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Age at first full-term pregnancy (FTP) has long been thought to be the major reproductive risk factor in breast cancer but a Norwegian study suggested that age at last FTP might be more important. In Norway "high parity" means 4 or more deliveries. Does this finding hold in an area with a much broader distribution of parity? Data from a case-control study done in 1980-82 in Fortaleza and Recife, two cities in Brazil's impoverished north-east, have been used to explore further the influence of age at last FTP. The cases were 509 women with histologically diagnosed breast cancer who were matched with hospital controls for age and area of residence. The analysis was based on case-control pairs interviewed by the same person. High breast cancer risk was associated with low parity; after adjustment for parity, breast cancer risk was related both to late age at first FTP (odds ratio [OR] 1.21 for each 5 year increase, p = 0.008) and to late age at last FTP (OR 1.24, p = 0.0007). However, multivariate analysis revealed that the effect of age at last FTP dominated that of age at first FTP: once age at last FTP was taken into account the effect of age at first FTP was no longer significant (OR 1.08, p = 0.38) while the association with parity became more striking. These results challenge the view that age at first FTP is the principal reproductive variable related to breast cancer risk. Moreover, they suggest that high parity is protective independent of ages at first and last FTP. Given recent worldwide reductions in fertility rates, breast cancer incidence may be expected to increase. Balancing that may be the willingness of some women to complete their families by, say, age 35 if they were to be told that this might reduce their risk of breast cancer.

The Lancet now incorporates statistical review of submitted papers which remain candidates for publication after conventional review. We summarise here criticisms noted by the statistical reviewers for 191 such papers received between November, 1990, and June, 1991. Only 54% of papers were deemed acceptable or acceptable after revision; the others were either recommended for rejection (14%) or for more substantial revision and re-review (32%). Descriptions of methods and of results were found inadequate in about half of the papers; about one-quarter of papers had inadequate abstracts and conclusions. Major errors of inference were made in 48 papers and went hand in hand with major criticisms of analysis or design in those papers. The natural focus of statistical review is whether conclusions drawn are justified by study design and statistical analysis. In this, there is room for improvement by authors.

Baseline data are presented of the ECAT Angina Pectoris Study. Both plasminogen activator inhibitor and fibrinogen were positively associated with a number of cardiovascular risk factors such as smoking, body mass index, and also with the presence of coronary stenosis. Results indicate a role of the hemostatic system in the progress of coronary arteriosclerosis.

Screening for a disorder may be carried out by assessing the risk that an individual is affected given the values of variables whose distributions alter when the disorder is present. An optimal screening policy is obtained by identifying those individuals whose risk is greater than some cut-off value. This paper summarizes the way in which risk is derived from the likelihood ratio of being affected by the disorder, and compares three different methods of estimating the likelihood ratio, namely direct estimation, logistic regression and distribution modelling. For continuous variables that have a multivariate normal distribution, screening by risk is equivalent to the use of quadratic discrimination. The paper shows how estimates of the risk and associated detection and false positive rates can be derived for a screening policy which uses specified risk cut-offs. Screening by risk has the counter-intuitive property that as the separation in the distribution of screening variables between affected and unaffected individuals increases, the detection and false positive rates may both increase. The approach is explored using data on antenatal screening for Down's syndrome. The method of choice is model-based; the model is described and tested for goodness of fit. Complications arising from outliers and non-normality must be overcome before an appropriate assessment of risk can be made. The concept of shrinkage is used to estimate the detection of false positive rates that may be expected in a new data set.

The enthusiasm for meta-analyses (or overviews) expressed by their proponents is not always shared by the broader medical community. To encourage constructive debate, we adopt a critical perspective on the conduct and interpretation of meta-analysis. We focus particularly on some of the statistical issues, especially heterogeneity between studies, and also on the extrapolation of meta-analysis findings to clinical practice. We conclude that meta-analysis is not an exact statistical science that provides definitive simple answers to complex clinical problems. It is more appropriately viewed as a valuable objective descriptive technique, which often furnishes clear qualitative conclusions about broad treatment policies, but whose quantitative results have to be interpreted cautiously.

