Detection rate of serrated polyps and serrated polyposis syndrome in colorectal cancer screening cohorts: a European overview.

OBJECTIVE: The role of serrated polyps (SPs) as colorectal cancer precursor is increasingly recognised. However, the true prevalence SPs is largely unknown. We aimed to evaluate the detection rate of SPs subtypes as well as serrated polyposis syndrome (SPS) among European screening cohorts. METHODS: Prospectively collected screening cohorts of ≥1000 individuals were eligible for inclusion. Colonoscopies performed before 2009 and/or in individuals aged below 50 were excluded. Rate of SPs was assessed, categorised for histology, location and size. Age-sex-standardised number needed to screen (NNS) to detect SPs were calculated. Rate of SPS was assessed in cohorts with known colonoscopy follow-up data. Clinically relevant SPs (regarded as a separate entity) were defined as SPs ≥10 mm and/or SPs >5 mm in the proximal colon. RESULTS: Three faecal occult blood test (FOBT) screening cohorts and two primary colonoscopy screening cohorts (range 1.426-205.949 individuals) were included. Rate of SPs ranged between 15.1% and 27.2% (median 19.5%), of sessile serrated polyps between 2.2% and 4.8% (median 3.3%) and of clinically relevant SPs between 2.1% and 7.8% (median 4.6%). Rate of SPs was similar in FOBT-based cohorts as in colonoscopy screening cohorts. No apparent association between the rate of SP and gender or age was shown. Rate of SPS ranged from 0% to 0.5%, which increased to 0.4% to 0.8% after follow-up colonoscopy. CONCLUSIONS: The detection rate of SPs is variable among screening cohorts, and standards for reporting, detection and histopathological assessment should be established. The median rate, as found in this study, may contribute to define uniform minimum standards for males and females between 50 and 75 years of age.

Occupation and cancer in Britain.

BACKGROUND: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens. METHODS: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed. RESULTS: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer). CONCLUSION: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.

Comparative analyses of multi-species sequences from targeted genomic regions.

The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates.

Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.

BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.

Evaluating the risk to humans from mineral oils in foods: Current state of the evidence.

Key issues around the evaluation of risks to humans from mineral oils in food and feedstuffs are discussed. MOHs (MOAH and MOSH) occur in food due to intentional use, contamination from environmental sources and during transport/processing, or through migration from food contact materials. Problems in setting and enforcing human health guidelines for MOH include uncertainty around MOH toxicity and the specialist expertise needed for analysis of complex food matrices. Currently, the method of choice for measuring mineral oils is LC-GC-FID, however some complex food matrices also require additional analytical techniques to differentiate between some naturally occurring hydrocarbons and those from other sources, including of petrogenic origin. This requires the skills of an experienced analyst. Significant toxicological gaps for MOHs prevent robust human health risk assessment and the derivation of guidance values. As food-grade mineral oils are virtually MOAH-free, the key issue explored here is the relevance to humans of liver (micro)granulomas observed in F344 rats following oral intake. Available data suggest that despite the ubiquitous nature of MOH in the human diet, the prevalence of liver lipogranulomas in the population is low. These are not associated with inflammation and based on current evidence are not considered of human health significance.

Physiological variation in alpha-adrenoceptor-mediated arterial sensitivity: relation to agonist affinity.

Vascular smooth muscle from different arteries of the rabbit varies in sensitivity to norepinephrine, even when factors known to contribute to this variation are excluded. Sensitivity to norepinephrine mediated through the alpha-adrenoceptor is linearly related to the agonist dissociation constant, but is not significantly related to receptor reserve. These results suggest that agonist affinity is the primary determinant of sensitivity to norepinephrine, at least in these arteries, and that this is a locally regulated characteristic which may account for regional sensitivity changes.

Multicenter study to assess potential hazards from exposure to lipid peroxidation products in soya bean oil from Trilucent breast implants.

