Thrombin generation in patients undergoing carotid endarterectomy: implications in acute vessel wall closure and antithrombotic therapy.

We determined the extent and duration of activation of coagulation during the first 24 hours after carotid endarterectomy. Serial blood samples were collected before, during and after surgery from 10 patients with severe stenosis (> 70%) undergoing carotid endarterectomy with heparinization. Platelet poor plasmas prepared from these samples, were analysed for activated prothrombin fragment F1 + 2 and thrombin-antithrombin III (TAT) levels, using commercially available ELISA kits. F1 + 2 and TATs were measured as indices of thrombin generation and inhibition respectively. Baseline F1 + 2 and TAT levels were 1.19 +/- 0.27 nMol/ml and 17 +/- 10 pMol/ml, respectively. Neither the F1 + 2 nor TAT level increased during surgery at a time when the patients were heparinized. However, both the F1 + 2 and TAT levels increased significantly within 3 hours after surgery and after the heparin had been neutralized with protamine, (p < 0.01). Moreover, both the F1 + 2 and TAT levels remained elevated in 75% of the patients for at least 24 hours, p < 0.01. We conclude that i) thrombin generation is significant post surgery in patients undergoing carotid endarterectomy despite their receiving heparin during surgery; ii) heparin may not be the ideal anticoagulant for carotid endarterectomy; and iii) persistent thrombin generation may contribute to early post-endarterectomy ischemic events.

Congenital malformations in twins in England and Wales.

STUDY OBJECTIVE: The aim was to compare congenital malformation rates in twin births with those in singleton births. DESIGN: The study was an analysis of malformation rates in singleton and twin births using data from the Office of Population Censuses and Survey's Congenital Malformation Notification Scheme. SETTING: This was a national survey of births in England and Wales in 1979-1980 and 1982-1985. PARTICIPANTS: The data comprised 95,510 reported malformations in 3.7 million singleton births, and 1925 reported malformations in 76,000 twin births. MEASUREMENTS AND MAIN RESULTS: Twin malformation ratios were calculated using maternal age specific singleton rates as standard. In comparison with singleton births, twins have significantly higher reported frequencies of indeterminate sex and pseudohermaphroditism; anencephaly; patent ductus arteriosis; exomphalos; hydrocephalus; anomalies of the umbilical vessels; atresia or stenosis of the large intestine or anus; and tracheo-oesophageal fistula, atresia or stenosis. Twins also have significant reported deficits of polydactyly and syndactyly; congenital dislocation of the hip; anomalies of the tongue, branchial cleft and auricular sinus; post-anal dimple; and Down's syndrome. CONCLUSIONS: Several major malformations were significantly more common in twins than in singletons. The excess of indeterminate sex and pseudohermaphroditism has not been described before and may be analogous to freemartinism in cattle. Most of the conditions less common in twins are minor, and the reported deficits may be due to underascertainment of the less serious conditions in twins. Down's syndrome is an exception, and the deficit may well be real.

Effects of tap water lead, water hardness, alcohol, and cigarettes on blood lead concentrations.

A survey of middle-aged men in 24 British towns has found pronounced geographical variation in blood lead concentrations. Towns with the highest mean blood lead concentrations have soft water supplies and have the highest water lead concentrations. Individual blood lead can be considerably increased by raised household tap water lead concentrations. Mean blood lead is estimated to be 43% higher for men when the concentration of lead in first-draw domestic tap water is 100 micrograms/l compared with a zero concentration. Individual blood lead is also affected by alcohol consumption and cigarette smoking, such that on average these two life-style habits together contribute an estimated 17% to the blood concentration of lead in middle-aged men. Lead in water should be given greater priority in any national campaign to reduce lead exposure.

Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.

