Conditions associated with extreme hyperferritinaemia (>3000 µg/L) in adults.

BACKGROUND: The clinical significance of extreme hyperferritinaemia has come under scrutiny with the increasing recognition of haemophagocytic lymphohistiocytosis (HLH) in adults. Most studies of hyperferritinaemia have focused on serum ferritin greater than 1000 µg/L, often in ambulatory patients. The conditions associated with more extreme hyperferritinaemia are poorly understood. AIMS: To examine conditions associated with extreme hyperferritinaemia greater than 3000 µg/L in acutely ill adults at a quaternary care hospital. METHODS: Patients with serum ferritin greater than 3000 µg/L at Vancouver General Hospital between 1 August 2011 and 1 August 2012 were identified. Those over 18 years of age and with clinical data available were included in the study. RESULTS: Eighty-three subjects were identified. Twenty-one cases (25%) were due to transfusional iron overload, 16 (19%) due to liver disease and 15 (18%) due to mixed factors. Haemophagocytic lymphohistiocytosis (HLH) was diagnosed in six of 83 patients (7%) with ferritin greater than 3000 µg/L, but six of eight patients (75%) with ferritin greater than 20 000 µg/L. CONCLUSIONS: Extreme hyperferritinaemia greater than 3000 µg/L is uncommon in adult patients. The highest serum ferritin values are seen in HLH, but the differential diagnosis for serum ferritin greater than 3000 µg/L remains broad with iron overload and liver disease being the most common causes.

Predictive performance of Acute Physiological and Chronic Health Evaluation releases II to IV: a single New Zealand centre experience.

There is debate in Australia and New Zealand around the appropriate use of illness severity scoring systems in Australasian intensive care units. The international benchmark is the Acute Physiological and Chronic Health Evaluation (APACHE) system. In order to compare the performance of recent APACHE releases, we audited 2080 sequential patients admitted between 1 January 2006 and 31 March 2008 to the Middlemore Hospital intensive care unit, Auckland, New Zealand. We compared the predictive performance of the proprietary APACHE II, IIIh, IIIj and IV releases, and the performance of a 'localised' version of APACHE II containing re-estimated coefficients derived from a legacy dataset (7703 sequential patients admitted between 1 January 1997 and 31 December 2005). Discrimination assessed by receiver operating characteristic curves was highest with the APACHE III and IV releases, and significantly better than the APACHE II releases. Calibration assessed by the Hosmer-Lemeshow statistic was poor with all releases, although it was best with APACHE IV and 'localised' version of the APACHE II release. Overall accuracy assessed by the Brier Mean Probability score and Shapiro's R statistic was best with APACHE IV. Our study suggests the possibility of improved prediction in moving to APACHE IV from older releases, although broader multicentre study within the Australian and New Zealand critical care community is warranted. Our study also suggests localisation of the APACHE system offers further opportunity to improve prediction, although these improvements may not be major without ground-up development of a new risk prediction model within our local critical care setting.

The impact of escalating regulatory requirements on the conduct of clinical research.

A discussion of the impact of escalating regulatory requirements is provided, from the point of view of the administration of the institutional review board of an academic institution, and from clinical investigators who conduct studies at that same institution. Current and anticipated future issues are discussed.

Plasma from poorly mobilizing human subjects inhibits cytokine-induced murine blood stem-cell mobilization.

BACKGROUND: Cytokine-induced mobilization of hematopoietic stem/progenitor cells to the circulation facilitates efficient harvest of blood stem cells by leukapheresis. Up to 30% of autologous, and 10-20% of allogeneic blood stem-cell donors respond poorly to mobilizing cytokines and preliminary studies implicated a circulating inhibitor of mobilization. METHODS: In this study, plasma from 11 allogeneic and 23 autologous stem cell donors was assayed for inhibition of mobilization in mice. RESULTS: There were significant correlations between CD34(+) cells collected/kg human donor weight and spleen weight, CD34(+) CD45(+) cells, GMCFC and HPP-CFC per spleen in murine recipients of these plasma samples. Overall, there was a positive association between transforming growth factor beta (TGF-beta) levels and CD34(+) cells per liter of blood processed (LBP). However, when arbitrarily segregated into good versus poor mobilizers, based on less or greater than 15 million CD34(+) cells collected per LBP, the majority (64%) of normal donors were good mobilizers. The majority of the poor mobilizers (83%) were patients. For a subset of 12 individuals whose plasma strongly inhibited mobilization in the mouse, a significant positive correlation of the extent of inhibition with TGF-beta levels was found. For 11 individuals whose plasma, based on colony assays, enhanced mobilization when injected into mice, no correlation with TGF-beta levels was evident. DISCUSSION: Elevated plasma TGF-beta levels in some stem-cell donors may be associated with poor stem-cell mobilization. It remains to be determined whether elevation of TGF-beta levels is a cause of, or a compensatory response to, poor mobilization.

Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.

Oligonucleotides offer the potential to manipulate gene expression in targeted cells which might be exploitable for therapeutic benefit. The effects of combining a phosphorothioate oligonucleotide OL(1) p53, which transiently down-regulates p53 levels, with an anthracycline, Idarubicin, on the growth of wild-type p53 WMN gene-expressing lymphoma cells was evaluated. Fluorescent OL(1) p53, was used to demonstrate oligonucleotide uptake and retention by the WMN cells. Uptake was maximal at 24 hours and compared to baseline (0 hours) increasing apoptotic cells were evident in WMN cells treated with OL(1) (1 microM) alone and in combination with Idarubicin (0.2 nM) for 24 to 48 hours. In cells treated with OL(1) p53 and Idarubicin, truncated p53 message of a predicted 201 base pair length based on RNAase H cleavage of the OL(1) p53-p53 mRNA heteroduplex was detected after 7 hours of incubation. The message for p53 was transiently downregulated as detected by RT-PCR analysis at 24 hours, and protein levels transiently reduced at 36 hours, as shown by a quantitative Western blot. Corresponding to these events, the growth of WMN cells ceased after 48 hours in the concurrent presence of OL(1) p53 and Idarubicin and, the lymphoma cells were dead after 72 hours. No reduction in hematopoietic colony forming cell capacity of similarly treated hematopoietic progenitor cells harvested from cytokine-mobilized blood by apheresis was observed. Therefore, synergistic cytotoxicity of Idarubicin for lymphoma cells treated with an oligonucleotide targeting p53 message was demonstrated at oligonucleotide and Idarubicin concentrations which were minimally toxic to hematopoietic progenitor cells. This approach offers new opportunities for purging of lymphoma cells from hematopoietic harvests and systemic lymphoma therapy.

Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes.

OBJECTIVE: In normal adults, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to a glucose load, especially in those with the poorest glucose tolerance. We hypothesized that an acute catalytic dose of fructose would also improve glucose tolerance in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Five adults with type 2 diabetes underwent an oral glucose tolerance test (OGTT) on two separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without the addition of 7.5 g fructose (OGTT + F or OGTT - F), in random order. Arterialized blood samples were collected from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 3 h afterward. RESULTS: The area under the curve (AUC) of the plasma glucose response was reduced by fructose administration in all subjects; the mean AUC during the OGTT + F was 14% less than that during the OGTT - F (P < 0.05). The insulin AUC was decreased 21% with fructose administration (P = 0.2). Plasma glucagon concentrations declined similarly during OGTT - F and OGTT + F. The incremental AUC of the blood lactate response during the OGTT - F was approximately 50% of that observed during the OGTT + F (P < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTTs. CONCLUSIONS: Low-dose fructose improves the glycemic response to an oral glucose load in adults with type 2 diabetes, and this effect is not a result of stimulation of insulin secretion.

Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention--results on smoking.

BACKGROUND: No long-term impact has yet been observed with the use of the social-influences approach to school-based smoking prevention for youth. However, whether this lack of impact is due to methodologic problems with the studies or to the failure of the interventions is unclear. The Hutchinson Smoking Prevention Project (HSPP), conducted from September 1984 through August 1999, aimed to attain the most rigorous randomized trial possible to determine the long-term impact of a theory-based, social-influences, grade 3-12 intervention on smoking prevalence among youth. METHODS: Forty Washington school districts were randomly assigned to the intervention or to the control condition. Study participants were children enrolled in two consecutive 3rd grades in the 40 districts (n = 8388); they were followed to 2 years after high school. The trial achieved high implementation fidelity and 94% follow-up. Data were analyzed with the use of group-permutation methods, and all statistical tests were two-sided. RESULTS: No significant difference in prevalence of daily smoking was found between students in the control and experimental districts, either at grade 12 (difference [Delta] = 0.2%, 95% confidence interval [CI] = -4.6% to 4.4%, and P =.91 for girls; Delta = 0.3%, 95% CI = -5.0% to 5.5%, and P =.89 for boys) or at 2 years after high school (Delta = -1.4%, 95% CI = -5.0% to 1.6%, and P =.38 for girls; Delta = 2.6%, 95% CI = -2.5% to 7.7%, and P =.30 for boys). Moreover, no intervention impact was observed for other smoking outcomes, such as extent of current smoking or cumulative amount smoked, or in subgroups that differ in a priori specified variables, such as family risk for smoking. CONCLUSION: The rigor of the HSPP trial suggests high credence for the intervention impact results. Consistent with previous trials, there is no evidence from this trial that a school-based social-influences approach is effective in the long-term deterrence of smoking among youth.

