Atopic eczema and the home environment.

BACKGROUND: There is strong evidence to suggest that the prevalence of atopic eczema is increasing in developed countries. Environmental factors have been implicated in the disease. OBJECTIVES: This descriptive case-control study sheds light on the possible association between atopic eczema in school children and various home environmental factors, and generates hypotheses for further studies. METHODS: The study uses data on reported atopic eczema symptoms collected via a cross-sectional parental postal survey (n = 1350) in Nottingham, U.K. Estimates of the risk of reported eczema associated with various home environmental factors were calculated by means of odds ratios (OR), along with population attributable risk percentages. RESULTS: The study showed statistically significant associations between atopic eczema symptoms and dampness in the home [OR 1.40; 95% confidence interval (CI) 1.00-1.97], the use of a radiator to heat the child's bedroom (OR 1.50; 95% CI 1.05-2.16) and the use of synthetic pillows (OR 1.51; 95% CI 1.01-2.28). Frequent vacuuming in the home was associated with a decreased prevalence of atopic eczema (OR 0.74; 95% CI 0.58-0.94). The associations with dampness in the home, synthetic pillows and frequency of vacuuming were not altered significantly after adjustment for age, sex and socio-economic status. Population attributable risk percentages for the use of a radiator and synthetic pillows indicate that although the relative risk estimates for these factors may be small, the population impact of these factors is considerable (26% and 28%, respectively), owing to the high prevalence of exposure to these factors among this group of school children. CONCLUSIONS: Further research is needed to confirm these associations and additional research is needed to see whether they might be causative. Practical public health advice about the importance of controlling the home environment may then be targeted at families with atopic eczema.

Is there a geographical variation in eczema prevalence in the UK? Evidence from the 1958 British Birth Cohort Study.

Some studies have suggested that the prevalence of atopic eczema may vary between geographical regions. This descriptive study investigates the regional and subregional geography of reported and examined eczema prevalence at the age of 7, 11 and 16 years in Britain using data from the 1958 birth cohort study (n = 828). Estimates of the relative risk of reported eczema associated with residence in each region of the country were calculated and the regional distribution of reported and examined eczema prevalence was compared. The reported prevalence of eczema was mapped at the smaller county level. Comparisons were made with the county-level distribution of asthma and hay fever prevalence. The study showed a marked and statistically significant variation in eczema prevalence across the regions in Britain which was present for examined as well as reported eczema. The highest risk was associated with four regions: North Midlands; Eastern; London and the South-East; and Southern. This regional pattern was not altered significantly after adjustment for social class and family size. The geographical distribution of eczema prevalence was largely maintained when analysed at the county level. Few similarities were found between the county-level distribution of eczema prevalence and that for asthma and hay fever. Explanations for this strong regional variation now need to be sought in terms of environmental and life-style associations.

Atopic eczema and domestic water hardness.

BACKGROUND: The environment plays an important part in the aetiology of atopic eczema, but specific causes are unknown. Exposure to hard water is thought to be a risk factor for eczema. We undertook an ecological study of the relation between domestic water hardness and the prevalence of eczema among Nottinghamshire schoolchildren. METHODS: Questionnaire details of 1-year period and lifetime prevalence of eczema were obtained from parents of 4141 randomly selected primary-school children and 3499 secondary-school children in southern Nottinghamshire. Geographical information systems (GIS) were used to link the geographical distribution of eczema prevalence with domestic water-hardness data (four categories). Adjustment was made for potential confounding by sex, age, socioeconomic status, and access to health care. FINDINGS: Among the primary-school children there was a significant direct relation between both 1-year period and lifetime prevalence of eczema and water hardness, both before and after adjustment for confounders. The 1-year period prevalence was 17.3% (261/1509) in the highest water-hardness category and 12.0% (94/786) in the lowest (adjusted odds ratio 1.54 [95% CI 1.19-1.99] p for trend <0.001). The corresponding values for lifetime prevalence were 25.4% (384/1509) and 21.2% (167/786; adjusted odds ratio 1.28 [1.04-1.58], p for trend=0.02). Eczema prevalence trends in the secondary-school population were not significant (adjusted odds ratio for highest compared with lowest hardness category for 1-year prevalence 1.03 [0.79-1.33], p for trend=0.46; for lifetime prevalence 0.99 [0.83-1.23], p for trend=0.93). Eczema prevalence in primary-school children increased in relation to chlorine content of water, but the trend across four chlorine-content categories was not independently significant after adjustment for confounders. INTERPRETATION: Exposure to hard water in the home may increase the risk of eczema in children of primary-school age.

