Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing.

Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p< 0.0001 for all). Trabecular bone volume, assessed by µCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p< 0.05), and was 2-3 fold higher in SclAbII-treated groups (p< 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone mass, particularly in the trabecular compartment. Altogether, these results demonstrate the efficacy of sclerostin antibody therapy in preventing astronaut bone loss during terrestrial solar system exploration.

Spaceflight and hind limb unloading induce similar changes in electrical impedance characteristics of mouse gastrocnemius muscle.

OBJECTIVE: To assess the potential of electrical impedance myography (EIM) to serve as a marker of muscle fiber atrophy and secondarily as an indicator of bone deterioration by assessing the effects of spaceflight or hind limb unloading. METHODS: In the first experiment, 6 mice were flown aboard the space shuttle (STS-135) for 13 days and 8 earthbound mice served as controls. In the second experiment, 14 mice underwent hind limb unloading (HLU) for 13 days; 13 additional mice served as controls. EIM measurements were made on ex vivo gastrocnemius muscle. Quantitative microscopy and areal bone mineral density (aBMD) measurements of the hindlimb were also performed. RESULTS: Reductions in the multifrequency phase-slope parameter were observed for both the space flight and HLU cohorts compared to their respective controls. For ground control and spaceflight groups, the values were 24.7±1.3°/MHz and 14.1±1.6°/MHz, respectively (p=0.0013); for control and HLU groups, the values were 23.9±1.6°/MHz and 19.0±1.0°/MHz, respectively (p=0.014). This parameter also correlated with muscle fiber size (ρ=0.65, p=0.011) for spaceflight and hind limb aBMD (ρ=0.65, p=0.0063) for both groups. CONCLUSIONS: These data support the concept that EIM may serve as a useful tool for assessment of muscle disuse secondary to immobilization or microgravity.

Malaria and anaemia at different altitudes in the Muheza district of Tanzania: childhood morbidity in relation to level of exposure to infection.

Parallel monthly surveys of children aged 6-71 months were conducted in the Muheza district of Tanzania. The aim was to compare highland villages, where the mean, annual entomological inoculation rate (EIR) for malaria is 34 and mean annual prevalences of parasitaemia range from 33%-76%, with culturally similar villages of the lowlands, where the mean EIR is 405 and prevalences of parasitaemia range from 80%-84%. The total survey population could be divided into six geographical subgroups, which can be arranged in order of increasing prevalence of parasitaemia. The prevalences of dense parasitaemia, of febrile malaria, and of anaemia all increased in the same order across this series of groups, the trends being statistically significant. The results of previous studies have indicated a paradoxical effect whereby children in regions with a lower exposure to malarial infection suffer, in the long term, a higher incidence of severe attacks of malaria. In the present study there was no sign of any such paradoxical inverse relationship between the level of exposure and the prevalence of malarial illness or anaemia. However, child mortality rates are similar in the highlands and lowlands, as are the median ages of children admitted to hospital. Overall, the present findings indicate that, for the populations studied, an artificial reduction in EIR would be beneficial, even in the long term, with regard to the chronic effects of malaria. This does not necessarily conflict with previous studies reporting opposite conclusions with regard to the incidence of severe,acute effects.

Is psychological wellbeing impaired in long-term survivors of breast cancer?

OBJECTIVE: To measure anxiety and depression in long term survivors of breast cancer. DESIGN: Case-control study. SETTING: Follow up of the trial of early detection of breast cancer in the South West Surrey Health District. SUBJECTS: 331 patients with breast cancer aged 50-78, attending mammographic follow up, who had been invited to screening before diagnosis, and 584 controls who had attended the same clinic but did not have breast cancer. The sample included 290 pairs matched by screening attendance pattern and year of birth. MAIN OUTCOME MEASURE: Anxiety and depression scores on the Hospital Anxiety and Depression Scale. RESULTS: Significantly fewer symptoms of anxiety and depression were reported by patients with cancer than by controls and significantly fewer had high scores suggesting the presence of psychological morbidity meriting treatment. Among the patients with cancer anxiety was more common at the first annual follow up than at later visits. Symptom scores were not significantly related to the manner of detection or to the type of initial treatment. Potentially confounding social and personal factors did not account for the differences between patients with cancer and controls. CONCLUSION: The prevalence of anxiety and depression is not increased in long term survivors of breast cancer who are apparently free from disease and is not substantially affected by the manner in which a cancer is detected or by the treatment given. In the light of these findings it is difficult to justify large "quality adjustments" to the estimates of recurrence-free years of life saved by screening. Those who counsel patients with breast cancer should be aware that although the initial distress can be severe, meriting psychological treatment, patients do recover their normal ability to enjoy life.

