The rising incidence of anal cancer in England 1990-2010: a population-based study.

AIM: Although anal cancer is rare, its incidence has been reported to be rising in several countries. This study aimed to determine whether there have been any changes in incidence over time in England. METHOD: In the cancer registry component of the English National Cancer Data Repository, 13 940 patients were identified with a primary diagnosis of anal cancer made between 1990 and 2010. Tumours were grouped according to the ICD-O morphology codes into squamous cell carcinoma, basaloid and cloacogenic carcinoma, adenocarcinoma and other cancer types. The incidence over this period was investigated in relation to type of tumour, age and sex. RESULTS: In men there was a 69% increase in squamous cell anal carcinoma from 0.43 per 100 000 population in 1990-94 to 0.73 in 2006-10. For women these rates were 0.50 in 1990-94 and 1.13 in 2006-10, a rise of 126%. CONCLUSION: The study showed that between 1990 and 2010 there was a substantial rise in the incidence of anal cancer in England. This effect was more marked in women than men.

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis.

BACKGROUND: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. METHODS: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. RESULTS: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. CONCLUSION: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research.

Population-based study of laparoscopic colorectal cancer surgery 2006-2008.

BACKGROUND: Clinical guidelines recommend that, where clinically appropriate, laparoscopic tumour resections should be available for patients with colorectal cancer. This study aimed to examine the introduction of laparoscopic surgery in the English National Health Service. METHODS: Data were extracted from the National Cancer Data Repository on all patients who underwent major resection for a primary colorectal cancer diagnosed between 2006 and 2008. Laparoscopic procedures were identified from codes in the Hospital Episode Statistics and National Bowel Cancer Audit Project data in the resource. Trends in the use of laparoscopic surgery and its influence on outcomes were examined. RESULTS: Of 58 135 resections undertaken over the study period, 10 955 (18·8 per cent) were attempted laparoscopically. This increased from 10·0 (95 per cent confidence interval (c.i.) 8·1 to 12·0) per cent in 2006 to 28·4 (25·4 to 31·4) per cent in 2008. Laparoscopic surgery was used less in patients with advanced disease (modified Dukes' stage 'D' versus A: odds ratio (OR) 0·45, 95 per cent c.i. 0·40 to 0·50), rectal tumours (OR 0·71, 0·67 to 0·75), those with more co-morbidity (Charlson score 3 or more versus 0: OR 0·69, 0·58 to 0·82) or presenting as an emergency (OR 0·15, 0·13 to 0·17). A total of 1652 laparoscopic procedures (15·1 per cent) were converted to open surgery. Conversion was more likely in advanced disease (modified Dukes' stage 'D' versus A: OR 1·56, 1·20 to 2·03), rectal tumours (OR 1·29, 1·14 to 1·46) and emergencies (OR 2·06, 1·54 to 2·76). Length of hospital stay (OR 0·65, 0·64 to 0·66), 30-day postoperative mortality (OR 0·55, 0·48 to 0·64) and risk of death within 1 year (hazard ratio 0·60, 0·55 to 0·65) were reduced in the laparoscopic group. CONCLUSION: Laparoscopic surgery was used more frequently in low-risk patients.

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme.

BACKGROUND: Colorectal cancer is common in England and, with long-term survival relatively poor, improving outcomes is a priority. A major initiative to reduce mortality from the disease has been the introduction of the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). Combining data from the BCSP with that in the National Cancer Data Repository (NCDR) allows all tumours diagnosed in England to be categorised according to their involvement with the BCSP. This study sought to quantify the characteristics of the tumours diagnosed within and outside the BCSP and investigate its impact on outcomes. METHODS: Linkage of the NCDR and BCSP data allowed all tumours diagnosed between July 2006 and December 2008 to be categorised into four groups; screen-detected tumours, screening-interval tumours, tumours diagnosed in non-participating invitees and tumours diagnosed in those never invited to participate. The characteristics, management and outcome of tumours in each category were compared. RESULTS: In all, 76 943 individuals were diagnosed with their first primary colorectal cancer during the study period. Of these 2213 (2.9%) were screen-detected, 623 (0.8%) were screening-interval cancers, 1760 (2.3%) were diagnosed in individuals in non-participating invitees and 72 437 (94.1%) were diagnosed in individuals not invited to participate in the programme due to its ongoing roll-out over the time period studied. Screen-detected tumours were identified at earlier Dukes' stages, were more likely to be managed with curative intent and had significantly better outcomes than tumours in other categories. CONCLUSION: Screen-detected cancers had a significantly better prognosis than other tumours and this would suggest that the BCSP should reduce mortality from colorectal cancer in England.