Data were analyzed from 33 prospective studies to assess the evidence for a long-term association of low serum cholesterol with cancer. In subjects with cancer diagnosed within two years of the cholesterol measurement or causing death within five years (n = 4,661), the level of serum cholesterol was on average lower than in controls by 0.18 (SE = 0.02) mmol/l in men and 0.11 (SE = 0.04) mmol/l in women; this effect can be attributed to preclinical cancer. For cancers presenting after these intervals (n = 22,030), the average differences were smaller but statistically significant (0.04 [SE = 0.01] mmol/1 [P less than 0.001) in men, and 0.03 [SE = 0.01] mmol/1 [P = 0.005] in women), equivalent to about a 15 percent increase in cancer incidence in the lowest cholesterol quintile. This cannot be attributed entirely to preclinical cancer. In men, there was significant (P = 0.01) heterogeneity between studies as to the extent of a long-term association. The heterogeneity could be substantially explained by socioeconomic status, the association being pronounced in studies of manual workers but absent in studies of professional men. The overall long-term association was attributable mainly to lung cancer in men, and partly to hemopoietic cancers (representing prolongation of survival by treatment). Colon cancer and other cancers unrelated to smoking showed no long-term association with low cholesterol. The data collectively do not justify concern that lowering serum cholesterol to reduce ischemic heart-disease risk might cause cancer. The long-term association with lung cancer is probably caused by smoking and we propose a mechanism.

The correlation between cotinine concentrations in a single specimen of urine and in serum collected on the same occasion from 279 male smokers was 0.83. This was significantly increased, to 0.91, by adjusting the urinary cotinine levels for urinary creatinine concentration to take account of variations in urinary dilution between people. The adjustment used was based on the observed regression relationship between urinary cotinine and urinary creatinine concentrations. Expressing urinary cotinine values as a ratio to urinary creatinine, which has been used as a method of adjustment by others, did not improve the correlation between serum and urinary cotinine levels. The method of adjusting urinary cotinine for urinary creatinine is, therefore, important. The principle of such adjustment should apply not only to cotinine but also to other urinary biochemical measurements.

The reliability of screening for high serum total cholesterol is adversely affected by the variability of cholesterol levels over time. This problem is investigated using data on repeated cholesterol measurements for 14,600 men and women in the MRC Mild Hypertension Trial. For measurements 1 year apart, the within-person coefficient of variation (CV) is 7%, which is substantial compared with the between-person CV of 15%. In a screening programme, this within-person variability may lead to the misclassification of individuals and inappropriate intervention. For example, 28% of middle-aged British men with a single cholesterol measurement above 6.9 mmol/l have a long-term average cholesterol below that value even without intervention. Using averages of several cholesterol measurements reduces, but does not eliminate, these problems. Furthermore, monitoring the effect of interventions in individuals by sequential cholesterol measurement may be unhelpful or even misleading. These problems cast serious doubt on the value of general population screening for high cholesterol levels.

The serum concentrations of prolactin (PRL), follicle stimulating hormone (FSH) and luteinizing hormone (LH) and the plasma concentrations of testosterone, 5-alpha-dihydrotestosterone (DHT) and oestradiol were measured in 80 infertile men and 38 men of known fertility. The infertile men had a lower mean concentration of prolactin and a higher mean concentration of FSH than the fertile controls. The mean FSH was particularly high in infertile men without antisperm antibodies but with oligospermia (sperm density up to 20 million/ml), who also had a higher mean serum LH level than the fertile controls. Both FSH and LH showed an inverse relationship with sperm density. There were no significant differences in plasma testosterone, DHT or oestradiol between fertile and infertile men. In both the fertile and infertile groups strong positive associations were found between the concentrations of FSH and LH, and between testosterone and DHT. Weaker relationships were found between DHT and oestradiol, and between testosterone and PRL. In the fertile men, positive associations were also found between LH and testosterone, and between oestradiol and both FSH and LH. Testosterone and oestradiol were associated only in infertile men. The relevance of these findings to the aetiology of male infertility is discussed.