Investigating changes in awareness about cutaneous malignant melanoma in Britain using the Omnibus Survey.

Awareness about cutaneous malignant melanoma and sun protection was investigated in a national sample of 3961 adults. Awareness about malignant melanoma seems to have increased in England since the mid-1980s but it is lower in men, the under 25s, the elderly, those without a partner and the poorer socioeconomic groups. As mortality rates for melanoma are higher in elderly men than other age-sex groups, the possibility for improved awareness and prevention needs to be explored further within this group. Most people in the survey knew about sun protection. Further primary prevention initiatives should be monitored, using markers for behaviour such as the incidence of sunburn, as the potential benefits of a reduced incidence of skin cancer might not be seen for up to 20 years.

Survival of patients with breast cancer diagnosed in the United Kingdom trial of early detection of breast cancer. United Kingdom Trial of Early Detection of Breast Cancer Group.

OBJECTIVE: To examine the survival of patients with breast cancer diagnosed in different centres and by different methods in the United Kingdom trial of early detection of breast cancer, in order to investigate the contribution of different factors to the previously observed reductions in breast cancer mortality. SETTING: A non-randomised trial of the early detection of breast cancer, in which women aged 45-64 in two districts were offered annual screening for seven years, women in a further two districts were offered education about breast self examination (BSE), and those in four districts formed a comparison group. METHODS: Patients with breast cancer are classified according to the type of centre, method of detection, and attendance for BSE education. Univariate and multivariate survival analyses are carried out, including tumour size, dissemination status, and use of adjuvant treatment as additional variables. RESULTS: In the univariate analysis, patients with breast cancer who are non-attenders for screening have a significantly worse prognosis than those in the comparison centres. Patients whose cancer is detected by mammography have the best survival rate. The inclusion of size and dissemination status in the multivariate analysis explains only about one third of the improved prognosis in these cases. There is a significant difference between prognosis in the two BSE centres. CONCLUSIONS: The use of prognostic factors as recorded in this trial to predict breast cancer mortality may be inadequate.

Meeting The Health of the Nation target for skin cancer: problems with tackling prevention and monitoring trends.

The White Paper The health of the nation challenges us to halt the rising incidence and mortality from skin cancer. Means of achieving this include various approaches to educating the public and modifying sun exposure and promotion of early detection of cancers. Some initiatives can be organized locally but others require national coordination. Evaluation of the impact on health and the cost of preventive programmes is important because the effectiveness of health education packages and campaigns that aim to reduce the incidence or death from skin cancer has yet to be proved. As the majority of skin cancers do not metastasize, it is on melanoma that efforts to improve registration should be focused. Cancer registries have particular difficulty in monitoring the incidence of skin cancer where treatment is simply excision. Improved ascertainment and a shift towards early diagnosis will cause artefactual increases in incidence. Investigation of the trends will therefore require careful interpretation.

Consistency of histopathological reporting of breast lesions detected by screening: findings of the U.K. National External Quality Assessment (EQA) Scheme. U. K. National Coordinating Group for Breast Screening Pathology.