The problem of atopic eczema: aetiological clues from the environment and lifestyles.

Atopic eczema is the most common inflammatory skin disease in children, affecting around 10% of children in the developed world. It can be a distressing condition, influencing children's well-being, personal and educational development, and family life, and it has huge economic implications for health services and individual budgets. Like other atopic diseases such as asthma and hay fever, the prevalence of atopic eczema has increased substantially over the last 30 years, for reasons largely unknown. Although a genetic predisposition to the disease has been implicated, evidence from a range of sources suggests that environmental factors play a crucial role in the disease expression. This paper reviews the epidemiology of atopic eczema, with particular attention to potential environmental aetiological factors and draws evidence from studies in the UK and internationally. First, atopic eczema has been found to vary socially and to be more prevalent in the UK among social class I and II families than among other socio-economic groups. Second, it has been suggested that cross infection from other siblings in large families may have a protective role in atopic disease expression. Third, it has been proposed that an increased risk of atopic eczema may result from decreases in helminthic infestation. Fourth, studies of migrant groups have shown large increases in disease prevalence compared with migrants' country of origin, suggesting clues as to the importance of socio-economic and environmental changes such as those associated with industrialization. Finally, a distinct and consistent geographical pattern of eczema has been observed in the UK which cannot be explained by social class distribution. The various types of study have attempted to identify reasons for differences in prevalence but, to date, no definitive causation has been identified. In some cases, specific risk factors have been suggested and include house dust mites, dietary allergens and irritants. It is argued here that the aetiology is unlikely to be simple or uni-causal and that an understanding of the relationships between the disease and behaviour, lifestyle, home and external environmental factors is crucial. This paper reports the preliminary stages of an interdisciplinary research project involving dermatologists, epidemiologists and health geographers, and calls for investigation into associations between atopic eczema and possible environmental and lifestyle factors. These include behavioural factors, microenvironment factors and macroenvironments.

Focus groups in dermatology.

Focus groups have considerable potential for study of the attitudes and experiences of patients and health care providers within dermatology. This article describes the use of such groups, using specific dermatological examples.

Radiation-induced cell cycle delay measured in two mouse tumors in vivo using bromodeoxyuridine.

The magnitude of the delay of cells in the phases of the cell cycle after irradiation may be related to the radioresponsiveness of tumor cell populations. In this study we have quantified division delay in two mouse tumors in vivo after single and fractionated doses of X rays and single doses of neutrons. The incorporation of bromodeoxyuridine and flow cytometry provided a sensitive and quantitative method to detect cell cycle perturbations after radiation treatment. The more rapidly growing SAF tumor showed less G2-phase delay per gray than a more slowly proliferating tumor, the Rh (0.9 vs 1.8 h). In addition, the SAF tumor failed to show any G1/S-phase delay while the Rh tumor experienced a longer G1-phase delay than that measured for G2 phase (3.1 vs 1.8 h). There was a trend in both tumors for lower doses to be more effective in producing cell cycle delays. Neutrons caused longer G2-phase delays on a unit dose basis, 2.5 and 5.4 h for the SAF and Rh tumors, respectively. The RBE for neutrons for division delay was found to be 2.9 and 2.8 for the SAF and Rh tumors, while the RBE for growth delay was 3.4 and 3.5. Fractionation of the X-ray dose caused a reduction in division delay at higher total doses (10 or 12 Gy) but was without effect at the lower dose studied (6 Gy). These studies show the feasibility of measuring cell cycle delays in vivo, and future developments are suggested for a possible predictive test in patients receiving radiotherapy.

Proliferative changes in two murine tumours in response to single or fractionated doses of X-rays.