The Hutchinson Smoking Prevention Project trial: design and baseline characteristics.

INTRODUCTION: This paper describes the experimental design and baseline characteristics of the Hutchinson Smoking Prevention Project (HSPP), a 15-year trial to determine to what extent a grade 3-12 school-based tobacco use prevention intervention can deter tobacco use throughout and beyond high school. DESIGN: Trial design features include use of the school district as the unit of randomization, inclusion of the school district's entire enrollment of 3rd graders, long-term follow-up of the entire original cohort, and sample size and evaluation methods that account for the group-randomization and intraclass correlation of endpoints within school districts. The theory-based intervention is teacher-led and includes grade 3-10 curriculum units, teacher training, grade 9-12 tobacco use cessation materials, and high school staff newsletters. RESULTS: Baseline data were collected on the trial cohort of 8388 children and their parents and on the 40 collaborating school districts and communities. A comparison of the distribution of baseline variables between experimental conditions shows good balance. CONCLUSIONS. The HSPP trial's experimental design will provide a rigorous test of the intervention. The balance in baseline variables between the experimental and control conditions will help provide assurance that the trial's intervention effectiveness results, scheduled for publication in 2000, will be unbiased.

Experimental design and methods for school-based randomized trials. Experience from the Hutchinson Smoking Prevention Project (HSPP).

Nonadherence to accepted design principles for randomized trials has been a limitation of school-based intervention research. Designed to overcome these limitations, the Hutchinson Smoking Prevention Project (HSPP) is a 15-year randomized trial to determine the extent to which a school-based (grades 3-12) tobacco use prevention intervention can deter youth tobacco use throughout and beyond high school. This paper presents the HSPP experimental design, together with methods for its implementation, and an evaluation of the degree to which HSPP has adhered to principles of randomized trials. Results from the experimental design and its conduct include (1) a recruitment rate of 97.6% (40 of 41 targeted school districts), (2) full and active participation for the trial's duration by 100% of the 40 school districts recruited, (3) implementation by virtually all teachers (99%+), with 86% implementation fidelity, and (4) outcome determination for 94.3% (7910) of 8388 original study participants identified 12 years previously at baseline. The high degree of rigor achieved by the HSPP experimental design ensures confidence in the trial's soon-to-be available intervention effectiveness results. Equally important, for future school-based trials, the HSPP design and its execution have illustrated that school-based research can adhere to the principles of rigorous randomized trials, with high rates of implementation, and very high rates of recruitment, maintenance, and follow-up of study participants, even for studies with decade-long follow-up periods. Rigor in school-based trials can be achieved through a combination of (1) commitment to the principles of randomized trials, (2) attention to the special challenges of trials specific to the school setting, (3) adoption and meticulous execution of proven methods for trial conduct, and (4) establishment at the outset of principles for maintaining positive collaborative relationships with participating school districts for the duration of the trial. These findings are important in light of the great potential for using the nation's schools to access youth for health promotion/risk-factor prevention.

Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults.

In animal models, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to the glucose load. Therefore, we examined the effect of fructose on glucose tolerance in 11 healthy human volunteers (5 men and 6 women). Each subject underwent an oral glucose tolerance test (OGTT) on 2 separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without 7.5 g fructose (OGTT+F or OGTT-F), in random order. Arterialized blood samples were obtained from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 2 h afterward. The area under the curve (AUC) of the change in plasma glucose was 19% less in OGTT+F vs. OGTT-F (P: < 0.05). Glucose tolerance was improved by fructose in 9 subjects and worsened in 2. All 6 subjects with the largest glucose AUC during OGTT-F had a decreased response during OGTT+F (31 +/- 5% decrease). The insulin AUC did not differ between the 2 studies. Of the 9 subjects with improved glucose tolerance during the OGTT+F, 5 had smaller insulin AUC during the OGTT+F than the OGTT-F. Plasma glucagon concentrations declined similarly during OGTT-F and OGTT+F. The blood lactate response was about 50% greater during the OGTT+F (P: < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTT. In conclusion, low dose fructose improves the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response. Fructose appears most effective in those normal individuals who have the poorest glucose tolerance.