The aim of the scheme was to determine consistency of histopathological reporting in the United Kingdom National Breast Screening Programme. This external quality assessment scheme involved 51 sets of 12 slides which were circulated to 186-251 pathologists at intervals of 6 months for 3 years. Participants recorded their diagnoses on standard reporting forms, which were submitted to the U.K. National Cancer Screening Evaluation Unit for analysis. A high level of consistency was achieved in diagnosing major categories of breast disease including invasive carcinoma and the important borderline lesions, radial scar and ductal carcinoma in situ (DCIS), the latter exceeding a national target set prior to the onset of the scheme. Atypical hyperplasia (AH) was reported with much less consistency although, where it was the majority opinion, over 86% of diagnoses were of benign disorders and only 14% were of DCIS. Inconsistency was encountered in subtyping and measuring DCIS, the former apparently due to current uncertainties about classification and the latter to poor circumscription, variation in size in different sections and merging with zones of AH. Reporting prognostic features of invasive carcinomas was variable. Measurement of size was achieved with adequate consistency except in a small number of very poorly circumscribed tumours. Grading and subtyping were inconsistent although the latter was not specifically tested and will be the subject of future study. Members of the National Coordinating Group achieved greater uniformity than the remainder of the participants in all diagnostic categories, but both groups experienced similar types of problem. Our findings suggest that participation in the scheme improves diagnostic consistency. In conclusion, consistency in diagnosing invasive carcinoma and radial scar is excellent, and good in DCIS, but improvements are desirable in diagnosing atypical hyperplasia, classifying DCIS and reporting certain prognostic features of invasive tumours. Such improvements will require further research, the development of improved diagnostic criteria and the dissemination of clearer guidelines.

Breast self-examination programmes in the trial of early detection of breast cancer: ten year findings.

Programmes of education in breast self-examination with specialist clinics for self-referral were introduced in two health districts around 1980. Combining the results from the two centres showed no reduction in mortality from breast cancer over the following 10 years but the mortality was low in one of the centres whilst in the other it was higher than in four geographically separate comparison centres in which there was similar careful monitoring of breast cancer incidence and mortality. Because this was not a randomised controlled trial and lacked a uniform treatment protocol, biases may be responsible for the differences observed, but it is also possible that BSE education with annual reinforcement contributed to the breast cancer mortality reduction seen in one district. The overall conclusion however is that the value of breast self-examination remains unproven.

Interval cancers and sensitivity in the screening centres of the UK trial of early detection of breast cancer.

The incidence rates of interval cancers following a negative breast screen in two screening centres which offered women aged 45-64 annual screening by mammography and/or clinical examination are examined. Sensitivity of screening is estimated by comparing the incidence rate of interval cancers with that expected in the absence of screening, and the results are compared with those from alternative methods of calculating sensitivity. The incidence rate of cancers diagnosed within 12 months of a negative screen by mammography plus clinical examination was reduced by 70% for women aged 45-54, and 84% for women aged 55+. There is no indication from this that sensitivity in the UK trial was substantially lower than in other studies which have achieved larger reductions in mortality.

A case-control evaluation of the effect of breast cancer screening in the United Kingdom trial of early detection of breast cancer.

OBJECTIVE: The aim was to assess the extent to which selection bias affects a case-control study of breast cancer screening in which attenders and non-attenders for screening are compared. DESIGN: There were two retrospective case-control studies, one estimating the risk of death from breast cancer in women in the screening district relative to those in the comparison district (study A), the second estimating the relative risk for women who had ever been screened compared with women who had never been screened in the screening district alone (study B). For cases and controls in study B, the women's screening history was summarised for the time period from date of entry to diagnosis of the case, or the equivalent time from date of entry for the matched controls. For cases detected by screening, the screen at which cancer was detected was included in the screening history. SUBJECTS: Cases were deaths from breast cancer in women with disease diagnosed after entry to the trial, up to 31 December 1986 or a maximum of seven years from date of entry, in one of the screening districts (Guildford) and one of the comparison districts (Stoke) participating in the UK Trial of Early Detection of Breast Cancer: study A: 198 deaths in Guildford and Stoke; study B: 51 deaths in Guildford only. There were five age matched controls for each case, with length of follow up at least as great as the time from entry to death of the case. MAIN RESULTS: The estimate of the risk of death from breast cancer in the screening district relative to the comparison district from study A was 0.76, thus implying a reduction of 24% in the screening district, similar to that obtained from a cohort analysis of data from the two districts. In contrast, the relative risk in study B for ever v never screened women was 0.51, which, taking the 72% compliance into account, would result in a relative risk of 0.65 for the screening district if there were no selection bias. The risk of breast cancer mortality in the never screened relative to the comparison district was 1.13, despite the fact that incidence rates in the two populations were similar. This suggested that cancers in the never screened group had a particularly poor prognosis, contributing to selection bias. CONCLUSIONS: The possible existence of selection bias should lead to caution in interpretation of the results of case-control studies of the effect of breast cancer screening on mortality.