Community-based service provision for the prevention and management of maternal obesity in the North East of England: a qualitative study.

OBJECTIVES: This study was conducted to develop a better understanding of community-based initiatives relating to maternal obesity, and to gain community service providers' views on maternal obesity services and their perceived role in the management and prevention of maternal obesity. STUDY DESIGN: An interpretive constructionist approach using semi-structured interviews and focus groups. METHODS: Semi-structured interviews and focus groups were carried out with community service providers in the North East of England, UK. Data were analysed using thematic content analysis. RESULTS: Five dominant themes emerged: community-based obesity services, understanding maternal obesity services, participation in maternal obesity services, challenges in the development of community maternal obesity services, and factors contributing to successful maternal obesity services. Community service providers identified their role in tackling maternal obesity alongside maternity services. Participants identified a lack of community maternal obesity services, distinct training requirements, and felt that a multi-agency approach was likely to be required. CONCLUSIONS: Increasing rates of maternal obesity and the relationship between maternal obesity and childhood obesity mean that the preconception, pregnancy and postnatal periods are important and timely stages in the life course for public health intervention. However, current public health and community service provision lacks structured maternal obesity objectives.

A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989-2007.

BACKGROUND: There is an absence of national statistics for maternal obesity in the UK. This study is the first to describe a nationally representative maternal obesity research data set in England. DESIGN: Retrospective epidemiological study of first trimester obesity. METHODS: Data from 34 maternity units were analysed, including 619 323 births between 1989 and 2007. Data analysis included trends in first trimester maternal body bass index status over time, and geographical distribution of maternal obesity. Population demographics including maternal age, parity, ethnic group, deprivation and employment were analysed to identify any maternal obesity-associated health inequalities. All demographics were tested for multicollinearity. Logistic regression analyses were adjusted for all demographics as confounders. RESULTS: First trimester maternal obesity is significantly increasing over time, having more than doubled from 7.6% to 15.6% over 19 years (P<0.001), and shows geographic variation in incidence. There are also demographic health inequalities associated with maternal obesity, including increased odds of being obese with increasing age, parity, Black ethnic group and deprivation. There is also an association between morbid obesity and increased levels of unemployment. CONCLUSIONS: The increase in maternal obesity has serious implications for the health of mothers, infants and service providers, yielding an additional 47 500 women per year requiring high dependency care in England. The demography of women most at risk of first trimester obesity highlights health inequalities associated with maternal obesity, which urgently needs to be addressed.

Workplace-based assessment in radiology-where to now?

Assessment of doctors is in a state of flux. Traditional methods of assessment have been critically examined and found inherently limited. The wholesale shift towards outcome-orientated education in the last 10 years has led to the relatively rapid development of a radically different method of assessment. This method focuses on assessing what doctors do in everyday practice rather than written or practical simulations. Known collectively as "workplace-based assessment" tools, these have been embraced in North America, whereas they have been more cautiously adopted in the UK. However, many of these assessment tools have not been rigorously studied and, moreover, few have been specifically developed for assessing radiologists. However, they are likely to be incorporated into radiology training in the near future. This paper critically analyses both the underpinning assumptions behind this method and the evidence behind existing tools, and looks at the work that is required to develop, adopt or adapt such tools for use in radiology.

Public health observatories on the international stage.

This article reviews the involvement of public health observatories in the UK in international public health. It does not aim to be a comprehensive review, but to offer some examples of work in an international context.

Integration of ethylene and jasmonic acid signaling pathways in the expression of maize defense protein Mir1-CP.

In plants, ethylene and jasmonate control the defense responses to multiple stressors, including insect predation. Among the defense proteins known to be regulated by ethylene is maize insect resistance 1-cysteine protease (Mir1-CP). This protein is constitutively expressed in the insect-resistant maize (Zea mays) genotype Mp708; however, its abundance significantly increases during fall armyworm (Spodoptera frugiperda) herbivory. Within 1 h of herbivory by fall armyworm, Mir1-CP accumulates at the feeding site and continues to increase in abundance until 24 h without any increase in its transcript (mir1) levels. To resolve this discrepancy and elucidate the role of ethylene and jasmonate in the signaling of Mir1-CP expression, the effects of phytohormone biosynthesis and perception inhibitors on Mir1-CP expression were tested. Immunoblot analysis of Mir1-CP accumulation and quantitative reverse-transcriptase polymerase chain reaction examination of mir1 levels in these treated plants demonstrate that Mir1-CP accumulation is regulated by both transcript abundance and protein expression levels. The results also suggest that jasmonate functions upstream of ethylene in the Mir1-CP expression pathway, allowing for both low-level constitutive expression and a two-stage defensive response, an immediate response involving Mir1-CP accumulation and a delayed response inducing mir1 transcript expression.