Concurrent partial body radiation prevents cytokine mobilization of blood progenitor cells: an effect mediated by a circulating factor.

Mobilization of stem and progenitor cells into blood, which facilitates the collection of blood-derived autograft and allograft products, can be accomplished with administration of myelosuppressive chemotherapy, hematopoietic growth factors, or both. Autologous donor indifference to mobilization attempts has been correlated with prior administration of chemotherapy and radiation therapy. To investigate whether concurrent administration of radiation therapy inhibits mobilization, five daily injections of a potent combination of mobilizing cytokines, 500 U/kg erythropoietin (EPO) plus 15 microg/kg G-CSF, were administered each morning to Balb/c mice. Each afternoon, a 2 Gy fraction of Co-60 radiation was administered to either the lower limb or the upper or lower hemibody. Each day, mice were necropsied, and blood stem cell mobilization was determined by assaying the number of hematopoietic colony-forming cells in the blood and in the spleen. Unirradiated cytokine-injected mice showed a significant mobilization effect evident as increased colony-forming cells in blood and spleen compared with saline-injected unirradiated controls. The irradiated mice showed markedly inhibited or absent mobilization regardless of the part of the body irradiated. To investigate the mechanism of radiation-induced mobilization inhibition, heparinized plasma was obtained from mice whose lower bodies were irradiated with 2 Gy 18 h previously, and 0.5 ml was injected i.v. into intact mice 10 min before they received 15 microg/kg G-CSF and 500 U/kg EPO. Unlike mice that received G-CSF + EPO only and showed mobilization of progenitors from marrow to spleen, recipients of plasma from irradiated mice before and after cytokine administration showed significantly reduced mobilization of progenitors. Thus, radiation-induced inhibition of stem cell mobilization is mediated by an unidentified circulating factor.

Increased hematopoietic progenitor cell maintenance in long-term bone marrow cultures containing minimal numbers of contaminating breast cancer cells.

The maintenance of hematopoietic progenitor cells as assayed in the mixed colony (CFU-GEMM) assay in human long-term bone marrow cultures was compared between normal allogeneic marrow transplantation donor collections and those from candidates for high-dose therapy and autologous bone marrow transplantation (ABMT). To be eligible for ABMT, patients were required to have a histologically normal appearing bone marrow and therefore any tumor contamination was at minimal levels and detectable only after evaluation of the cultured harvests. Marrow from 15 normal donors, 36 patients with breast cancer, and 30 patients with Hodgkin's disease was evaluated. The number of mononuclear cells placed in culture was standardized. In all groups, significantly more progenitor cells were recovered at 4-6 weeks of culture that at 12-14 weeks. At 4-6 and 12-14 weeks, there were no significant differences in the number of progenitor cells recovered from the cultures of normal donors and tumor negative cultures of breast cancer or Hodgkin's disease patients. However, following 4-6 and 12-14 weeks of culture, progenitor cell numbers of cultures which contained breast cancer cells were significantly higher than the pooled values for cultures from the concurrent normal controls, and those from breast cancer and Hodgkin's disease patients with tumor negative cultures. These results suggest that minimal breast cancer cell contamination of the bone marrow can influence the production of marrow progenitor cells. Exposure to prior chemotherapy or radiation therapy does not appear to be the cause of this effect. The most likely mechanism is the local production of cytokines by the tumor cells, although a process involving direct adhesive contact of the tumor cells with hematopoietic cells, which is sometimes observed in semisolid cultures, cannot be excluded.

Comparison of molecular cytokeratin 19 reverse transcriptase polymerase chain reaction (CK19 RT-PCR) and immunocytochemical detection of micrometastatic breast cancer cells in hematopoietic harvests.