Verification of the cause of death in the trial of early detection of breast cancer. UK Trial of Early Detection of Breast Cancer Group. Trial Co-ordinating Centre.

The limitations of case review as a means of identifying errors in death certificates among breast cancer patients in a non-randomised trial of screening are illustrated by the findings of this large study. Records of 928 out of 990 deaths were available for review but were very variable in quality. Definite errors were found in 1%, errors were suspected in a further 5% and uncertainty about the cause of death, despite review, was recorded for 27%. The overall bias in reporting breast cancer deaths was less than 1%. It was concluded that the certified underlying cause of death without review provides an adequate endpoint for evaluating breast cancer screening programmes in the UK.

Psychiatric morbidity associated with screening for breast cancer.

The 28-item GHQ was used to assess psychiatric morbidity in 302 women attending for routine breast cancer screening, 300 women attending for further investigation of a positive screening result and 150 women referred for investigation of breast symptoms. The GHQ-28 was administered on arrival at the relevant clinic and three months later. Medical records were used to determine the outcome of the clinic attendance. Women were classified into routinely screened women, women with false positive screening results, symptomatic women with a benign diagnosis, newly diagnosed cancer patients and previously treated cancer patients. When tested on arrival at the clinic, 25% of routinely screened, 30% of women with false positive results and 35% of symptomatic women with benign conditions were probable cases of psychiatric morbidity. The only statistically significant difference was between the routinely screened and symptomatic benign groups. Levels of anxiety were significantly higher in those with false positive results and in the symptomatic benign group than in the routinely screened. Three months later the prevalence of probable psychiatric morbidity had fallen to 19% in both the routinely screened and those with false positive results but remained significantly higher in the symptomatic benign group (31%). Probable cases of psychiatric morbidity among newly detected cancer patients rose from 34 to 46% over the 3-month period. Among women who had had breast cancer diagnosed in the past prevalence remained at 21%. The prevalence of probable psychiatric morbidity in screened women is similar to that in the general population. Among women referred for further investigation because of a false positive screening result prevalence was only slightly increased and there was no evidence of a sustained increase in anxiety. Provided that delays are kept to a minimum and that women are kept informed, a breast cancer screening programme does not increase psychiatric morbidity. Further research is required in cancer patients to determine whether those diagnosed in asymptomatic women have a higher and more sustained degree of psychiatric morbidity than those diagnosed in women who are aware of symptoms.

Improving the effectiveness of cervical cancer screening.

A review of 100 cases of invasive cervical cancer was designed to assess what changes in cervical screening services might be most effective in reducing mortality. In 68 cases there had apparently never been screening: no system of individual invitation existed for unscreened women. In 10 cases the last smear was reported as normal over five years earlier: a five-year recall system existed but was inefficient. In 13 cases suspicious cervical smear reports had not been followed up adequately. Two cases might have been diagnosed earlier, in spite of ;normal or inflammatory' smears, if the symptoms had been fully elicited. For the remaining seven cases one or more smear was reported as normal within five years of diagnosis of invasive cancer. Overall, 15 cases might have been picked up earlier if suitable opportunities for screening which did arise had been exploited. It was concluded that a substantial proportion of these 100 women might have received treatment at an earlier stage solely by the rigorous implementation of the present screening policy.

Making physiotherapy more accessible: open access for general practitioners to a physiotherapy department.

Open access to a physiotherapy outpatient department of a district general hospital was offered to general practitioners to whom domiciliary physiotherapy was already available. The effects of the new service have been monitored. Delays are reduced and consultants economise on time spent in merely confirming need for physiotherapy. Policies determining treatment, placing emphasis on prevention and self-help rather than prolonged treatment, are adhered to equally well by physiotherapists whether patients are referred directly or indirectly. It had proved unnecessary to restrict access to physiotherapy by insisting that general practitioners refer all patients first to consultant clinics. General practitioners have been sufficiently selective in referral and physiotherapists sufficiently economical in selecting treatment and determining its duration for the service to remain within the limits of available resources.