Health indicators in the European regions: expanding regional comparisons to the new countries of the European Union - ISARE III.

OBJECTIVES: Most comparisons of health in Europe take place at the national level. However, there is increased interest in looking at health data at a sub-national level. This study aimed to establish the availability of health data at a regional level and to develop a methodology for the comparisons of health indicators at a sub-national level. In previous work on indicators at a regional level in the European Union, the authors recommended the development of such indicators. This paper takes into account the expansion of the European Union which took place in 2004. STUDY DESIGN: Observational study using routinely available data. METHODS: Similar to previous projects, a network of country correspondents was used and data were collected on a similar range of topics. In addition, a supplementary list of data was collected from one region of each country. RESULTS: Twenty-three countries out of the 25 member states of the European Union participated in the study. Where available, data were of relatively good quality. Data on mortality were most readily available, but data on important public health topics such as obesity were much more difficult to obtain. CONCLUSIONS: A database and a set of indicators for relevant sub-national areas of countries in the European Union, including new countries, were constructed. Data collection from the new countries was more straightforward due to the requirement for them to adhere to the nomenclature of territorial units for statistics (NUTS) levels. The lack of adherence to NUTS levels in the 'old' countries of the European Union continues to create problems. There remains an urgent need to introduce comprehensive sub-national data collection on important public health topics such as obesity and smoking.

Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma.

Peripheral blood mononuclear cells (PBMC) were isolated from seven normal subjects, eight asthmatic subjects clinically sensitive to corticosteroids (CS), and eight asthmatic subjects clinically resistant to corticosteroids (CR). PBMC were cultured at 37 degrees C for 24 h in the absence or presence of 10(-16) to 10(-4) M hydrocortisone. Calcium ionophore (A23187)-activated neutrophils (PMN) primed by supernatants of PBMC from asthmatic subjects cultured in the absence of hydrocortisone generated approximately threefold more leukotriene B4 than PMN primed by supernatants of PBMC from normal subjects (P less than 0.05). Incubation of PBMC derived from CS subjects with 10(-8) M hydrocortisone completely inhibited the production of the enhancing activity (P less than 0.01), whereas in CR subjects hydrocortisone at concentrations up to 10(-4) M did not suppress the release of enhancing activity. The enhancing activity was produced by monocytes. Enhancing activity eluted with an Mr of 3,000 D and a pI of 7.1. It eluted at 10% acetonitrile after reverse-phase HPLC. The activity was destroyed by heating to 60 degrees C for 60 min and was sensitive to pronase treatment. The purified factor also enhanced superoxide generation by PMN which had been stimulated submaximally by phorbol myristate acetate.

Comparison of controlled internal drug release device and melengesterol acetate as progestin sources in an estrous synchronization protocol for beef heifers.

The objectives of this experiment were to compare estrous synchronization responses and AI pregnancy rates of beef heifers using protocols that included either CIDR or MGA as the progestin source. The hypotheses tested were that: (1) estrous synchronization responses after (a) progestin removal, and (b) PGF(2alpha); and, (2) AI pregnancy rates, do not differ between heifers synchronized with either progestin source. At the start of the experiment (Day 0) in both years, heifers were assigned randomly to receive, MGA supplement for 14 days (MGA-treated; n=79) or CIDR for 14 days (CIDR-treated; n=77). On Day 14 progestin was removed and heifers were observed for estrus up to and after PGF(2alpha) on Days 31 and 33 for CIDR-treated and MGA-treated heifers, respectively. Heifers that exhibited estrus within 60h after PGF(2alpha) were inseminated by AI 12h later; the remaining heifers were inseminated at 72h after PGF(2alpha) and given GnRH (100mug). More (P<0.05) CIDR-treated heifers exhibited estrus within 120h after progestin removal than MGA-treated heifers. Intervals to estrus after progestin removal were shorter (P<0.05) for CIDR-treated heifers than MGA-treated heifers. More (P<0.05) CIDR-treated heifers exhibited estrus and were inseminated within 60h after PGF(2alpha) than MGA-treated heifers. Pregnancy rates did not differ (P>0.10) between MGA-treated (66%) and CIDR-treated (62%) heifers. In conclusion, the use of CIDR as a progestin source in a 14-day progestin, PGF(2alpha), and timed AI and GnRH estrous synchronization protocol was as effective as the use of MGA to synchronize estrus and generate AI pregnancies in beef heifers.

