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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. 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. 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. 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.

In 1999, five randomized studies demonstrated that chemoradiation with cisplatin and low-dose rate (LDR) brachytherapy has a benefit in locally advanced cervical cancer and for surgically treated patients in high-risk situations. We evaluated the safety and efficacy of concomitant chemoradiation with cisplatin and high-dose rate (HDR) brachytherapy in patients with cervical cancer. 27 patients were included in our phase-II trial: 13 locally advanced cases (group A) and 14 adjuvant-therapy patients in high-risk situations (group B). A definitive radiotherapy was performed with 25 fractions of external beam therapy (1.8 Gy per fraction/middle shielded after eleven fractions). Brachytherapy was delivered at HDR schedules with 7 Gy in point A per fraction (total dose 35 Gy) in FIGO Stages IIB-IIIB. The total dose of external and brachytherapy was 70 Gy in point A and 52-54 Gy in point B. All patients in stage IVA were treated without brachytherapy. Adjuvant radiotherapy was performed with external beam radiotherapy of the pelvis with 1.8 Gy single-dose up to 50.4 Gy. Brachytherapy was delivered at HDR schedules with two fractions of 5 Gy only in patients with tumor-positive margins or tumor involvement of the upper vagina. The chemotherapeutic treatment schedule provided six courses of cisplatin 40 mg/m2 weekly recommended in the randomized studies GOG-120 and -123. A total of 18/27 patients (66.7%) completed all six courses of chemotherapy. Discontinuation of radiotherapy due to therapy-related morbidity was not necessary in the whole study group. G3 leukopenia (29.6%) was the only relevant acute toxicity. There were no differences in toxicity between group A and B. Serious late morbidity occurred in 2/27 patients (7.4%). 12/13 patients (92.3%) with IIB-IVA cervical cancer showed a complete response (CR). 13/14 adjuvant cases (92.8%) are free of recurrence (median follow up: 19.1 months). Concomitant chemoradiation with cisplatin 40 mg/m2 weekly x 6 using HDR brachytherapy represents a promising treatment of cervical cancer with an acceptable toxicity.

EDITOR-Ball et al report their low colonoscopy completion rates, performing an audit to identify areas for improvement. 1 The use of audit in colonoscopy is invaluable and the points highlighted are undoubtedly relevant to other colonoscopy units.

The sedimentary sequence on the shelf of the southern North Sea records Quaternary climatic changes in two ways. They are indicated directly by moraine and glaciofluvial deposits from the Elsterian, Saalian and Weichselian glacial periods when the British and the Scandinavian ice sheets covered parts of the area. An indirect response to the climate is indicated by sea-level changes. Phases of cooling are characterized by regressions and low sea-level stands; phases of warming are indicated by marine transgressions and high sea levels during the Holsteinian, Eemian and Holocene periods. The seismic characteristics of the different lithological units, the sedimentary sequences and their fossil content are described for the offshore area and the adjacent coastal zone. This provides a record of the interaction of sedimentary processes and the palaeogeographic development as a response to climatic changes.

Fifty-one sediment samples from a shallow (<15 m) bay of Curaçao, Spaanse Water, were clustered based on their components and grain size. Three main biofacies, in geographically distinct areas of the bay, are recognized. One, the Halimeda Faciés, dominated by the remains of the calcareous alga Halimeda (70), is related to coarse sediments (coarse and fine sand) and frames the coastal, shallow areas of the bay. Another, the Ostracod Faciés, shows a high ostracod (46), echinoid spine (11) and foraminifer (17) content, and is related to fine sediments, which cover the central basin, the eastern part and the channel of the bay. The third, Gastropod-Halimeda Faciés, is restricted to the western part of the bay and characterized by a poor microfauna and a relatively high percentage of gastropods (20). It comprises coarse sediments with a relative scarcity of the finest material and with common dark, coated grains. The Gastropod-Halimeda Faciés is shown to be a \"relict\" of the rich Halimeda Faciés. Its distribution coincides with an area of intense boating activity. Benthic foraminifera are widely distributed and make up 4-30 of the skeletal components. The assemblages are often related to the recognized facies. Increased abundances of the large, algal symbiont-bearing species as well as Elphidium poeyanum and E.discoidale are associated with the Halimeda Faciés, while Ammonia tepida, Nonion grateloupii, Reussella simplex and small, thin-shelled miliolids dominate the foraminiferal assemblage of the Ostracod Facies. The distribution pattern of foraminiferal assemblages appears to be related primarily to the nature of substrate (grain size) and light penetration (depth). The highest abundance (50) of Ammonia tepida is found in mangrove areas, where samples contain vegetable matter.