Studies were carried out to investigate proliferative changes in two murine experimental tumours in response to radiation. Results were generated using bromodeoxyuridine labelling and flow cytometry. This study demonstrates the possible ambiguity of previous studies using tritiated thymidine in which inability to discriminate normal and tumour cell components in murine tumours may lead to different values for cell kinetic parameters. In particular, the sarcoma F appeared to have a growth fraction of 0.62 when all cells were considered; in reality the growth fraction of the tumour cells only (based on DNA content discrimination) was close to unity. Radiation, administered either as single or fractionated doses, caused little change in the proliferative characteristics of the sarcoma F tumour but had profound effects on the adenocarcinoma Rhodesia tumour. Major changes were the accumulation of cells in G2 for several days after the end of the radiation treatment in both tumours and a dramatic drop in labelling index of the Rhodesia tumour. In neither tumour was there any evidence to suggest an increase in tumour cell proliferation during or after the irradiations. The diploid cells within the sarcoma F tumour showed an initial depression of labelling index followed by a rapid increase overshooting the control labelling index at higher radiation doses. Much of the effects could be attributed to cell cycle delays.

Tumor cell kinetics, local tumor control, and accelerated radiotherapy: a preliminary report.

The local tumor control achieved in patients treated in a pilot study of continuous, hyperfractionated, accelerated radiotherapy has been related to the tumor cell kinetics evaluated by in vivo administration of bromodeoxyuridine and flow cytometry. In 42 of 50 patients with advanced squamous cell carcinomas in the head and neck region it was possible to sample the primary tumor prior to treatment. In three further cases, involved regional nodes were studied: in the remaining five, tissue was obtained subsequently either from a local recurrence or from a distant metastasis. Successful cell kinetic measurements were made in 38 (90%) of the 42 primary tumors. The median values of the labelling index, the duration of the DNA synthetic phase and, thus, the potential doubling time for all primaries were 7.1%, 9.8 hr, and 3.9 days, respectively. Complete regression was achieved in 28 (74%) of the primary tumors and in 23 (61%) this was maintained to the time of observation for this report. There was no significant influence of any of the cell kinetic parameters upon the immediate or longer term local tumor control. This result is compatible with the overcoming of cellular repopulation by the acceleration of radiotherapy.

Combined analysis of DNA ploidy index and N-myc genomic content in neuroblastoma.

The aim of the study was to assess, in a group of nonselected patients with neuroblastoma, the prognostic value of both N-myc gene amplification and DNA ploidy index, taking into account potential confounding factors such as age and stage. Of 59 patients studied, 23 were younger than 1 year at diagnosis, 31 presented with stage IV, 10 with stage III, 5 with stage II, 8 with stage I, and 4 with stage IV-S. N-myc genomic content was analyzed by Southern blot hybridization technique and N-myc amplification (greater than or equal to 3 copies/haploid genome) was present in 6 stage IV, 2 stage III, and 1 stage IV-S. The DNA ploidy index was analyzed by flow cytometry. Of the 59 neuroblastomas, 26 were diploid (DNA index, 1) and 33 were aneuploid (DNA index, greater than 1). The majority of the aneuploid tumors (28 of 33) were near-triploid with DNA indexes between 1.25 and 1.68, 4 were near-diploid (DNA index up to 1.18), and 1 was hypotetraploid (DNA index, 1.85). The proportion of near-triploid tumors was significantly greater among patients under 1 year of age and among patients presenting with stages I, II, and IV-S. Interestingly, 0 of 28 near-triploid neuroblastomas exhibited N-myc gene amplification, compared to 9 of 31 in the group of diploid, near-diploid, and hypotetraploid tumors (Fisher's exact test, P less than 0.001). Four factors were significantly related to a high risk of relapse in univariate analysis, i.e., age, stage, DNA index, and N-myc amplification. In multivariate analysis, only N-myc amplification and the DNA index remained significantly associated with a high risk of relapse. The 2-year disease-free survival rate was 94% (95% confidence interval, 77-98%) for patients with near-triploid neuroblastoma, compared to 45 and 11% (95% confidence interval, 32-70 and 4-23%) for patients with diploid or near-diploid tumors, without and with N-myc amplification, respectively. We concluded that the combination of N-myc and DNA index should be included in routine management of neuroblastoma.

The rejoining of DNA double-strand breaks following irradiation with 238Pu alpha-particles: evidence for a fast component of repair as measured by neutral filter elution.