The effect of elevated temperature on gene transcription and aflatoxin biosynthesis.

The molecular regulation of aflatoxin biosynthesis is complex and influenced by several environmental conditions; one of these is temperature. Aflatoxins are produced optimally at 28-30 C, and production decreases as temperatures approach 37 C, the optimum temperature for fungal growth. To better characterize the influence of temperature on aflatoxin biosynthesis, we monitored the accumulation of aflatoxin and the expression of more than 5000 genes in Aspergillus flavus at 28 C and 37 C. A total of 144 genes were expressed differentially (P < 0.001) between the two temperatures. Among the 103 genes more highly expressed at 28 C, approximately 25% were involved in secondary metabolism and about 30% were classified as hypothetical. Genes encoding a catalase and superoxide dismutase were among those more highly expressed at 37 C. As anticipated we also found that all the aflatoxin biosynthetic genes were much more highly expressed at 28 C relative to 37 C. To our surprise expression of the pathway regulatory genes aflR and aflS, as well as aflR antisense, did not differ between the two temperatures. These data indicate that the failure of A. flavus to produce aflatoxin at 37 C is not due to lack of transcription of aflR or aflS. One explanation is that AFLR is nonfunctional at high temperatures. Regardless, the factor(s) sensing the elevated temperatures must be acute. When aflatoxin-producing cultures are transferred to 37 C they immediately stop producing aflatoxin.

Obesity and disability - a short review.

The prevalence of both obesity and disability is increasing globally and there is now growing evidence to suggest that these two health priorities may be linked. This paper explores the evidence linking obesity to muscular-skeletal conditions, mental health disorders and learning disabilities in both adult and child populations. The impact of obesity on the four most prevalent disabling conditions in the UK (arthritis, mental health disorders, learning disabilities and back ailments) has been examined through novel data analysis of the 2001 Health Survey for England and UK Back Exercise And Manipulation trial data. Together these analyses strongly suggest that whether the cause or result of disability, obesity is undeniably implicated, thus presenting a serious public health priority. Future research efforts are required to strengthen the evidence base examining obesity in back disorders, mental health and learning disabilities, in order to improve current clinical management.

Response of nitrosomethylurea-induced rat mammary tumor to endocrine therapy and comparison with clinical response.

We have compared the response of the N-methyl-N-nitrosourea-induced rat mammary tumor to various endocrine agents with response in patients with breast cancer. To do this, we have induced tumors in 228 animals (65% of intact rats developed tumors but only 14% of ovariectomized rats developed tumors). In intact rats, 4-hydroxyandrostenedione, tamoxifen, and a combination of tamoxifen, aminoglutethimide (AG), and danazol induced significant tumor regression (P less than 0.001, P = 0.01, P = 0.04, respectively), whereas danazol, AG, and trilostane were ineffective when used singly. Further investigation showed that the inactivity of AG in the rat was due to extensive acetylation of this compound. In order to mimic postmenopausal breast cancer, we ovariectomized rats after N-methyl-N-nitrosourea administration. In ovariectomized animals, AG was again ineffective in inducing tumor regression but 4-hydroxyandrostenedione was highly active when compared to controls (P = 0.002). Comparison with response of this model to endocrine therapy with response in patients indicates that this has good predictive capacity since it shows that agents which have minor activity in human breast cancer such as danazol and trilostane are inactive in the model. The intact rat model does not, however, predict whether a drug will be useful for pre- or postmenopausal patients. We recommend that before committing large numbers of patients to clinical trials on the basis of this model, the metabolism of new compounds should be compared in humans and rats.

A controlled trial of ondansetron in the pruritus of cholestasis.

BACKGROUND: In patients with pruritus of cholestasis, response to conventional drug treatment may be unsatisfactory. Activation of 5-hydroxytryptamine receptors on dermal sensory nerve-endings plays a role in the perception of pruritus. The 5-hydroxytryptamine(3) receptor antagonist, ondansetron, has been used in the treatment of pruritus of cholestasis, but there are few controlled data. AIM: To determine whether ondansetron is effective in treating the pruritus of cholestasis. METHODS: A total of 19 patients with resistant pruritus were randomized, double blind, to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for 5 days. Patients' perception of pruritus was recorded hourly using a visual analogue scale, and scratching activity measured by means of a piezo-electric crystal attached to the fingernail. RESULTS: Mean pruritus score using visual analogue scale and scratching activity were reduced on the first treatment day compared with baseline in both the ondansetron and placebo groups (P < 0.05), but there were no significant differences in mean pruritus perception or scratching activity between the two groups. CONCLUSION: Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.