Results from the Northwick Park Heart Study (NPHS) suggest that physiological levels of plasma fibrinogen may influence platelet aggregability. This possibility has been further studied by the addition of purified fibrinogen to the blood of 17 study participants with low plasma fibrinogen levels. The results, which were highly consistent between different individuals, showed that fibrinogen increases aggregability as measured by the ADP ED50, the dose of adenosine diphosphate at which aggregation proceeds at half its maximum velocity. However, an increasing plasma fibrinogen level was associated with decreasing aggregability measured by another parameter, the ADP EMR (estimated maximum response). Although the balance of evidence is that the plasma fibrinogen level enhances aggregability, these conflicting results emphasize the limitation of any simple concept of "platelet aggregability".

A retrospective analysis of data from 207 non-pregnant premenopausal women showed that the mean level of systolic blood pressure varied with the stage of the menstrual cycle, being higher on days 17-26, the part of the luteal phase during which the peak of progestogen levels develops, than during the luteal phase as a whole, and significantly higher than the mean for all other days of the cycle. The mean levels were 125.4 mmHg (SE 1.76) for days 17-26, 122.5 (SE 1.25) for days 15-28 and 120.1 (SE 1.07) for days 1-16, 27 and 28. This finding supported the hypothesis that endogenous progestogen might have a hypertensive effect, as does exogenous progestogen. However, a second study designed to confirm this finding failed to do so, showing no cyclical change in the level of blood pressure. The subjects in the first study may have been subject to greater psychological stress when the measurements were made than were those in the second, a possibility supported by the large difference in pressure between the two studies. The discrepancy between the two sets of results could be explained if the effect possibly associated with progestogen levels in the retrospective study was due not to a hypertensive action per se but to a progestogen-related increased reaction to stress.

Pyrithiamine, a thiamine phosphokinase inhibitor, was fed to rats on a thiamine-deficient diet, producing weight loss, ataxia and loss of righting reflex in 10 days. Some rats were then sacrificed; others were returned to a normal diet, to be sacrificed only when their weight had returned to pre-experimental levels. Rats were sacrificed for assay of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in homogenates of eight brain regions or were perfused for gamma-aminobutyric acid transaminase (GABA-T) histochemistry. GAD activity was significantly reduced in symptomatic rats in the thalamus greater than cerebellum greater than midbrain greater than pons/medulla. GABA-T staining was similarly reduced, with greatest losses in the thalamus greater than inferior colliculus greater than pons greater than medulla. ChAT activity was not significantly altered in any brain area. Following return to a normal diet. GAD activity was significantly recovered in all areas except the thalamus. GABA-T staining recovered, at least partially, in all areas affected.

The risk of an individual woman having a pregnancy associated with Down's syndrome was estimated from her age and her serum alpha-fetoprotein (AFP) level at 14-20 weeks gestation. The estimates were made using published data on the risk of Down's syndrome in relation to maternal age from 4528 affected and over 5 million unaffected pregnancies, and on the risk in relation to serum AFP from 68 affected and 36,645 unaffected pregnancies. Separate estimates were derived for AFP levels using gestational age based on the time since the first day of the last menstrual period and on an ultrasound biparietal diameter measurement. In each case this was done with and without adjusting AFP levels to take account of maternal weight. The same sources of data were also used to construct six Down's syndrome screening policies, each combining information on maternal age and serum AFP. For example with one policy the detection rate would be 28% and would involve selecting 2.8% of unaffected pregnancies for amniocentesis; using age alone the same detection rate could only be achieved by selecting 4.3% of unaffected pregnancies for amniocentesis--an increase of 50%. In general, screening for Down's syndrome using both maternal age and serum AFP is more efficient than either alone.