Detection of small numbers of breast cancer cells in patient blood, aphereses, and bone marrow has become increasingly important as data have accumulated showing immunocytochemically (ICC) positive tumor cells in up to 50% of women with stage I and II breast cancer, who were initially thought to be cured of their disease but later relapsed. The ability to rule out the presence of micrometastatic disease at any stage of the clinical management protocol, whether before, during, or after therapy, would provide a useful monitoring and diagnostic tool for both the clinician and the scientist. Monitoring for the presence of minimal residual disease (MRD) is traditionally performed using ICC. A more recently established RT-PCR technique uses a molecular marker (the presence of the cytokeratin 19, CK19, transcript) to identify MRD in patient samples, with a level of sensitivity reported to be one tumor cell in 10(6) nucleated cells. This level of sensitivity is generally higher than that claimed for ICC. Based on the discriminating results of this first study, a number of laboratories have evaluated this technique for its diagnostic potential. Results from several laboratories showed a higher than expected false positive rate due to a variety of identified and unidentified sources. Therefore, the current study was designed to achieve two aims: to establish the level of sensitivity and specificity of the RT-PCR technique and to dissect out the possible variables that may contribute to a false positive result using this molecular approach. To accomplish the first goal, two simulation strategies were used, limited dilution of tumor cells into apheresis harvests and semi-quantitative PCR using stepwise dilutions of extracted RNA from tumor cells in apheresis harvests. The second goal was accomplished by performing sequential blood drawings with variably timed sample processing to identify some of the more common variables (time, anticoagulant, sample sequence) that may contribute to false positive results. Of three variables investigated, including type of blood preservative, sequence of blood tube collection, and time point of sample processing, each may contribute to a false positive result. In addition to these problems, known events involving illegitimate transcription of specific genes nonspecifically in tissue is also a potential source of false positive results. These issues may be further compounded by lack of attention to the more common methodologic problems encountered in any laboratory using the PCR technique. However, recommendations can be developed for the effective application of this technique, whose greatest strength is the demonstration of tumor negativity of the sample.

Altered in vivo and in vitro behavior of butanol-modified bone marrow cells.

Cell-surface molecules, particularly glycoconjugates, appear to be involved in the in vivo homing of hematopoietic stem and progenitor cells and in their interactions with hematopoietic stromal cells. To study the role of cell-surface molecules of hematopoietic stem cells, the expression of some surface molecules was altered using n-butanol treatment. We examined the in vivo and in vitro colony-forming abilities, in vivo homing patterns, and cell-surface lectin receptor expression of butanol-treated bone marrow cells (BMC) from BDF1 mice. The butanol-treated/-modified BMC formed an increased number of significantly larger spleen colonies (CFU-S) in lethally irradiated (1050 rad) mice. The butanol-treated BM formed significantly larger in vitro granulocyte-macrophage progenitor cell colonies (CFU-C) and in vitro fibroblastic colonies (CFU-F), although the number of such colonies was not significantly altered. The homing pattern of butanol-treated BMC was studied by comparing the distribution in lethally irradiated mice of intravenously injected 51Cr-labeled butanol-treated BMC with that of untreated cells. The butanol treatment altered the in vivo homing pattern of these cells, with increased homing to liver, spleen, and bone marrow and decreased homing to thymus, lung, and mesenteric lymph nodes. Flow-cytometric analyses of butanol-treated BMC showed an increased expression of receptors for the lectins concanavalin A (conA) and wheat germ agglutinin (WGA), indicating an increased expression of mannosyl and galactosyl residues, which are known sugar moieties in hematopoietic stem/progenitor cell homing. These results indicate that cell surface modifications can influence homing and growth of transplanted BMC and that butanol treatment is a useful tool for studying the mechanisms of hematopoietic stem/progenitor cell homing in vivo and for further characterizing the molecules involved in this process.

Culture methods for the detection of minimal tumor contamination of hematopoietic harvests: a review.

The evaluation of minimal residual disease in patients and hematopoietic cell grafts is of considerable importance for staging disease, determining the response to treatment, and monitoring the efficiency of ex vivo purging or positive selection procedures. The most widely used techniques are immunocytochemical staining and the polymerase chain reaction; however, these assays do not measure the viability or clonogenic capacity of the detected cells. For this purpose, a culture technique must be used. This paper reviews the status, advantages, and limitations of this approach and the detection of tumor cells in bone marrow and peripheral blood.

Re-thinking the analysis of intergenerational social mobility: a comment on John W. Fox's "Social class, mental illness, and social mobility".