The induction and repair of DNA double-strand breaks (DSB) following exposure to 238Pu alpha-particles was examined in V79-379A cells. The technique of neutral filter elution was used in these investigations at both pH 9.6 and pH 7.2. The initial dsb yield was found to be similar to that seen after 250 kVp X-ray or 2.3 MeV neutron exposure. However, the pattern of dsb rejoining after alpha-particle irradiation did not follow that seen after X-rays or neutrons. A very fast initial component, complete within 2 min of incubation following irradiation, removed 70 per cent of the dsb seen after 40 Gy alpha-particles; very little slow rejoining was seen. This contrasts sharply with the dsb rejoining seen after X-ray or neutron exposure, and presumably reflects the differences in the nature of the dsb induced and the way they are repaired.

The effect of post-irradiation anisotonic treatment on cell survival and repair of DNA damage.

V79 379A cells were irradiated and then exposed to anisotonic PBS for 20 min. This enhanced the radiation effect resulting from the fixation of potentially lethal damage. The induction of DNA single- and double-strand breaks is not increased by this treatment. Anisotonic treatment delayed the onset of repair of DNA damage. However when cells were returned to normal medium, they repaired the damage to a similar extent as cells not exposed to the anisotonic treatment. We suggest that the fixation of damage by post-irradiation anisotonic treatment is mediated through an increased probability of misrepair of DNA damage due to the delay in the onset of repair. This is supported by the observation that there is a reduced effect of post-irradiation anisotonic treatment on cells that have a markedly reduced ability to repair double-strand breaks.

Can cell kinetic parameters predict the response of tumours to radiotherapy?

Three potential predictive assays of the repopulation component in tumour response to therapy are considered. (1) The DNA index can easily be measured. It is of prognostic value for cancers of certain sites, aneuploidy being a bad prognostic indicator. It is not strictly an indicator of cell proliferation. (2) The in vitro labelling index is of predictive value in early stage operable breast cancer and in head and neck cancer. In the former a high pretreatment labelling index can identify patients who could benefit from adjuvant chemotherapy. (3) The tumour potential doubling time (Tpot) can be measured rapidly following in vivo labelling with bromodeoxyuridine or iododeoxyuridine. We have measured Tpot in over 100 solid tumours with a success rate of about 75 per cent. Nearly 50 per cent of the tumours have a pre-treatment potential doubling time of 5 days or less. These would be suitable candidates for accelerated fractionation.

Radiosensitization by misonidazole during recovery of cellular thiols following depletion by BSO or DEM.

V79 cells have been depleted of their endogenous thiols by treatment with 100 microM BSO for 16-18 hr, or 0.5 mM DEM for 1 hr. The recovery of cellular thiols after removal of the drugs was determined by h.p.l.c. or flow cytometry and the sensitizer enhancement ratio for 100 microM misonidazole was measured as a function of time after removal of the drugs. The SER of 1.2 for control (hypoxic) cells increased to 1.8 for BSO treated (hypoxic) cells and 2.2 for DEM treated ones, when thiol levels were below 10% of controls. The SER and thiol levels returned to control values within 5 hr of removing DEM. After BSO there was little change during the first 5 hr and then a gradual return to normal values by 24 hrs. The major fall in the SER after removal of the drugs occurred as the cellular thiols increased to 60% of control values.

Cell proliferation and differentiation in squamous cancer.

Cellular differentiation is generally regarded as an important histological predictor of tumour behaviour. Verrucous carcinoma is a very well-differentiated tumour characterised by slow enlargement and an unsatisfactory response to radiotherapy. Tumour cell kinetic studies using the intravenous administration of bromodeoxyuridine (BrdUrd) before tumour sampling have shown these tumours to have high labelling indices and short duration of DNA synthesis. These values result in short potential cell doubling times of these tumours although they then have a well-differentiated appearance histologically. Study of 20 other squamous cell carcinomas has shown no relationship between grade and cell proliferation.

Cell survival and DNA double-strand break repair following X-ray or neutron irradiation of V79 cells.

We have investigated the effects of 250kVp X-rays and 2.3 MeV (mean energy) neutrons on the cell survival, DNA double-strand break (dsb) induction and repair (using the Kohn neutral elution technique) in V79 cells. The lethal effects of neutrons were shown to be significantly greater than for a similar dose of X-rays (RBE = 3.55 at 10 per cent survival). However, the RBE for dsb induction, in a dose range of 10-50 Gy, was 1. On investigating the repair of DNA dsb induced by either X-ray or neutron irradiation, clear differences in the pattern of repair were found. Both a fast and a slow component of repair were seen in both cases; the former, however, was reduced following neutron irradiation and, since the amount of slow repair was similar in both cases, this resulted in proportionally more unrejoined breaks after neutrons. These experiments were carried out with elution buffer at pH 9.6; however, when similar experiments were performed at pH 7.2 the results obtained support our earlier findings. We suggest that these differences in DNA dsb repair reflect basic differences in the nature of the lesions induced by high- and low-LET ionizing radiations.