The incidence of ischaemic heart disease (IHD) is higher in postmenopausal women than in premenopausal women of the same age. The difference may be partly explicable in terms of differences between premenopausal and postmenopausal women in haemostatic function. This possibility has been studied in 833 White women in the Northwick Park Heart Study (NPHS). Mean levels of factor VIIC, fibrinogen, and cholesterol were between 6% and 10% higher in postmenopausal women than in premenopausal women of the same age. When allowances were made for associations between these variables, the difference between the two groups in cholesterol was no longer evident. By analogy with NPHS data on men, the differences in factor VIIC, fibrinogen, and cholesterol would increase the risk of fatal IHD in postmenopausal women by about 40% compared with the risk in premenopausal women of the same age.

In the BUPA study, a prospective study of 22,000 men attending a screening centre in London, the mean serum cholesterol level of the 267 men who developed cancer was 6.66 mmol l-1, not significantly different from the mean level of 6.72 mmol l-1 among the 525 unaffected controls matched for age, smoking history and the calendar quarter of their attendance at the screening centre. There was, however, a significant difference in serum cholesterol levels among men who were diagnosed as having cancer less than 2 years after the date of blood collection (6.49 mmol l-1 for the 116 cancer subjects and 6.78 mmol l-1 for the 224 controls (P = 0.02)) but not in men who developed cancer 2-11 years after blood collection (6.79 mmol l-1 for the 151 cancer subjects and 6.68 mmol l-1 for the 301 controls). The observation that the association between low serum cholesterol and cancer was confined to men in whom a diagnosis of cancer was made within 2 years after the date of blood collection suggests that the low serum cholesterol is a metabolic consequence rather than a precursor of the cancer. Our results, which are consistent with the majority of other published studies, indicate that a low serum cholesterol is not a cause of cancer.

Splenocytes from BALB/c mice immunized with a gentamicin-hemocyanin conjugate were fused with X63-Ag8.653 murine myeloma cells to produce hybridomas that secreted monoclonal antibody to gentamicin. Sixteen positive clones were obtained. The monoclonal antibody chosen for a gentamicin immunoassay has been characterized with respect to class, subclass, type of light chain, electrophoretic homogeneity, and binding affinity. Gentamicin monoclonal antibody purified from mouse ascites fluid was analyzed by immunoelectrophoresis, double immunodiffusion, enzyme-linked immunosorbent assay (ELISA), and polyacrylamide gel electrophoresis (PAGE). The results show that the antibody is an IgG2a (kappa). Two bands were detected when the purified antibody was electrophoresed on polyacrylamide gels: a major band and a less mobile minor component (5.6% of the major band). Both were IgG2a (kappa). The major band contained antibody which bound 2.1 moles of the substrate-labeled gentamicin derivative, beta-galactosyl-umbelliferone sisomicin, per mole of IgG, whereas one mole of the minor band bound only 0.095 moles of the substrate-labeled conjugate. The antibody has an affinity constant of 1.22 X 10(10) M-1.

The antihypertensive efficacy of propranolol in the treatment of mild hypertension was significantly impaired in cigarette smokers, whereas that of bendrofluazide was not affected by smoking habit. This diminished efficacy of propranolol in smokers may be one of several possible factors operating to reduce its primary preventive action against strokes, and possibly against coronary events.

Blood samples taken at 28 and 34 weeks of pregnancy from 495 women were assayed for factor VIII clotting activity (VIIIC) and factor VIII related antigen (VIIIR) to examine the distribution of these factors and to determine whether there was any relationship with birthweight. There was a small positive relationship of little clinical value between factor VIIIR and birthweight only when birthweight was adjusted for gestational age, sex of infant and parity. In pregnancies resulting in a male infant the level of factor VIIIC was lower at 34 weeks gestation than in pregnancies resulting in a female infant. A greater rise in the ratio of VIIIR/VIIIC was observed in women who had any type of hypertension when compared with normotensive pregnancies, but this was not associated with lower birthweight. Both factors VIIIR and VIIIC at 28 weeks gestation were lower for multiparous than for primiparous women, and were lower for those with eventual greater gestation at birth. Asian women had higher mean factor VIIIC than Caucasian women, a finding independent of the fact that women with blood group O had lower mean levels of factors VIIIR and VIIIC than women of other blood groups.

