The nature of local recurrence after colorectal cancer resection.

OBJECTIVE: Local recurrence (LR) after rectal cancer resection has long been regarded as a particular problem, its incidence having been high. This study aims to determine the reasons why. METHOD: A prospective record was kept of all 887 cases of colorectal adenocarcinoma referred to one surgeon between 1989 and 2000. Of these, 802 underwent major resection. They were followed up for 5 years or until death. RESULTS: There was no significant difference between LR rates throughout the colorectum (P = 0.74). LR was significantly related to tumour grade (P < 0.001) and to tumour stage (P < 0.001), but not to the need to resect involved adjacent structures (P = 0.08), nor, after restorative rectal resection, to the distal margin of clearance (P = 0.97). A difference became apparent between recurrence resulting from tumour left in or implanted into the operation field and tumour resulting from pre-excision metastasis, here called, respectively, technique-related (TLR) and pre-excision metastatic (MLR) local recurrence. MLR was significantly related to tumour stage (P < 0.001), while TLR was not. Some TLR can be curatively excised. CONCLUSION: Rectal LR is no more common than colonic LR. There may be practical merit in discriminating between TLR and MLR.

Platelet beta-secretase activity is increased in Alzheimer's disease.

beta-Secretase activity is the rate-limiting step in Abeta peptide production from amyloid precursor protein. Abeta is a major component of Alzheimer's disease (AD) cortical amyloid plaques. beta-Secretase activity is elevated in post mortem brain tissue in AD. The current study investigated whether beta-secretase activity was also elevated in peripheral blood platelets. We developed a novel fluorimetric beta-secretase activity assay to investigate platelets isolated from individuals with AD (n=86), and age-matched controls (n=115). Platelet membrane beta-secretase activity (expressed as initial rate) varied over fourfold between individuals, raising important questions about in vivo regulation of this proteolytic activity. Nonetheless, we identified a significant 17% increase in platelet membrane beta-secretase activity in individuals with AD compared to controls (p=0.0003, unpaired t-test). Platelet membrane beta-secretase activity did not correlate with mini-mental state examination (MMSE) score in the AD group (mean MMSE=17.7, range 1-23), indicating that the increase did not occur as a secondary result of the disease process, and may even have preceded symptom onset.

'Losing my touch': decline in self-reported confidence in performing practical procedures in consultant oncologists.

This study aimed to compare the confidence of oncology consultants and specialist registrars (SpRs) in the performance of practical procedures, to contrast this with confidence in other areas of practice and to determine at what grade they felt most confident. Questionnaires were sent to all 57 oncology consultants and SpRs in the South-West region. Respondents scored confidence on a five-point Likert scale. The response rate was 70%. SpRs were significantly more confident in cardiopulmonary resuscitation (p = 0.003) and central line insertion (p = 0.006). Consultants were significantly more confident in developing management plans (p = 0.001) and performing committee work (p = 0.002). Only 6% of consultants felt most confident performing practical procedures as a consultant, and were less confident about these than other tasks (p = 0.001). Some 86% of SpRs considered they were more confident performing practical procedures as senior house officers (SHOs). In conclusion, self-reported confidence in performing practical procedures declines during career progression in oncology. This raises questions about the teaching and supervision of these procedures. If there is a greater emphasis on a consultant-provided service, their educational needs will need to be recognized and retraining or outsourcing of these procedures to other specialties may be necessary.

Plasma somatostatin and gastrointestinal peptides in Alzheimer's disease and vascular dementia.

Few markers distinguish between different dementia types. As dementia affects many body systems outside the central nervous system, we investigated gastrointestinal regulatory peptides as possible disease markers in Alzheimer's Disease (AD) and vascular dementia (VaD). Subjects with mild-to-moderate dementia were diagnosed as probable AD and VaD according to defined criteria. Gastrointestinal peptides were stimulated using a standardized meal test, administered after an overnight fast to 58 dementia patients (40 AD, 18 VaD) and 47 controls matched for age and sex. Blood samples were taken at designated time intervals, and basal and stimulated plasma concentrations of eleven peptides were determined by radio-immunoassay. Results were analysed using the Kruskal-Wallis one-way analysis of variance; the Mann-Whitney U test was used in post hoc analysis where appropriate. There were significant differences in somatostatin levels but in none of the other peptides. Basal somatostatin was significantly increased in VaD compared to controls (p<0.05), and AD (p<0.005). Maximum stimulated levels were significantly elevated in VaD compared to AD (p<0.01). Median basal and stimulated levels of somatostatin were increased in VaD compared to AD, but the overlap in individual values between the groups makes it unlikely to be useful in distinguishing the two types of dementia.