In response to a Hazard Notice by the Medical Devices Agency of the UK in 2000 regarding the Trilucent breast implant (TBI), an expert panel was convened to implement a research program to determine whether genotoxic compounds were formed in the soybean oil filler (SOF) of TBIs and whether these could be released to produce local or systemic genotoxicity. The panel established a research program involving six laboratories. The program recruited 47 patients who had received TBIs (9 patients had received silicone implants previously). A reference group (REBI) of 34 patients who had exchanged either silicone (17 patients) implants (REBI-E) or patients (17) who were to receive primary implantation augmentation with silicone (REBI-PIA), and who were included as needed to increase either the pre- or post-explantation sample number. Of the 17 REBI-E patients, 5 had silicone implants and 12 had saline implants previously (prior to the last exchange). Investigation was undertaken before and after replacement surgery in the TBI patients and before and after replacement or augmentation surgery in the REBI patients. The pre- to post-operative sample interval was 8-12 weeks. Pre-operative samples were collected within 7 days prior to the operation. Information on a variety of demographic and behavioral features was collected. Biochemical and biological endpoints relating to genotoxic lipid peroxidation (LPO) products potentially formed in the SOF, and released locally or distributed systemically, were measured. The SOF of explanted TBIs was found to have substantial levels of LPO products, particularly malondialdehyde (MDA), and low levels of trans-4-hydroxy-2-nonenal (HNE) not found in unused implants. Mutagenicity of the SOF was related to the levels of MDA. Capsules that formed around TBIs were microscopically similar to those of reference implants, but MDA-DNA adducts were observed in capsular macrophages and fibroblasts of only TBI capsules. These cell types are not progenitors of breast carcinoma (BCa) and the location of the implants precludes LPO products reaching the mammary epithelial cells which are progenitors of BCa. Blood levels of LPO products were not increased in TBI patients compared to REBI patients and did not change with explantation. In TBI patients, white blood cells did not show evidence of increased levels of LPO-related aldehyde DNA adducts. In conclusion, based on a number of measured parameters, there was no evident effect that would contribute to breast or systemic cancer risk in the TBI patients, and the recommended treatment of TBI patients involving explantation was judged appropriate.

What do patients want from their endoscopy experience? The importance of measuring and understanding patient attitudes to their care.

Understanding and addressing patient attitudes to their care facilitates their engagement and attendance, improves the quality of their experience and the appropriate utilisation of resources. Gastrointestinal endoscopy is a commonly performed medical procedure that can be associated with patient anxiety and apprehension. Measuring patient attitudes to endoscopy can be undertaken through a number of approaches with contrasting benefits and limitations. Methodological validation is necessary for accurate interpretation of results and avoiding bias. Retrospective post-procedure questionnaires measuring satisfaction are easily undertaken but have limited value, particularly in directing service improvements. Patient experience questionnaires indicate areas of poor care but may reflect the clinician's not the patient's perspective. Directly assessing patient priorities and expectations identifies what is important to patients in their healthcare experience (patient-reported value) that can also provide a basis for other forms of evaluation. Published studies of patient attitudes to their endoscopy procedure indicate the importance of ensuring that endoscopists and their staff control patient discomfort, have adequate technical skill and effectively communicate with their patient relating to the procedure and results. Environmental factors, including noise, privacy and the single-sex environment, are considered to have less value. There are contrasting views on patient attitudes to waiting times for the procedure. Implementing patient-centred care in endoscopy requires an understanding of what patients want from their healthcare experience. The results from available studies suggest implications for current practice that relate to the training and practice of the endoscopist and their staff.

Trophic effects of peripheral adrenergic nerves on vascular structure.

In the rat and rabbit, evidence for a trophic action of sympathetic nerves on vascular pattern and structure has been reviewed. Effects have been identified by denervation and reinnervation techniques in blood vessels of different size from different regions. Following denervation, increased nonspecific sensitivity to constrictor agents occurs at all ages. In contrast, sympathetic trophic effects on muscle mass, extracellular artery components, and vessel number in the microvasculature were observed predominantly during growth. The mechanism of this action is not known, but the central ear artery in the rabbit was associated with nerve impulses.

