Maternal mortality and Millennium Development Goal 5.

INTRODUCTION: The maternal mortality ratio (MMR) is a key indicator for measurement of progress against Millennium Development Goal 5 (MDG 5). For many countries, especially those with a presumed high number of maternal deaths, only estimates are available. SOURCES OF DATA: Recent global estimates and the reasons for high maternal mortality are reviewed. AREAS OF AGREEMENT: There is international consensus that efforts to reduce maternal mortality globally need to be intensified. AREAS OF CONTROVERSY: Many countries lack accurate data on number of deaths in women of reproductive age and number of births. Therefore, statistical modelling has been used to calculate estimates, which generally have wide confidence intervals and may be disputed by individual countries. GROWING POINTS: There is renewed focus on MMR as 2015 approaches. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need to adapt and implement methods for measuring maternal mortality to generate more accurate estimates. More data on cause of death are needed.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer.

Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

Effects of retinol, fatty acids and glycerol monooleate on the fusion of chick embryo myoblasts in vitro.

Cell fusion of embryonic chick myoblasts has been studied in the presence of fat-soluble agents that induce erythrocytes to fuse. Retinol inhibited myoblast fusion but the cells recovered their ability to fuse within 48 h of removal of the retinol from the medium. Myristic acid, oleic acid, glycerol monooleate, linolenic acid and arachidonic acid similarly prevented fusion in myogenic cultures. By contrast, linoleic acid moderately enhanced the fusion of chick skeletal myoblasts. In addition, stearic acid, which does not fuse erythrocytes, inhibited myoblast fusion whereas the saturated, non-fusogenic fatty acid, arachidic acid, was without effect.

Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique.

AIMS: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. METHODS/RESULTS: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater. The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. CONCLUSIONS: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices.

Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin.

Normal human skin is remarkably resistant to infection from the large numbers of microorganisms that routinely colonize its surface. In addition to the role of skin as a mechanical barrier, it has long been recognized that skin and other epithelia can produce a range of anti-microbial chemicals that play an important part in eliminating potential cutaneous pathogens. Anti-microbial peptides are an important evolutionarily conserved innate host defense mechanism in many organisms. Human beta defensin-1 and -2 are cysteine-rich, cationic, low molecular weight anti-microbial peptides that have recently been shown to be expressed in epithelial tissues. In this study, we describe the characterization of human beta defensin-1 and -2 mRNA and peptide expression in normal human skin. Using reverse transcription-polymerase chain reaction we demonstrate that human beta defensin-1 is consistently expressed in skin samples from various body sites. Human beta defensin-2 demonstrates expression that is more variable and is more readily detectable in facial skin and foreskin compared with skin from abdomen and breast. In situ hybridization localizes the human beta defensin-1 and -2 transcripts to keratinocytes within interfollicular skin. Using specific antibodies, we have shown that human beta defensin-1 and -2 peptides are localized to the Malpighian layer of the epidermis and/or stratum corneum and that there are interindividual and site-specific differences in intensity of immunostaining and the pattern of peptide localization. The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.

Dietary fiber and cholesterol metabolism in rabbits and rats.

Rabbits fed semipurified diets have elevated plasma cholesterol levels, and they oxidize [26-14C]cholesterol to expired 14CO2 more slowly than rabbits on a natural ingredient diet. Addition of several different types of fibrous material to a semipurified diet failed to prevent the hypercholesterolemic response. Rats on semipurified diets also oxidized [26-14C]cholesterol more slowly and tended to have somewhat higher plasma cholesterol levels than rats on commercial feed. Cholesterol oxidation was not stimulated by addition of fibrous materials to the semipurified diet, but rats fed a semipurified diet containing raw potato starch oxidized cholesterol at a rate comparable to that of rats on commercial diet. Raw potato starch was poorly digested by the rats. Cooked potato starch was well digested and failed to stimulate the rate of oxidation of cholesterol. A semipurified diet containing raw potato starch did not produce a hypercholesterolemic response in rabbits, even though the raw starch was well digested.