In the BUPA Study, a prospective study of 22,000 men attending a screening centre in London, serum samples were collected and stored. The concentration of beta-carotene was measured in the stored serum samples from 271 men who were subsequently notified as having cancer and from 533 unaffected controls, matched for age, smoking history and duration of storage of the serum samples. The mean beta-carotene level of the cancer subjects was significantly lower than that of their matched controls (198 and 221 micrograms l-1 respectively, P = 0.007). The difference was apparent in subjects from whom blood was collected several years before the diagnosis of the cancer, indicating that the low beta-carotene levels in the cancer subjects were unlikely to have been simply a consequence of pre-clinical disease. Men in the top two quintiles of serum beta-carotene had only about 60% of the risk of developing cancer compared with men in the bottom quintile. The study was not large enough to be able to indicate with confidence the sites of cancer for which the inverse association between serum beta-carotene and risk of cancer applied, though the association was strongest for lung cancer. The association may be due to beta-carotene affecting the risk directly or it may reflect an indirect association of cancer risk with some other component of vegetables or with a nonvegetable component of diet that is itself related to vegetable consumption.

Factor VII was assayed in healthy adults and pregnant women by a coagulation method (VIIc) and a procedure (VIIt) based upon activation of factor X. Although VIIc and VIIt were highly correlated (r 0.8) they apparently measured different aspects of VII activity. This difference was related to plasma lipid concentrations. Plasma VIIc showed independent positive associations in vivo with VIIt, cholesterol and triglyceride concentrations, but was unaffected by in vitro adjustment of plasma lipoprotein concentrations. The difference between assays might be due to differing reactivities of VII. The VIIc assay measures VII in its in vivo proportions as the single-chain protein and fully active double-chain form (alpha VIIa). In VIIt, all VII is converted to alpha VIIa before measurement. Thus an increase in VIIc but not VIIt with increasing lipid concentrations reflects an increased proportion of VII as alpha VIIa, possibly secondary to activation of the contact system. This effect may explain at least part of the increased VIIc and normal VIIt in pregnancy, and the increased VIIc of hyperlipidaemias in general. The relative values of VIIc and VIIt are proposed as a measure of flux within the coagulation system, and as a measure of coagulability in hyperlipidaemia and other states.

Eighty infertile men and 38 men of known fertility were studied for investigation of both the importance of zinc, copper, cadmium, and lead to fertility and the possible interrelationships between these trace elements. The infertile men had higher mean concentrations of plasma copper than those of proven fertility. The difference was statistically significant (P less than 0.01) but was of small magnitude (approximately 1.5 mumol mean difference). The concentrations of plasma zinc, erythrocyte zinc, whole blood lead and cadmium, and seminal plasma zinc and copper did not differ significantly between infertile and fertile men. There was a significant positive relationship between sperm density and seminal plasma zinc concentration in the fertile, but not in the infertile, men. The infertile men with antisperm antibodies or counts greater than 20 million/ml had significantly higher mean levels of seminal plasma zinc than infertile men with oligospermia. The higher semen zinc in these two groups may reflect an abnormal fragility of the spermatozoa, resulting in the release of zinc, but the absence of significant overall differences between fertile and infertile men suggests that measurement of the concentration of zinc in plasma or zinc and copper in seminal plasma has little value in the routine investigation of infertility.

A gas chromatographic method has been developed for the determination of amitriptyline and nortriptyline in plasma. OV-17 is used in a 1 m long packed column, with a flame ionization detector and an electronic integrator. Five internal standards are added. The base-specific extraction procedure and the method of calibrating the chromatograph are described in detail. The accuracy, precision and reliability of the method are demonstrated by the results of nearly 700 determinations of each drug, at concentrations ranging from 5 to 400 ng/ml in the plasma. An interlaboratory comparison with a double radioactive isotope derivative assay for nortriptyline has also shown satisfactory agreement.

