Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

The creation of the Faculty of Community Medicine (now the Faculty of Public Health Medicine) of the Royal Colleges of Physicians of the United Kingdom.

The National Health Service Act 1946 transferred responsibility for the non-voluntary hospitals and certain clinical services from the public health departments of counties and county boroughs to new regional hospital boards, thereby substantially reducing the functions of their medical officers of health and creating a separate cadre of doctors concerned with the planning and management of hospital and specialist services. At around the same time there was pressure to develop in each medical school a department of social and preventive medicine with full-time staff involved in research work. Reviewing the situation 20 years later, the Royal Commission on Medical Education recommended that doctors in public health, medical administration or related teaching and research should form a single professional body concerned with the assessment of specialist training for and standards of practice in 'community medicine'. Immediately after the publication of the Commission's Report in 1968, J. N. Morris invited leaders in the three strands of activities to meet and discuss the proposal. A series of informal meetings led to the setting up, in 1969, of a Working Party (chairman, J. N. Morris) which negotiated with the Royal Colleges of Physicians of Edinburgh, Glasgow and London for them to create a faculty of community medicine. In November 1970 the Colleges set up a Provisional Council (chairman, W. G. Harding), later Board, and the Faculty formally came into existence on 15 March 1972. The key decisions and some of the complications and hitches encountered in achieving this radical outcome are described in this paper.

Correlation of in-vitro parameters of antimicrobial activity with prophylactic efficacy in an intradermal model of Staphylococcus aureus infection.

Cephalosporins differ in their ability to prevent staphylococcal wound infection. Although the reasons for the observed differences are not fully understood, the susceptibility of cephalosporins to hydrolysis by staphylococcal beta-lactamase has been correlated with failures of prophylaxis. To investigate the effect of beta-lactamase stability and other in-vitro parameters of the bacterial-antimicrobial interaction on the efficacy of antimicrobial prophylaxis, two beta-lactamase-stable agents, cefuroxime and cefmetazole were compared to cefazolin and cefamandole in an in-vivo model of intradermal infection employing four strains of Staphylococcus aureus. Following intraperitoneal administration of a single dose of cephalosporin or placebo, guinea pigs were inoculated at multiple intradermal sites with 2 x 10(7) cfu of a strain of staphylococcus. For three strains, the area of induration at 24 h following inoculation was significantly smaller in guinea pigs receiving prophylaxis with cephalosporins versus placebo; no cephalosporin was effective against the fourth strain. Differences were also noted among the cephalosporins; prophylaxis with cefuroxime and cefmetazole resulted in smaller lesions than seen in animals given cefazolin or cefamandole. Poor correlation was noted between results of the in-vivo model and in-vitro determinants of the bacterial-antimicrobial interaction which were MIC values, time-kill curves, and the rates of beta-lactamase-mediated cephalosporin hydrolysis by the different strains. The model demonstrated unexplained failures of prophylaxis and unexpected differences in efficacy of various cephalosporins as has been described before. This study highlights the need for an improved animal model of surgical antimicrobial prophylaxis and the identification of in-vitro determinants that predict in-vivo prophylactic efficacy more accurately.

The Canterbury studies of disablement in the community: prevalence, needs and attitudes.

The Health Services Research Unit at the University of Kent at Canterbury was set up in 1971, with financial support from the Central Government's Department of Health and Social Security. One area of major concern has been the study of the number and needs of disabled people living at home and of services provided to meet those needs. In a City-wide survey of the whole population, it was found that about 5 per cent of the people living at home had significant impairments, about half of whom had or required some support. Registers of disabled people and records of services helping them were found to be an inadequate source of data for estimating total numbers and needs. A separate study validated the broad clinical information given by the respondents. The original population of impaired people were revisited years after the first survey. 13 per cent had died, mortality being highest among those with the severer degrees of dependency; 25 per cent had had at least one episode of serious illness; and 61 per cent reported more difficulties overall than they had in the initial survey. Although 75 per cent of the needs expressed in the initial survey had been met or ameliorated. Other studies have examined means of detecting visual disability, the value of domiciliary physiotherapy, and occupational therapy and the need for special dental services for some disabled people. Inevitably some biases are introduced into the design of population-wide surveys of disabled people. Important among these are the definitions used of 'impairment', 'disability' and 'handicap'; the orientation of the questions asked (which tend define 'need' in terms of the perceptions of the provider of services rather than of the disabled person); and, in the measures used to quantify the data collected. Further areas of research needed are discussed at the end of the paper.

A randomized controlled trial of a stroke rehabilitation ward.

In S.E. Kent, during 1978 and 1979, 225 patients, representing 228 occurrences of hemiplegia, were referred to a new 20-bed stroke rehabilitation ward. These patients were randomly allocated to treatment in the special ward (group A 112 strokes) or to remain in conventional treatment locations (group C 116 strokes); the two groups were closely similar, except for the initial level of consciousness. Survivors were observed at four-month intervals to one year. There are indications of benefit for patients in group A by comparison with Group C in terms of treatment received (number treated by remedial therapists, the extent of treatment, and the arrangements for after-care), and in outcome (survival and the proportion returned to the community). The direction of the trend of advantage is consistent with another recent controlled trial, although not all modes of improvement are identical in the two trials. It is suggested that every health district should develop a comprehensive policy of stroke management.

Mortality in relation to the functional capacities of people with disabilities living at home.

The mortality experienced by a group of 1534 impaired people identified by means of a census-type survey of all households in the City of Canterbury is related to the degree of difficulty in carrying out selected self-care activities as reported by the impaired people. Although not entirely consistent, the findings in relation to people in their own homes agree with previously reported findings among patients in long-stay hospitals and residents in institutions that increasing difficulties in self-care (and therefore of dependency) are associated with increased mortality rates. These findings suggest that there is no clear boundary between some services for disabled people and those for terminal care, and that many severely handicapped people at home require co-ordinated and flexible care from nurses, social workers, and doctors.

Prescriptive screening for adolescent idiopathic scoliosis: a review of the evidence.

Published data relating to prevalence, natural history, treatment and prevention adolescent idiopathic scoliosis (AIS) are examined. Screening programmes could lead to about 10% of 11-15 year old schoolchildren being referred for diagnosis, involving, for many, an X-ray of the spine. About 1 in 5 of the children referred would be diagnosed as having AIS; of these 1 in 10 would have treatment, either by the wearing of a brace, or in more severe cases by operation and fusion of the vertebrae. The data suggest that in most cases of AIS the spinal curve regresses or at least does not progress. Treatment, whether by brace or operation, is onerous and not always successful. Very little is known for certain about the causation of AIS and the interplay of various factors in its development and regression. The case for widespread adoption of prescriptive screening programmes is not yet established. There is an urgent need to coordinate and increase research designed to determine the aetiology, incidence, prevalence and course of AIS; to find factors that distinguish a rarer progressive form, commoner in girls than boys, from a more frequent and apparently benign form; to develop reliable and valid screening techniques; and to evaluate different forms of treatment. Some of these studies will have to be carried out by collaboration between a number of centres. Current screening programmes should be rigorously evaluated, all children who are referred for diagnosis and treatment should be examined in designated centres and the findings and details of treatment should be recorded systematically, using agreed definitions and criteria that will ensure that the experience of collaborating centres can be collated.