BACKGROUND: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds. METHODS: We analysed postmenopausal women (mean age 64 years [SD 9]) with localised breast cancer randomly assigned to anastrozole (n=3125) or tamoxifen (n=3116). Efficacy measures, including death and risk-benefit indices, were analysed by intention to treat. Safety analyses were based on treatment first received (n=3092 for anastrozole and n=3094 tamoxifen). We calculated a risk-benefit analysis using the two global indices for the Women's Health Initiative and for Disease-Free Survival and Serious Adverse Events. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: At median follow-up of 68 months (range 1-93), treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen (1884 [61%] vs 2117 [68%]; p<0.0001), as did treatment-related serious adverse events (146 [5%] vs 277 [9%]; p<0.0001) and adverse events leading to withdrawal (344 [11%] vs 442 [14%]; p=0.0002). Patients given anastrozole had significantly fewer overall events for the Global Index of the Women's Health Initiative (744 [24%] vs 851 [27%]; hazard ratio 0.85 [95% CI 0.77-0.94], p=0.001) and the Global Index of Disease-Free Survival and Serious Adverse Events (1453 [46%] vs 1594 [51%]; 0.88 [0.82-0.94]; p=0.0004). INTERPRETATION: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events. Furthermore, it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen.

Symptoms perceived and recorded by patients.

Health diaries were kept by 198 randomly-chosen women between the ages of 20 and 44. Symptoms were recorded on one day in three and on 57 per cent of symptom-days self-medication occurred. Even a minor shift from self-care to doctor care could make intolerable demands on the general-practitioner service in this country.Only a minority of symptoms (one in 37) are taken to the doctor and patients are highly selective in deciding which symptoms are appropriate for medical care. The perception of symptoms and the response of seeking medical advice are both significantly related to anxiety as measured by a personality questionnaire.

Smoking and drinking by middle-aged British men: effects of social class and town of residence.

In 7735 men aged 40-59, selected at random from general practices in 24 towns throughout Britain, pronounced differences were noted in the prevalences of smoking and drinking between the social classes. Social class differences also existed for frequency and quantity of drinking, type of beverage, and several aspects of smoking behaviour. Increasing amounts of smoking were associated with higher prevalences of moderate to heavy drinking, particularly in daily rather than weekend drinkers. Between drinking groups, however, the relation with smoking was more U-shaped, with light and heavy drinkers smoking more than moderate drinkers. The lowest rates of moderate to heavy smoking were observed in frequent light drinkers, particularly in the nonmanual workers. The proportion of moderate to heavy drinkers was no higher among ex-cigarette smokers than among current smokers. When the data were examined by town of residence social class differences persisted. Controlling for social class still showed pronounced differences between towns in both smoking and drinking behaviour. These data confirm that town of residence and social class have independent effects on smoking and drinking. The established regional and social class differences in cardiovascular disease may be due in part to the independent influences of town and social class on smoking and drinking behaviour.

Herpes simplex virus gD and virions accumulate in endosomes by mannose 6-phosphate-dependent and -independent mechanisms.

Herpes simplex virus (HSV) glycoprotein D (gD) is modified with mannose 6-phosphate (M6P) and binds to M6P receptors (MPRs). MPRs are involved in the well-characterized pathway by which lysosomal enzymes are directed to lysosomes via a network of endosomal membranes. Based on the impaired ability of HSV to form plaques under conditions in which glycoproteins could not interact with MPRs, we proposed that MPRs may function during HSV egress or cell-to-cell spread (C. R. Brunetti, R. L. Burke, B. Hoflack, T. Ludwig, K. S. Dingwell, and D. C. Johnson, J. Virol. 69:3517-3528, 1995). To further analyze M6P modification and intracellular trafficking of gD in the absence of other HSV proteins, adenovirus (Ad) vectors were used to express soluble and membrane-anchored forms of gD. Both membrane-bound and soluble gD were modified with M6P residues and were localized to endosomes that contained the 275-kDa MPR or the transferrin receptor. Similar results were observed in HSV-infected cells. Cell fractionation experiments showed that gD was not present in lysosomes. However, a mutant form of gD and another HSV glycoprotein, gI, that were not modified with M6P were also found in endosomes in HSV-infected cells. Moreover, a substantial fraction of the HSV nucleocapsid protein VP6 was found in endosomes, consistent with accumulation of virions in an endosomal compartment. Therefore, it appears that HSV glycoproteins and virions are directed to endosomes, by M6P-dependent as well as by M6P-independent mechanisms, either as part of the virus egress pathway or by endocytosis from the cell surface.

Why do women consult doctors? Social factors and the use of the general practitioner.