Does the response to aspirin and clopidogrel vary over 6 months in patients with ischemic heart disease?

BACKGROUND: Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, mostly clopidogrel, is the default therapy in both acute coronary syndrome (ACS) and after intracoronary stents. It is well established that responses to antiplatelet therapy (APT), particularly clopidogrel, are subject to considerable interindividual variability. OBJECTIVES: We investigated whether responses to APT in individuals vary significantly over time. METHODS: Simultaneous assay with VerifyNow(™) and short thrombelastography (s-TEG) was performed before and at four time points over 6 months after hospital discharge in 40 patients receiving DAPT. Serum thromboxane B2 levels were also measured. RESULTS: While aspirin response units (ARU) by VerifyNow(™) and serum thromboxane B2 levels remained stable over time, arachidonic acid (AA)-mediated platelet aggregation with s-TEG (i.e. area under the curve at 15 min in AA channel, AUC15AA ) increased at 1 week compared with predischarge (P < 0.008). In addition, platelet reactivity units (PRU) by VerifyNow(™) (P = 0.046) and adenosine diphosphate (ADP)-mediated platelet aggregation with s-TEG (i.e. AUC15ADP ) also increased at 1 week compared with predischarge (P = 0.026). There were no significant changes in either platelet reactivity or rates of high on-treatment platelet reactivity while receiving clopidogrel beyond 1 week. CONCLUSIONS: This study demonstrates important variability in responses to APT within individuals between predischarge and 1 week but not thereafter. The use of a single early (predischarge) platelet function assay as an indicator of future response may therefore be flawed. The design of future strategies to assess individual responses for tailored therapy needs to take this into account.

1,25-Dihydroxyvitamin D3 binding in estrogen-responsive rat breast tumor.

Receptors for 1,25 dihydroxyvitamin D3 [1,25-(OH)2D3] have been reported in breast tissue; however, the presence of multiple binding sites and limited availability of human tumor tissue have precluded complete biochemical characterization of the receptor in breast cancer. In the present study, binding proteins for 1,25-(OH)2D3 in breast tumor tissue were analyzed using a rat model of breast cancer. Breast tumors were induced in adult female rats with the carcinogen nitrosomethylurea. Such tumors previously have been shown to possess high levels of estrogen receptors and are estrogen dependent. Binding proteins for 1,25-(OH)2D3 in 0.3 M KCl extracts of tumor tissue were analyzed on sucrose density gradients. Two binding proteins were detected: one sedimenting at 5-6 S representing binding of 1,25-(OH)2D3 to the 25 hydroxyvitamin D3 (25OHD3) binding protein and a second moiety sedimenting, like the rat intestinal receptor, at 3.3 S. Binding of the dihydroxy metabolite to the faster sedimenting protein could be eliminated by inclusion of radioinert 25OHD3 in the incubation medium. Receptor content of rat breast tumor was investigated using an hydroxylapatite assay by incubating tumor extracts with a saturating concentration of 1,25-(OH)2-[3H]D3, plus unlabeled 25OHD3 to eliminate binding of the hormone to the 5-6 S species. Scatchard analysis of 1,25-(OH)2D3 binding to the tumor extracts yielded an apparent dissociation constant (Kd) of 0.33 nM. In summary, breast tumors induced in rats by nitrosomethylurea were shown to contain high affinity 1,25-(OH)2D3 receptors with properties very similar to those reported for the receptor in other mammalian target organs. The presence of receptors for 1,25-(OH)2D3 in these rat breast tumors implies that the tissue is potentially responsive to the hormone.

Survival from adolescent cancer in Yorkshire, UK.

The aim of this study was to investigate survival rates for adolescents with cancer and identify factors associated with differential long-term prognosis in Yorkshire, UK. A survival analysis of a population-based cohort of young adults aged 15-24 years, diagnosed with a malignancy in the former Yorkshire Regional Health Authority between 1985 and 1994 was carried out. The main outcome was death from all causes. Overall survival for the 1097 adolescents with a malignancy increased by 30% between 1985-1989 and 1990-1994 (P=0.004). This improvement was reflected in most subgroups of cancer. Large scale geographical differences in survival rates were observed across Yorkshire, with an increased risk of death in North Yorkshire and Humberside of 34% and 45%, respectively, compared with West Yorkshire. Small scale analyses showed reduced survival in areas of high population density, but no consistent trends were associated with socio-economic status. Improved survival from all cancers in young adults over the last decade is clearly seen. Reasons for differential survival by geographical area are unclear and warrant further investigation.