuResist engine performed comparably to or better than human experts. The system warrants further investigation as a treatment‐decision support tool in clinical practice.     

Early endosseous integration enhanced by dual acid etching of titanium: a torque removal study in the rabbit

Textured implant surfaces are thought to enhance endosseous integration. Torque removal forces have been used as a biomechanical measure of anchorage, or endosseous integration, in which the greater forces required to remove implants may be interpreted as an increase in the strength of bony integration. The purpose of this study was to compare the torque resistance to removal of screw-shaped titanium implants having a dual acid-etched surface (Osseotite) with implants having either a machined surface, or a titanium plasma spray surface that exhibited a significantly more complex surface topography. Three custom screw-shaped implant types - machined, dual acid-etched (DAE), and titanium plasma sprayed (TPS) - were used in this study. Each implant surface was characterized by scanning electron microscopy and optical profilometry. One DAE implant was placed into each distal femur of eighteen adult New Zealand White rabbits along with one of the other implant types. Thus, each rabbit received two DAE implants and one each of the machined, or TPS, implants. All implants measured 3.25 mm in diameter x 4.00 mm in length without holes, grooves or slots to resist rotation. Eighteen rabbits were used for reverse torque measurements. Groups of six rabbits were sacrificed following one, two and three month healing periods. Implants were removed by reverse torque rotation with a digital torque-measuring device. Three implants with the machined surface preparation failed to achieve endosseous integration. All other implants were anchored by bone. Mean torque values for machined, DAE and TPS implants at one, two and three months were 6.00+/-0.64 N-cm, 9.07+/-0.67 N-cm and 6.73+/-0.95 N-cm; 21.86+/-1.37 N-cm, 27.63+/-3.41 N-cm and 27.40+/-3.89 N-cm; and 27.48+/-1.61 N-cm, 44.28+/-4.53 N-cm and 59.23+/-3.88 N-cm, respectively. Clearly, at the earliest time point the stability of DAE implants was comparable to that of TPS implants, while that of the machined implants was an order of magnitude lower. The TPS implants increased resistance to reverse torque removal over the three-month period. The results of this study confirm our previous results that demonstrated enhanced bony anchorage to dual acid-etched implants as compared to machined implants. Furthermore, the present results indicate that dual acid etching of titanium enhances early endosseous integration to a level which is comparable to that achieved by the topographically more complex TPS surfaces.     

Extensive nodular cutaneous amyloidosis: an unusual presentation

Amyloidosis is characterized by the deposition of a group of unrelated proteins leading to changes in tissue architecture and function. The nodular variant is the rarest form of the cutaneous amyloidoses. We report a patient with localized nodular amyloidosis without systemic amyloid involvement or paraproteinaemia after 6 years of follow-up. The unusual aspects of our case were a plaque presentation rather than nodular, and the disseminated pattern observed.