The seabed of the Dutch sector of the North Sea is one of most densely sampled marine areas in the world. Sampling started in the mid-1960s with the exploration of fill sand in the coastal zone. Since that time, a reconnaissance mapping programme of the entire territory has been carried out in close cooperation with the North Sea Directorate of the Dutch Ministry of Public Works and Water Management and the Hy-drographic Office of the Royal Netherlands Navy. The sample spacing varies much from north to south and from east to west, reflecting the differing relevance of various areas to policymakers and industry. In the northern part, the mean sample density is one per 2 5 square kilometres, and in the southern part the interval in the coastal zone west of the port of Rotterdam, The Netherlands, increases to one per square kilometre. To establish the boundaries between the different grain-size classes of the seabed sediments, bathymetric and side scan sonar data collected by the Hydrographic Office have been used. The interpretations that followed have led to a better understanding of bed forms, sedimentation and erosion patterns. The interpretations have also allowed for the continuous improvement of seabed sediments maps.

Medication-related visits to the emergency department are an important but poorly understood phenomenon. We sought to evaluate the frequency, severity and preventability of drug-related visits to the emergency department. We performed a prospective observational study of randomly selected adults presenting to the emergency department over a 12-week period. Emergency department visits were identified as drug-related on the basis of assessment by a pharmacist research assistant and an emergency physician; discrepancies were adjudicated by 2 independent reviewers. Among the 1017 patients included in the study, the emergency department visit was identified as drug-related for 122 patients (12.0%, 95% confidence interval [CI] 10.1%-14.2%); of these, 83 visits (68.0%, 95% CI 59.0%-76.2%) were deemed preventable. Severity was classified as mild in 15.6% of the 122 cases, moderate in 74.6% and severe in 9.8%. The most common reasons for drug-related visits were adverse drug reactions (39.3%), nonadherence (27.9%) and use of the wrong or suboptimal drug (11.5%). The probability of admission was significantly higher among patients who had a drug-related visit than among those whose visit was not drug-related (OR 2.18, 95% CI 1.46-3.27, p < 0.001), and among those admitted, the median length of stay was longer (8.0 [interquartile range 23.5] v. 5.5 [interquartile range 10.0] days, p = 0.06). More than 1 in 9 emergency department visits are due to drug-related adverse events, a potentially preventable problem in our health care system.

Shigellosis, is a leading cause of moderate-to-severe diarrhoea and related mortality in young children in low and middle income countries (LMICs). Knowledge on naturally acquired immunity can support the development of Shigella candidate vaccines mostly needed in LMICs. We aimed to quantify Shigella-specific antibodies of maternal origin and those naturally acquired in Zambian infants. Plasma samples collected from infants at age 6, 14 and 52-weeks were tested for Shigella (S. sonnei and S. flexneri 2a) lipopolysaccharide (LPS) antigen specific immunoglobulin G (IgG) and A (IgA) by enzyme-linked immunosorbent assay. At 6 weeks infant age, the IgG geometric mean titres (GMT) against S. sonnei (N = 159) and S. flexneri 2a (N = 135) LPS were 311 (95% CI 259-372) and 446 (95% CI 343-580) respectively. By 14 weeks, a decline in IgG GMT was observed for both S. sonnei to 104 (95% CI 88-124), and S. flexneri 2a to 183 (95% CI 147-230). Both S. sonnei and S. flexneri 2a specific IgG GMT continued to decrease by 52 weeks infant age when compared to 6 weeks. In 27% and 8% of infants a significant rise in titre (4 fold and greater) against S. flexneri 2a and S. sonnei LPS, respectively, was detected between the ages of 14 and 52 weeks. In our setting, transplacental IgG anti-Shigella LPS is present at high levels in early infancy, and begins to decrease by age 14 weeks. Our results are consistent with early exposure to Shigella and indicate naturally acquired IgG and IgA antibodies to S. flexneri 2a and S. sonnei LPS in part of infants between 14 and 52 weeks of age. These results suggest that a potential timing of vaccination would be after 14 and before 52 weeks of age to ensure early infant protection against shigellosis.

Use of an alternative open reading frame, potentially as a result of cellular stress, drives production of an unconventional insulin epitope that is recognized by cytotoxic T cells from individuals with type 1 diabetes; these T cells kill beta cells in vitro . Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking 1 , 2 . Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8 + T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.