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Background: The prevention of dementia is a global priority but its etiology is poorly understood. Early life cognitive ability has been linked to subsequent dementia risk but studies to date have been small and none has examined sex differences., Methods: In the 1932 Scottish Mental Survey cohort, we related intelligence test scores at age 11 years in 16,370 boys and 16,097 girls (born in 1921) to incident dementia ages ≥65 years as ascertained using probabilistic linkage to electronic health records up to the age of 92 years (1,231 cases in men, 2,163 in women; median follow-up 15 years)., Results: Compared with the highest intelligence group (IQ ≥115), dementia risk was raised in the lowest-scoring category (<85) and these associations were stronger for women (hazard ratio; 95% confidence interval: 1.51; 1.29, 1.76) than men (1.19; 0.98, 1.44; P value for interaction by gender: 0.054). There was evidence of a dose-response association between childhood IQ and dementia in women (IQ 100-114.9 compared with ≥115: 1.18; 1.03, 1.34; IQ 85-99.9: 1.32; 1.15, 1.51; P value for trend <0.001) but not in men (1.05; 0.89, 1.24 and 1.01; 0.85, 1.21; 0.44)., Conclusions: Childhood intelligence is related to subsequent dementia risk but this association is not the same in men and women. See video abstract at, http://links.lww.com/EDE/B184.

Sir Christopher Booth looks at the major medical achievements of the 20th century, from the discovery of vitamins to the eradication of smallpox, and asks where scientific development might lead physicians in the new millennium.

Established 50 years ago by The British Council, to promote medical science abroad, the British Medical Bulletin (BMB) has evolved from a stencilled list of abstracts into a distinguished medical periodical. It has reflected the extraordinary diversity of advances that have been made in medicine in this country. During these 5 decades anti-microbial chemotherapy has become firmly established; organ and tissue transplantation have become a reality; the significance of Watson and Crick's discovery of the structure of DNA has been realised by the increasing applications of molecular biology to human disease; and modern investigative techniques, particularly magnetic resonance imaging, have made the human body virtually transparent. At the same time the BMB has mirrored fresh concerns, with, for example, industrial and environmental hazards, with newly recognised infectious agents, and increasingly with the medico-social problems of the modern era. This paper reviews the scientific contributions of the Bulletin and some of the administrative and financial structures that have supported it.

Extracellular levels of calcium at 1.05 mM or higher induce terminal differentiation and senescence in the mortal (MCF-10M) line of human breast epithelial cells, but does not retard the growth or induce differentiation in the immortal (MCF-10A) and oncogene transformed (MCF-10AneoT) lines. Intracellular levels of calcium and inositol triphosphate were determined in MCF-10M, MCF-10A, and MCF-10AneoT, under conditions of low and high extracellular calcium. We hereby report that increases in extracellular calcium is translated into significant increases in intracellular levels of calcium and inositol triphosphate in MCF-10M, but not in MCF-10A and MCF-10AneoT. This difference in the apparent calcium buffering capacity between the mortal and the immortalized human breast epithelial cells could account for the latter's unperturbed growth potential in high extracellular calcium environment.

Coeliac patients are at greater risk than the general population of developing malignant neoplasms, particularly lymphomas. The establishment at the Clinical Research Centre of a national collaborative study of coeliac patients with malignancy provided the opportunity to carry out HLA typing for 55 HLA-A, B and C and the 10 recognised DR antigens on a group of coeliac patients with malignancy. Study of a sample of 44 patients with biopsy proven coeliac disease and histologically confirmed malignancy, including 12 with malignant histiocytosis, and 57 coeliac patients without malignancy, failed to show any significant differences in antigen frequencies between patients with and without malignancy. These results indicate that there are no HLA genetic markers associated specifically with the development of malignancy in coeliac disease.

Patients with coeliac disease are at greater risk than the general population for the development of malignant neoplasms, particularly lymphomas. Of 259 histologically confirmed malignancies in 235 patients with histologically proven coeliac disease, 133 were malignant lymphomas, the predominant histological type being malignant histiocytosis and the commonest site of this lesion the small intestine. Patients with coeliac disease also have a greatly increased risk for the development of small-intestinal adenocarcinomas. Among 116 invasive non-lymphomatous malignancies there were 19 small-intestinal adenocarcinomas, compared with 0 . 23 expected from national cancer registrations adjusted for sex and age. There were also more oesophageal and pharyngeal squamous carcinomas than expected.

Coeliac disease may be defined as a condition in which there is an abnormal jejunal mucosa with loss of villi, which improves morphologically after treatment with a gluten-free diet. Pathologically, there is damage to the jejunal enterocytes, with hyperplasia of crypt cells so that overall enteropoiesis is increased. On conventional or scanning electron microscopy the enterocytes are markedly abnormal. Histochemically, the normal punctate appearance of the lysosomes is lost and sensitive lysosomal enzyme assays on mucosal biopsy samples using isopycnic centrifugation techniques show that there is an increase in total lysosomal activity with reduction in lysosomal latency. Studies following gluten feeding in patients whose mucosa has returned to normal after treatment with a gluten-free diet show that pathological abnormalities appear within 4--8 hours of gluten challenge. Complement together with extracellular IgM can be demonstrated in the lamina propria, suggesting the formation of immune complexes. In untreated coeliac disease there is a significant reduction in serum levels of C3 and C4. There is also evidence indicating the presence of immune complexes in the serum. Coeliac disease may therefore be an intestinal model of an immune complex disease, in which an antigen derived from gluten reacts with an antibody formed locally in the gut, fixing complement and causing damage to the enterocyte by activation of lysosomes.

Intestinal biopsies from 146 patients with adult coeliac disease and 13 patients with intestinal villous atrophy of different aetiology were assessed for the presence of subepithelial collagen and compared with a group of 20 control subjects. Subepithelial collagen was a common and non-specific finding observed in intestinal biopsies from patients suffering from adult coeliac disease (36%) and tropical sprue. In adult coeliac disease the described subepithelial changes usually regress following treatment, though marked subepithelial collagen deposition may indicate a poor prognosis. The study showed that the presence of marked subepithelial collagen in a flat jejunal biopsy does not define a separate clinical entity.

In coeliac disease there is an abnormality of the intestinal mucosa which is caused by ingesting gluten. The intestinal lesion affects predominantly the proximal small intestine and the ileum is either normal or less severely involved than the jejunum. In some cases adaptive changes occur in the ileum, producing enhanced absorption in that region when there is malabsorption in the jejunum. The characteristic absorptive abnormality in coeliac disease is therefore jejunal malabsorption and ileal hyperabsorption. When such a situitation develops it is possible that an indivisual with a flat jejunal mucosa may develop no symptoms of the disease, since the adaptive changes in the ileum compensate for the jejunal lesion. This may explain why in Western society there are probably more cases of coeliac disease undiagnosed in the community that have been treated by their doctors. The basic lesion in coeliac disease appears to be genetically determined and it is likely to be a failure to clear antigen which normally enters the lamina propria of the gut resulting in the formation of immune complexes with complement fixation at gut level.