Cell kinetics in human malignancies studied with in vivo administration of bromodeoxyuridine and flow cytometry.

Bromodeoxyuridine (BrdUrd) is a pyrimidine analogue which is incorporated into the DNA of proliferating cells. When in vivo BrdUrd infusion is coupled with bivariate flow cytometry to measure cell BrdUrd incorporation and DNA content, both the percentage of DNA-synthesizing cells [BrdUrd-labeling index (LI)] and the DNA synthesis time (TS) can be determined on the same tissue sample. From experimentally determined LI and TS, the potential doubling time of the population and its cell production rate are calculated. To ascertain whether the BrdUrd infusion method is clinically feasible and if data are reliable, we studied patients with leukemia, refractory anemia, multiple myeloma, and brain and gastric tumors. The BrdUrd incorporation data were compared with those determined on duplicate samples with the techniques conventionally used for LI and TS values, i.e., 3H- and 14C-labeled thymidine autoradiography, respectively. The complete BrdUrd procedure takes 6-9 h, and no immediate toxicity from BrdUrd administration has been observed. In an 8-month period, 154 patients were studied. Successful LI and TS determinations were obtained in 78.9 and 59.7% of cases, respectively, more often in hematological than in solid tumors. The values for LI and TS assessed with the BrdUrd technique were very close to those found with 3H- and 14C-labeled thymidine autoradiography (r = 0.88, P less than 0.005, and r = 0.89; P less than 0.005, respectively). The potential doubling time and production rate were accordingly similar. These data indicate that in vivo BrdUrd infusion coupled with flow cytometry measurements can be performed in clinical settings and that this method is reliable. It could be used for kinetic studies in clinical trials aimed at evaluating the prognostic relevance of proliferative parameters and for planning radio- and/or chemotherapy.

Measurement of cell kinetics in human tumours in vivo using bromodeoxyuridine incorporation and flow cytometry.

The proliferative potential of human solid tumours, in vivo, was investigated using bromodeoxyuridine (BrdUrd) incorporation and flow cytometry (FCM). Patients with solid tumours from a variety of sites were injected with 500 mg BrdUrd, intravenously, several hours prior to biopsy or surgical excision. The labelling index (LI), duration of S-phase (Ts) and thus the potential doubling time (Tpot) could be measured within 24 h of sampling. The results show that both the LI and Ts vary greatly between tumours (Ts ranges from 5.8 to 30.7 h). However, within this study of 26 evaluable patients, tumours of the same tissue origin tended to have similar Ts values. Melanomas had the shortest Ts (8.8 h), nine patients with head and neck cancer had Ts values ranging from 5.8 to 18.8 h (median 12.5 h). The longest Ts values (24 h) were found in lung and rectum. The estimates of Tpot ranged from only 3.2 days in an oat cell carcinoma to 23.2 days in a lymphoma. The striking feature of the study was that 38% of the tumours had a potential doubling time of 5 days or less. We found no relationship between proliferation and histopathological differentiation or DNA ploidy. It should now be possible to assess the prognostic significance of pretreatment cell kinetic measurements which may, in the future, aid in the selection of treatment schedules for the individual patient.

Interaction between X-ray and alpha-particle damage in V79 cells.

V79 cells have been exposed to X-rays or 238Pu alpha-particles or to X-rays following priming alpha-particle doses of 0.5, 2 or 2.5 Gy. The survival curve for exposure to alpha-particles was exponential with a D0 of 0.89 Gy. Following exposure to priming alpha-particle doses the resulting X-ray survival curves had the same slope as the single dose X-ray curve, but a reduced shoulder. For alpha-particle priming doses of 0.5 and 2 Gy this reduction was the same as for the same X-ray doses. 2.5 Gy alpha-particles reduced the subsequent X-ray curve Dq to almost zero. alpha-particles do cause damage capable of interacting with X-ray damage.