Successful pregnancy following bone marrow transplantation for leukaemia.

We report three pregnancies with successful outcomes in two women following allogeneic bone marrow transplantation (BMT) for acute leukaemia using high dose melphalan alone as conditioning therapy. The increasing application and success of BMT together with the instigation of conditioning regimens that do not include total body irradiation should increase such cases. These and previous cases document that a normal outcome of pregnancy is likely in these patients.

Poor agreement between reported and recorded nocturnal cough in asthma.

Reported presence or absence of night cough was compared with tape recorded cough in 15 children with perennial asthma (median age, 9 years; range, 7-14) who reported troublesome nocturnal symptoms. Measurements were made and diaries kept for 7 consecutive nights. Cough was reported on 66 of 105 (66%) and recorded on 93 (90%) available nights with poor overall agreement (Cohen's coefficient of assessment, kappa +0.30, range -0.17 to +1). The poor agreement between subjective and objective assessment of an important symptom of nocturnal asthma raises questions on the validity of symptom reporting and may in part explain the not infrequent disagreement between medical and patient assessment of disease severity.

Malignant spinal cord compression: NICE guidance, improvements and challenges.

BACKGROUND AND AIM: Malignant spinal cord compression (mSCC) is one of the most serious complications of cancer. Recent NICE guidance has aimed to improve patient pathways and outcomes for patients with mSCC. We have examined the current presentations, management and outcomes for patients with mSCC in West London following the implementation of the NICE guidance. MATERIALS AND METHODS: The electronic records and clinical notes were reviewed for all patients assessed for confirmed or potential mSCC at Charing Cross Hospital in 2012. Details on the number of referrals, the proportion with confirmed mSCC, the cancer diagnosis, treatment and outcome were analysed. RESULTS: 191 patients were reviewed with 127 (66%) cases of confirmed mSCC. The commonest tumour types were prostate cancer (26 cases), lung cancer (26), breast cancer (21) and kidney cancer (15). 21% of the patients had no previous cancer diagnosis; mSCC was their presenting diagnostic event. Radiotherapy was the predominant management, 24% of the patients had first line surgical treatment. At presentation 62% of patients were either chair or bed bound. Treatment brought important mobility benefits to all patients groups with 20% of the initially chair or bed bound patients leaving the hospital with independent mobility. CONCLUSION: Enhanced patients pathways with ease of access, rapid assessment and prompt treatment can improve outcomes. Despite these pathways many patients still present with gross motor impairment and over 20% have no previous diagnosis of cancer. Ongoing work to maintain awareness for patients and primary care of the diagnosis and emergency pathways is essential to optimize outcomes.

Urinary tract infection after stroke.

BACKGROUND: Urinary tract infection (UTI) is a recognized complication of stroke. We aimed to determine the incidence of UTI after acute stroke, the risk factors associated with this complication, and its association with outcome. METHODS: Prospective study of consecutive acute stroke patients admitted to an urban teaching hospital. Routine clinical assessment included the modified National Institutes of Health Stroke Scale (mNIHSS) and modified Rankin scale (mRS). Patients were followed up for 3 months, including recording of clinician diagnosis of UTI. RESULTS: We studied 412 patients; 65 (15.8%) were diagnosed with UTI, at a median of 14 days (IQR = 4-39) post-stroke. In a binomial multivariate regression analysis, UTI was associated with urinary catheterization (OR = 3.03, 95% CI 1.41-6.52), higher mRS (OR = 1.85, 1.29-2.64) and increasing age (OR = 1.51, 1.13-2.00 for each decade). UTI was associated with death or disability at 3 months, however, this link was attenuated and became non-significant when measures of stroke severity and pre-stroke morbidity were included in a multivariate analysis. CONCLUSION: UTI is common after acute stroke. It is associated with urinary catheterization, post-stroke disability and increasing age. Avoidance of catheterization might reduce the incidence of this common complication.