Transient and persistent changes in rabbit blood vessels associated with maintained elevation in arterial pressure.

Arteries and veins of hypertensive rabbits were examined 8 weeks after partially constricting the abdominal aorta above both kidneys, and compared with those from sham-operated animals. Structural and functional changes in blood vessels after 2 weeks, when the arterial pressure first attained a new elevated level, have been described previously, and are now compared with changes 6 weeks later. The increase in blood vessel mass could be correlated with an increase in deoxyribonucleic acid (DNA) content. In contrast to the status at 2 weeks postoperatively, there was no increased uptake of 3H-thymidine, 3H-proline, or 3H-lysine at 2 months. Furthermore, at this time cell nuclei labeled with 3H-thymidine were infrequent. Some vessels showed evidence of change in the physical characteristics of their wall. Only minimal changes were observed in those parameters of adrenergic nerve function measured -- neuronal 3H-norepinephrine uptake and vessel wall catecholamine content -- that had been markedly changed at 2 weeks. The results of this work, together with those of other studies of this model, suggest two phases of response of the arterial wall to pressure rise: an initial dynamic proliferative cellular response mainly of vascular smooth muscle associated with changes in adrenergic neuronal parameters, and a subsequent equilibrium phase characterized by an increased number of smooth muscle cells, some changes in the extracellular components, and minimal changes in the adrenergic innervation.

The psychiatric resident as an ex-officio community board member.

The authors describe a program in which third-year psychiatric residents participate as ex-officio members on the boards of community service agencies. Experience as board members gives residents a broad understanding of issues related to the delivery of community mental health services and encourages them to continue community involvment after their training is completed.

Chemiluminescence determination of hydroperoxides following radiolysis and photolysis of free amino acids.

Hydroperoxides were determined in selected amino acids using three free radical generating systems by a sensitive (50 pmol limit of detection) and specific high performance liquid chromatography (HPLC)/chemiluminescence method. UVB and gamma radiation produced significant hydroperoxide formation, particularly in the aromatic amino acids tyrosine and tryptophan. Hydroperoxide yield was found to be dependent on both amino acid and irradiation source. Generation of hydrogen peroxide as a by-product of irradiation caused interference with chemiluminescence detection demonstrating the need for catalase addition. Hydroperoxides were not detectable following metal-catalysed H2O2 breakdown. We suggest that metal ions could interfere with the detection of hydroperoxides by causing preferential decomposition.

Experimental chronic cerebrovascular spasm in the monkey: an assessment of the functional changes in the cerebral arteries and their protection by diltiazem.

The structure and function of cerebral arteries obtained from a monkey model of chronic cerebral vascular spasm 5 days after hemorrhage have been examined. Narrowing of the larger cerebral arteries demonstrated by angiography at all sites of measurement seems to be due primarily to an increased wall rigidity associated with cellular damage, the resultant inflammatory response and large, long-lasting spontaneous increases in muscle tone. Changes in agonist sensitivity were extremely variable. The reduction of contractility of the vessel wall to a mean of 30% of control diminished the consequence of any changes in active tone characteristics. Neurogenic control on the side of the lesion was remarkably depressed. When treated with diltiazem, beginning 1 day before induction of hemorrhage and continuing to the time of sacrifice, arterial diameter was reduced at only 1 of the 6 standard sites of measurement and then by only a small amount. Neurologic effects invariably seen in the untreated monkeys were prevented by diltiazem. Many of the changes in the artery wall, including structural alterations, were diminished by the drug. Abnormal spontaneous myogenic tone was present but was less in the diltiazem-treated group; however, nerve damage and its functional consequences were not prevented. It is concluded that diltiazem, presumably by preventing the accumulation of intracellular calcium within the cell, prevents the initial events in the evolution of chronic cerebrovasospasm or narrowing. This is probably achieved by a diminishing of the direct vasoconstrictor effects and the toxicity of putative spasmogens released from blood clots, nerves and the brain on the vascular smooth muscle, thus interrupting the sequence leading to pathologic change.