Analysing spatially referenced public health data: a comparison of three methodological approaches.

In the analysis of spatially referenced public health data, members of different disciplinary groups (geographers, epidemiologists and statisticians) tend to select different methodological approaches, usually those with which they are already familiar. This paper compares three such approaches in terms of their relative value and results. A single public health dataset, derived from a community survey, is analysed by using 'traditional' epidemiological methods, GIS and point pattern analysis. Since they adopt different 'models' for addressing the same research question, the three approaches produce some variation in the results for specific health-related variables. Taken overall, however, the results complement, rather than contradict or duplicate each other.

Primary care workshops can reduce and rationalize antibiotic prescribing.

We describe a controlled study comparing the effects on primary care prescribing in west Gloucestershire, UK, where antibiotic workshops were offered, with those in east Gloucestershire, where microbiology tutorials were given. The year-on-year changes in quantity and costs of antibiotics dispensed following general practice prescriptions were measured. There was no significant difference in the number of antibiotic items prescribed across the county, but the number of prescriptions for broad-spectrum agents (quinolones, cephalosporins and co-amoxiclav) declined by 15.4% in west Gloucestershire, compared with a 6.5% increase in east Gloucestershire (P: = 0.002). Use of narrow-spectrum antibiotics (penicillin V, trimethoprim and nitrofurantoin), whose use was encouraged, did not change in west Gloucestershire practices, but decreased by 12% in east Gloucestershire practices (P: = 0.003). There was increased use of clarithromycin and azithromycin in both groups of practices. Antibiotic workshops held in the primary care setting can rationalize antibiotic prescribing. This can reduce prescribing costs and selection pressure by broad-spectrum antimicrobial agents and, perhaps, go some way to reducing the development of resistance.

Glomerular hyperfiltration, high renin, and low- extracellular volume in high blood pressure.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Is a man's facial appearance predictive of how he will die?

The ability of a range of health professionals including an oncologist, a haematologist, a cardiologist, a general practitioner and a counsellor to predict the cause of death from facial appearance has been evaluated. Each participant was asked to predict the cause of death from facial photographs of 200 caucasian male doctors whose cause of death was known to be due to either arterial disease or neoplasia. Statistically significant concordance was found between the oncologist and both the GP and the counsellor in their predictions of cause of death, although the individual accuracy was no greater than would be expected by chance. This suggests that common judgments based on facial appearances may be shared among certain health professionals.

Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease.

We studied the plasma chain-breaking antioxidants alpha carotene, beta carotene, lycopene, Vitamin A, Vitamin C, Vitamin E and a measure of total antioxidant capacity, TAC, in 79 patients with Alzheimer's disease (AD), 37 patients with vascular dementia (VaD), 18 patients with Parkinson's disease and dementia (PDem), and 58 matching controls, together with 41 patients with Parkinson's disease (PD) and 41 matching controls. Significant reductions in individual antioxidants were observed in all dementia groups. When compared to controls, the following were reduced: Vitamin A in AD (p < 0.01) and VaD (p < 0.001); Vitamin C in AD (p < 0.001), VaD (p < 0.001) and PDem (p < 0.01); Vitamin E in AD (p < 0.01) and VaD (p < 0.001); beta carotene in VaD (p = 0.01); lycopene in PDem (p < 0.001). Lycopene was also reduced in PDem compared to AD (p < 0.001) and VaD (p < 0.001). Antioxidant levels in PD were not depleted. No significant change in TAC was seen in any group. The reduction in plasma chain-breaking antioxidants in patients with dementia may reflect an increased free-radical activity, and a common role in cognitive impairment in these conditions. Increased free-radical activity in VaD and PDem could be associated with concomitant AD pathology. Individual antioxidant changes are not reflected in TAC.

Human alpha-adducin gene, blood pressure, and sodium metabolism.

The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Abnormal epinephrine release in young adults with high personal and high parental blood pressures.

BACKGROUND: Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. METHODS AND RESULTS: Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. CONCLUSIONS: Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

Continuous hyperfractionated accelerated radiotherapy (CHART) in localized cancer of the esophagus.