The impact of improving outcomes guidance on surgical management of vulval squamous cell cancer in southwest England (1997-2002).

OBJECTIVE: The objective of this study was to assess the impact of reorganisation of gynaecological services in southwest England following adoption of regionally agreed evidence-based guidelines and publication of the National Improving Outcomes Guidance in 1999. DESIGN: Prospective audit with cross-checking against histological reports. SETTING: All 19 acute hospitals in the four Cancer Networks of southwest England. SAMPLE: All subjects with squamous or verrucous vulval cancer diagnosed between 1997 and 2002. METHOD: A one-page minimum data set proforma agreed by the South West Gynaecology Tumour Panel was completed by surgeons after treatment of each patient, and was sent to South West Cancer Intelligence Service for entry, collation and analysis. Data are presented for the years 1997 to 2002 inclusive, and comparisons were made between each of the three 2-year cohorts. MAIN OUTCOME MEASURES: These are standards derived from the guidance. RESULTS: There were 436 squamous or verrucous vulval cancers registered. Recording of staging was missing in 20% of subjects. The percentage of subjects operated upon by lead gynaecological cancer surgeons increased from 78% in cohort 1 to 93% in cohort 3 (P < 0.001). There is a trend towards more conservative operations, which have lower co-morbidity. High activity surgeons achieved better rates of tumour-free skin margins, but even these were adequate only in 49% of operations. Lymphadenectomy rates did not follow guidance. CONCLUSION: Centralisation of care of this rare cancer should continue, but specialists need to increase their efforts to ensure adequate skin margins and lymphadenectomy rates while balancing morbidity and the likelihood of recurrence in both fit and frail patients.

Construction of tissue microarrays from prostate needle biopsy specimens.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

The way we teach: reproductive biology.

At the University of Nottingham, students are taught aspects of reproductive biology throughout the Part I Basic Medical Science Course. Teachers from the Departments of Physiology and Pharmacology, Human Morphology, Biochemistry, Obstetrics and Gynaecology, and Psychiatry are involved, and an obstetrician in training (the author) has been appointed full-time lecturer in Physiology and Pharmacology to provide an additional link between the basic science and clinical content of the course. The Part II course includes an Honours Year, to give students an opportunity to explore further the application of scientific method in clinical practice. One project, in which students were involved in physiological measurement used in current obstetric practice, is described here. In addition to carrying out practical tasks, students were required to submit written reports and to prepare a learning resource on fetal acid-base balance for use by their junior colleagues. Supervision was provided by obstetric and paediatric registrars and senior house officers, and senior midwives, while staff in the Department of Physiology and Pharmacology assisted students with data analysis. Each project task was assessed by a supervisor and an independent observer. The project proved acceptable to students, supervisors and hospital staff, and avoided interfering with the other responsibilities of a busy obstetric unit. It is intended to repeat the exercise with minor modifications.

Effects of dietary carbohydrate on cholesterol metabolism in rats and rabbits.

Semipurified diets produce a marked hypercholesterolemia in rabbits and tend to elevate the level of plasma cholesterol in rats. They also decrease rates of oxidation of [26-14C]cholesterol to respiratory 14CO2 and excretion of label in fecal lipid, compared with commercial feed. In both species, the hypercholesterolemia was prevented and the rate of oxidation of [26-14C]cholesterol increased by using unmodified potato starch as the carbohydrate component of the semipurified diets. Potato starch was poorly digested by rats but appeared to be well utilized by rabbits. A semipurifed diet containing cooked potato starch gave results in rats comparable to those obtained with diets containing other types of carbohydrate. Cooked potato starch produced diarrhea in rabbits, thus complicating interpretation of the results. When the diarrhea was treated with antibiotics, the results were similar to those obtained with other carbohydrates. Rats fed commercial diet which had been heated in an oven or autoclaved had higher plasma levels than those fed untreated commercial diet but no significant differences in rates of oxidation or excretion of cholesterol were observed.