Blood pressure measurements recorded during the medical Research Council's treatment trial for mild hypertension have been analysed according to the calendar month in which the readings were made. For each age, sex, and treatment group systolic and diastolic pressures were higher in winter than in summer. The seasonal variation in blood pressure was greater in older than in younger subjects and was highly significantly related to maximum and minimum daily air temperature measurements but not to rainfall.

Components of the haemostatic system which may be involved in the pathogenesis of ischaemic heart disease (IHD) were measured in the Northwick Park Heart Study. Of 1510 white men aged 40-64 at recruitment, 49 have since died. 27 died from cardiovascular disease (IHD in all but 3), 18 from cancer, and 4 from other causes. The mean recruitment levels of factor VIIc, factor VIIIc, and fibrinogen were significantly higher in those who died of cardiovascular disease than in those who survived. The independent associations of factor VIIc and fibrinogen with cardiovascular death were at least as strong as the association of blood cholesterol with cardiovascular death. A clustering of two or three high clotting-factor values (factor VIIc, factor VIIIc, and fibrinogen) was present at recruitment in 63% of those who died of cardiovascular disease, compared with 23% of those who survived. The clotting-factor results appeared to be specific for cardiovascular disease: there was no evidence that high levels of factor VIIc, factor VIIIc, and fibrinogen were associated with death from cancer. The general epidemiology of factor VIIc, factor VIIIc, and fibrinogen is consistent with their having a role in the pathogenesis of IHD.

The aim of this study was to characterise new users of hormonal replacement therapy (HRT) for the relief of menopausal symptoms and to compare these women with never-users of HRT; 402 new users and 804 never-users were studied. Hot flushes were the most common symptom in both users and non-users and were the most frequent reason for prescribing HRT. The prevalence of menopausal symptoms in non-users of HRT was high although substantially lower than that in users. HRT users were more likely to be current cigarette smokers than were never-users. There was also, within smokers, a significant relation between the number of cigarettes smoked and the likelihood of using HRT. This relation between HRT use and smoking could result from an anti-oestrogen effect of smoking, intensifying menopausal symptoms. Of potential clinical relevance is the suggestion that a proportion of women using HRT may be doing so in order to alleviate smoking-induced symptoms. Users of HRT were also more likely to have used oral contraceptives than were never-users; this relation was probably behavioural.

The Northwick Park Heart Study (NPHS) has investigated the thrombotic component of ischaemic heart disease (IHD) by the inclusion of measures of haemostatic function. Among 1511 white men aged between 40 and 64 at the time of recruitment, 109 subsequently experienced first major events of IHD. High levels of factor VII coagulant activity and of plasma fibrinogen were associated with increased risk, especially for events occurring within 5 years of recruitment. These associations seemed to be stronger than for cholesterol, elevations of one standard deviation in factor VII activity, fibrinogen, and cholesterol being associated with increases in the risk of an episode of IHD within 5 years of 62%, 84%, and 43% respectively. Multiple regression analyses indicated independent associations between each of the clotting factor measures and IHD but not between the blood cholesterol level and IHD incidence. The risk of IHD in those with high fibrinogen levels was greater in younger than in older men. Much of the association between smoking and IHD may be mediated through the plasma fibrinogen level. The biochemical disturbance leading to IHD may lie at least as much in the coagulation system as in the metabolism of cholesterol.

In Florida infant mortality increases with the birth rate. Midwives with superstition and ignorance constitute a source of danger, conditions of labor probably contribute somewhat, while insanitary conditions of the home and its surroundings are unfortunate factors. While the rates both for white and for colored population are below those of the Registration Area, they call for processes of betterment.

Solid-state devices developed primarily for nuclear gamma spectroscopy have many potential uses in x-ray analysis.