THE USE OF HEART RATE TO ESTIMATE OXYGEN CONSUMPTION OF FREE-RANGING BLACK-BROWED ALBATROSSES DIOMEDEA MELANOPHRYS

Heart rates (fh) and rates of oxygen consumption (V(dot)O2) were measured in eight black-browed albatrosses (Diomedea melanophrys) when walking on a treadmill, with the aim of using fh to predict V(dot)O2 in free-ranging albatrosses. The resulting relationship between the variables was: V(dot)O2 (ml min-1) = [0.0157fh (beats min-1)]1.60, r2=0.80, P<0.001. In addition to the calibration procedure, six of the albatrosses were injected with doubly labelled water (DLW), and fh and V(dot)O2 were monitored continuously over a 3 day period while the birds were held in a respirometer. During the 3 day period, the birds were walked for up to 3­4 h day-1 in bouts lasting approximately 0.5 h. The heart rate data were used to estimate the metabolic rates of these birds using the above regression. Estimates of metabolic rate derived from fh, DLW and respirometry did not differ (ANOVA; P=0.94), primarily because of the variance between individual birds. There was also no significant difference between the different estimates obtained from the different equations used to calculate energy expenditure from the DLW technique (ANOVA; P=0.95). Mean estimates of V(dot)O2 from fh under active and inactive conditions differed from measured values of V(dot)O2 by -5.9 % and -1.7 % respectively. In addition, the estimates of V(dot)O2 from fh at different walking speeds did not differ significantly from the measured values. It appears that, in the black-browed albatross, fh is as good a predictor of the mean metabolic rate of free-ranging birds as DLW or time­energy budgets combined with either respirometry or DLW. However, the method should be applied to as many individuals and as many instances of a particular behaviour as possible. The heart rate technique offers potential for much more detailed analyses of the daily energy budgets of these birds, and over much longer periods, than has previously been possible.

Heart rates and abdominal temperatures of free-ranging South Georgian shags, Phalacrocorax georgianus

The South Georgian shag (Phalacrocorax georgianus) shows a remarkable diving ability comparable to that of penguins, yet nothing is known of the physiology of these birds. In this study, heart rates and abdominal temperatures were recorded continuously in four free-ranging South Georgian shags using an implanted data-logger. A time­depth recorder was also attached to the back of the implanted birds to record their diving behaviour. The diving behaviour of the birds was essentially similar to that reported in other studies, with maximum dive durations for individual birds ranging between 140 and 287 s, and maximum depths between 35 and 101 m. The birds, while at the nest, had a heart rate of 104.0±13.1 beats min-1 (mean ± s.e.m.) and an abdominal temperature of 39.1±0.2 °C. During flights of 221±29 s, heart rate and abdominal temperature rose to 309.5±18.0 beats min-1 and 40.1±0.3 °C, respectively. The mean heart rate during diving, at 103.7±13.7 beats min-1, was not significantly different from the resting values, but the minimum heart rate during a dive was significantly lower at 64.8±5.8 beats min-1. The minimum heart rate during a dive was negatively correlated with both dive duration and dive depth. Abdominal temperature fell progressively during a diving bout, with a mean temperature at the end of a bout of 35.1±1.7 °C. The minimum heart rate during diving is at a sub-resting level, which suggests that the South Georgian shag responds to submersion with the 'classic' dive response of bradycardia and the associated peripheral vasoconstriction and utilisation of anaerobic metabolism. However, the reduction in abdominal temperature may reflect a reduction in the overall metabolic rate of the animal such that the bird can remain aerobic while submerged.

Altered endothelium-mediated relaxation after denervation of growing rabbit ear artery.

The relaxation response to methacholine and sodium nitroprusside was examined in ring segments from the posterior auricular artery and its continuation the central ear artery in growing rabbits 2, 4, 6 and 8 weeks following unilateral adrenergic and sensory denervation. The maximal relaxation achieved by methacholine (endothelium-dependent) was significantly depressed in the denervated arteries compared with the contralateral controls. Sodium nitroprusside (endothelium-independent relaxant agent) elicited the maximal relaxation in all tissues. These results demonstrated impaired arterial endothelium-dependent relaxation to methacholine after chronic denervation.