PURPOSE: To assess the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) in locoregional control compared with a historical group of patients treated with conventionally fractionated radical radiotherapy. METHODS AND MATERIALS: Between 1985 and 1994, 54 patients with localized esophageal cancer were treated with CHART. Twenty-eight patients received CHART alone (54 Gy in 36 fractions over 12 consecutive days) and 15 were given intravenous mitomycin C and cisplatin on days 10 and 13, respectively. Eleven patients received 40.5 Gy in 27 fractions over 9 days, followed by a single high-dose-rate intraluminal brachytherapy insertion of 15 Gy at 1 cm. RESULTS: Acute toxicity was well tolerated and dysphagia was improved in 35 patients (65%), with 28 (52%) eating a normal diet by week 12. This compares with an improvement in dysphagia score in 72% of the conventionally treated group. The median duration of relief of dysphagia was 7.8 months (range 0-41.4) in the CHART group compared with 5.5 months (range 0-48) in the controls. Strictures developed in 29 patients (61%) and 18 were confirmed on biopsy to be due to recurrent disease. Median survival was 12 months (range 0.5-112) in the CHART group and 15 months (range 3.6-56) in the control patients. CONCLUSION: CHART is well tolerated and achieves a high rate of local control. Palliation in the short overall treatment time of esophageal cancer is an advantage in these patients whose median survival is only 12 months.

Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults.

BACKGROUND: We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures. METHODS AND RESULTS: LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01), and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size. CONCLUSIONS: These findings provide evidence in humans that angiotensin II exerts a direct on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

The angiotensin I converting enzyme gene and predisposition to high blood pressure.

Phenotypic abnormalities of the renin-angiotensin system have been associated with the predisposition to high blood pressure. The angiotensin I converting enzyme (ACE) gene has been implicated as a candidate gene. We examined the distribution of common alleles of the ACE gene and measured circulating components of the renin-angiotensin system and urinary sodium excretion in 170 young Caucasian adults with contrasting genetic predisposition to high blood pressure. Predisposition was defined on the basis of personal and parental blood pressure levels by using the four corners sampling method. Young adults with greatest predisposition who had high blood pressure and two parents with high blood pressure did not show any significant difference in the distribution of the markers of the ACE gene, either as genotype or allele frequencies, when compared with young adults with least predisposition who had low blood pressure and two parents with low blood pressure. Offspring with urinary sodium excretion above the median (143.4 mmol per day) also showed no significant differences in the distribution of ACE alleles or genotype between groups. Different genotypes were associated with different average serum ACE concentrations (p < 0.0001), but plasma angiotensin II and aldosterone showed no significant variation with ACE genotype. These results suggest that in a group of Caucasians selected from the general population, the ACE gene is not associated with genetic predisposition to high blood pressure. In this population common ACE gene allelic markers would not be useful indexes of susceptibility to hypertension.

Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure.

AIM: To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people. SUBJECTS: Eight hundred and sixty-four people aged 16-24 years and their parents. SETTING: Ladywell Medical Centre, Edinburgh, Scotland, UK. METHOD: Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine samples were taken for biochemical and genetic analyses. RESULTS: Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure). CONCLUSION: The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new sampling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.

Prediction of high blood pressure in young people: the limited usefulness of parental blood pressure data.

Blood pressure was measured in 864 young people aged 16-24 years, 8 years after both of their parents had their blood pressures measured as part of the screening phase of the Medical Research Council Mild Hypertension Trial. Only 29% of offspring with a conventional 'family history of hypertension', defined in terms of having at least one parent with a score in the top 10% of the distribution, had a blood pressure score in the top 20% after 8 years. The positive predictive value was increased to 38% in offspring with two parents in the top 20%, but only 4% of offspring met this definition and only 7% of offspring in the top 20% after 8 years were identified by this method. Sensitivity was increased to 46% in offspring with at least one parent in the top 20%, but 33% of offspring met this definition and 74% of them did not have a blood pressure level in the top 20% after 8 years. It is concluded that parental blood pressure data are of limited value for the prediction of high blood pressure in young people and provide no scientific basis for a high risk strategy of prevention.

HIV infection and Scottish general practice: knowledge and attitudes.

To assess the knowledge and attitudes of general practitioners about HIV infection, a postal survey was undertaken of one in three of all principals in Scotland; 834 (77.6%) responded. Respondents' knowledge about HIV was often limited, and they found the discussion of sexual behaviour difficult. Most were in favour of routine HIV testing being offered to patients, but against testing without consent. Most general practitioners considered consent unnecessary for the passing of information about HIV status between medical colleagues, but necessary for informing others, in particular the patient's family and sexual partners. Most general practitioners would accept high-risk and HIV-positive patients onto their lists but less than half would accept intravenous drug users. Most respondents did not feel at significant personal risk of HIV infection, but expressed reservations about many other aspects of HIV infection in general practice. If practitioners are to fulfil their potential for tackling the problems of HIV infection, they need increased resources and a policy for education and training that is responsive to local needs.