This study was designed to investigate personal and social factors associated with demand for care by women aged between 20 and 44 years, a group unlikely to suffer from chronic illness. A random sample of women was drawn from the age-sex register of a south London group practice, and information was obtained concerning their daily symptom perception, anxiety level, social and health characteristics, and their consultations for one year. Social class, family involvement, number of children in household, satisfaction with the housing, and use of other health and social services were not associated with demand for general practitioner care. Absence of basic housing amenities, difficulties in running the household, brevity of stay in the house or neighbourhood, and lack of attachment of the neighbourhood were related to a high patient-initiated consultation rate. Some of the possible interpretations of these results are discussed together with their implications for social policy planning.

Identification of blast cells in the peripheral blood of patients with acute leukaemia using the Technicon H-1.

The Technicon H-1 counter represents a refinement of the cytochemistry-based technology of its predecessors, the H6000 and the Hemalog-D. It also has a new channel, the basophil-lobularity channel, which is said to enhance the sensitivity of leukaemic blast detection in comparison with previous instruments. To evaluate this facility, 35 adult patients with acute leukaemia at different phases of their disease were monitored for the presence of circulating leukaemic blasts during a 4-week period. The ability of the H-1 to detect blasts was compared to a careful manual review of a blood and bone marrow smear. Using the latter review as the standard, the sensitivity was 83.8% with a specificity of 78%. Exclusion of patients with severe leucopenia (less than 1.0 x 10(9)/l) increased the specificity to 89%, with little alteration in the sensitivity. We were unable to confirm the high degree of sensitivity claimed in previous reports. The H-1 blast flag, however, would appear useful for screening patients who are off therapy or on maintenance regimens.

British Regional Heart Study: cardiovascular risk factors in middle-aged men in 24 towns.

The British Regional Heart Study seeks to define risk factors for cardiovascular disease, to examine their interrelationships, and to explain the geographic variations in cardiovascular disease in Britain. A clinical survey of men aged 40-59 in 24 British towns was carried out and preliminary data from the survey analysed. On a town basis cardiovascular mortality was associated with mean systolic blood pressure and the prevalence of heavy cigarette smoking and heavy alcohol consumption. No such association was seen for body mass index or mean serum total cholesterol or high-density-lipoprotein cholesterol concentration. Cigarette smoking and alcohol intake and, to a less degree, systolic blood pressure were related to the social class (percentage of manual workers) of a town, and these factors may determine to some extent the increased risk of cardiovascular disease in manual workers. Blood pressure in individual subjects was affected predominantly by age, body mass index, and alcohol intake. Body mass index appeared to affect blood pressure to a greater extent than alcohol intake and did so with a consistent and positive linear trend. Nevertheless, the differences between towns in mean blood pressure readings appeared to be more closely associated with variations in the prevalence of heavy drinking than with variations in body mass index. Alcohol intake and body mass index explained only a part of the striking differences between towns in mean blood pressure readings, and some important "town"factors remained unexplained.

Effects of alcohol and smoking on blood lead in middle-aged British men.

A survey of middle-aged men in 24 British towns showed a strong association between blood lead concentrations, alcohol consumption, and cigarette smoking. The association with alcohol persisted after age, social class, body mass index, cigarette smoking, water lead concentrations, and the town of residence had been taken into account. There was an independent but less pronounced association between cigarette smoking and blood lead concentrations after adjustment for the other factors. The possible mechanisms include a decreased excretion of lead due to alcohol-induced hepatic dysfunction and an increased lead intake from cigarette smoking. These findings have implications for widespread measurement of blood lead concentrations in adults in the community and for all studies attempting to relate blood lead concentrations to environmental exposure.

Laboratory animal allergy in a pharmaceutical company.

A cross sectional survey was carried out on 138 workers exposed to laboratory animals. Sixty (44%) had symptoms in a self completed questionnaire that were consistent with laboratory animal allergy (LAA) of whom 15 (11%) had chest symptoms. There was a positive skin prick test to one or more animal urine extracts (rat, mouse, guinea pig, rabbit) in 13% and 38% had a positive radioallergosorbent test to urine extract. LAA chest symptoms were almost five times more common in atopic than non-atopic subjects (who were distinguished by skin test response to common, non-animal aeroallergens). A positive skin test to animal urine was associated with LAA chest symptoms and with atopy. Nose, eye, or skin symptoms without chest symptoms were not associated with atopy. There was an inverse relation between duration of employment at the firm and LAA chest symptoms, suggesting selection of affected people out of employment with animals.