Comparative study of supersensitivity to K+ after denervation and decentralization in rabbit ear artery.

The contractile response to potassium following denervation or decentralization of the central artery of the rabbit ear was studied in vitro. Denervation or decentralization for 8 weeks caused comparable supersensitivity to potassium: mean EC50 values obtained with isotonic high potassium solution were 21.3 mM in the denervated artery and 18.7 mM in the decentralized artery, and these values were significantly less than those (25-26 mM) of their respective contralateral control arteries (P less than 0.005, paired t-test). The maximum responses to potassium did not differ among the control, denervated and decentralized arteries. Phentolamine (3 X 10(-7) M) and propranolol (3 X 10(-7) M) had no significant effect on the response to potassium. Sensitivities to potassium with hypertonic high KCl solution and hypertonic high K2SO4 solution were virtually identical to those obtained with isotonic high potassium solution. The results suggest that denervation and decentralization produce identical postjunctional supersensitivity to potassium and that the lack of tonic activity of sympathetic nerves may be responsible for the phenomenon in the rabbit ear artery.

Vascular alpha-adrenoceptor affinity variation is not due to varying populations of subtypes distinguished by WB 4101 and chlorethylclonidine.

Interaction with chlorethylclonidine has been used to subdivide populations of alpha 1-adrenoceptors in some tissues. WB 4101 can distinguish high and low affinity states of the receptor. The present study was carried out to determine if different populations or affinity states of alpha 1-adrenoceptors distinguished by either of these compounds, could explain the variation in alpha 1-adrenoceptor agonist affinity found amongst rabbit arteries. Five arteries were studied whose affinity for noradrenaline vary between 4.8 and 6.4. These were the thoracic aorta, renal, superior mesenteric, ear and ovarian arteries. WB 4101 was found to be equally effective in antagonizing noradrenaline on all arteries. Chlorethylclonidine caused a 20-fold rightward shift of the noradrenaline dose-contraction curve in the thoracic aorta; but had little or no effect on the other vessels. Thus, the combination of different proportions of subsets of alpha 1-adrenoceptors distinguished by WB 4101 or chlorethylclonidine does not explain the variation in alpha 1-adrenoceptor affinity found in these rabbit arteries.

Equity and medical practice variation: relationships between standardised discharge ratios in total and for selected conditions in English districts.

STUDY OBJECTIVE: The aim was to investigate relationships for residents of English district health authorities between rates of discharges from acute hospitals for all conditions and variations in discharge rates for eight common conditions (five surgical, three medical). DESIGN: Hospital Inpatient Enquiry data on discharges for 1984 were analysed. Standardised discharge ratios (ratios of actual to expected numbers of discharges x 100) were derived for selected conditions and all conditions; and correlation coefficients for these statistics were calculated. Districts were grouped into quintiles according to the value of the standardised discharge ratio, and systematic variation within each quintile was calculated for the selected conditions. SETTING: The study involved all 192 English district health authorities, but 57 were excluded because the proportion of unspecified diagnoses exceeded 5%. PATIENTS: The analyses were based on 336,799 cases from 135 districts. MEASUREMENTS AND MAIN RESULTS: Discharge ratios for the medical conditions and one surgical condition were significantly correlated with the levels of total discharge rates (p less than 0.01). The medical conditions showed greater systematic variation in discharge ratios than the surgical conditions. There was no consistent pattern in the values of systematic variation for the selected conditions across the different levels of discharge ratios for all conditions. CONCLUSIONS: It is argued that the changes in the NHS introduced in April 1991 are intended to introduce greater equity in the standardised discharge ratios and increase the total numbers of discharges. The results of this analysis suggest that, even if these objectives were achieved, they may not result in increased levels of elective care, nor result in greater equity in terms of rates of discharge for individual conditions.