The method of analyzing social mobility described by Fox (1990) is flawed in its adjustment for between-group differences in destination status when estimating the extent of the mentally ill's mobility as compared with the general population. Use of the recommended model with hypothetical data sets resulted in a significant finding when no overall upward or downward mobility occurred, and a non-significant result when the downward mobility of a psychotic group was contrived to be massive. An alternative model for the test of group differences in mobility is suggested within the framework of log-linear analysis commended by Fox (1990). This method indicated significantly more downward and less upward mobility in mentally ill groups when data from four studies were re-analyzed. We conclude that the weight of evidence from published studies supports the notion of social selection-drift, although this does not imply the inconsequence of social factors in the aetiology of schizophrenia (and other psychoses) or in its prognosis and occupational consequences.

Generation differences in hospital inpatient care of children aged 1 to 5 years.

STUDY OBJECTIVE: To describe differences in childhood hospital admissions at ages 1 to 5 years in two generations, and to compare the intergenerational differences in risks of admission. DESIGN: Information was taken from a longitudinal birth cohort study of a national sample and their firstborn offspring. SETTING: England, Wales, and Scotland. SUBJECTS: the 5022 birth cohort members for whom information is available from ages 1 to 5 years and their 2205 firstborn offspring. MEASUREMENTS AND MAIN RESULTS: Data comprised reports of hospital admissions, which were checked with hospitals. Mean numbers of days spent in hospital were fewer in the offspring generation than in their parents, but the proportion ever admitted fell by only 1%. Low birth weight babies (< 2500 g), who comprised 6% of cohort births and 7% of the following generation, used a high proportion of all inpatient time in the offspring population, rising from 3% to 14% of all days of admission. CONCLUSIONS: Compared with the early years of the NHS, published statistics show that the effectiveness of paediatric care has improved greatly, and that childhood mortality and the risk of serious illness have decreased significantly. This study reports intergenerational changes in the reasons for hospital admission and shows, with the benefit of good denominator data, that although there was only a small intergenerational decrease in the proportion of children treated in hospital, there was a large reduction in the time spent in hospital and an increase in admissions of children of low birth weight.

Accumulation of factors influencing respiratory illness in members of a national birth cohort and their offspring.

STUDY OBJECTIVE: The aim was to investigate predictors of childhood lower respiratory tract illness in two generations, and predictors of adult lower respiratory disorders in the first generation. DESIGN: Data on respiratory health and environmental factors from a national birth cohort study were examined from birth to 36 years. Data were also collected on the parents of the subjects and on the subjects' first born offspring from birth to eight years. Main outcome measures were: reports of lower respiratory tract illness before 2 years; lower respiratory tract illness of a week or more between age 20 and 36 years; regular phlegm production at 25 and 36 years; reports of wheeze or asthma at age 36 years; peak expiratory flow rate (PEFR) at age 36 years measured by nurses during home visits; and mothers' reports of lower respiratory illness in first born offspring before 2 years. SUBJECTS: Subjects were a sample of 5362 single, legitimate births taken from all those occurring in England, Wales, and Scotland in one week in 1946, and studied regularly from birth to age 43 years. Data on the subjects' parents and on their 1676 first offspring born while they were aged 19-25 years were also collected. MAIN RESULTS: Lower respiratory tract illness before 2 years fell from 25% in the population born in 1946 to 13% in their first born offspring. In those born in 1946, poor home environment, parental bronchitis, and atmospheric pollution were the best predictors of lower respiratory illness before 2 years, and these three factors and childhood lower respiratory illness and later smoking were the best predictors of adult lower respiratory tract problems. Risk factors for lower respiratory illness in the offspring were manual social class, parental and grandparental lower respiratory disease, and parental smoking. CONCLUSIONS: Risks for adult lower respiratory problems accumulated in childhood through illness, poor social circumstances, and atmospheric pollution. Smoking exacerbated early life risks and was an independent risk factor. In the offspring generation, parental smoking was a risk factor for early life chest illness, together with parental illness and low social class. Reduction of prevalence in the offspring generation was probably accounted for by improvement in home circumstances, reduced atmospheric pollution, and lower rates of parental lower respiratory illness, but current rates of smoking seem likely to prevent much further reduction in early life lower respiratory illness, and thus in this aspect of risk for subsequent adult lower respiratory problems. The accumulation of risk in childhood and adolescence for later adult problems implies a long time scale for the reduction of adult lower respiratory disorders.

Loss and representativeness in a 43 year follow up of a national birth cohort.

STUDY OBJECTIVE: The aim was to describe rates of loss and assessment of representativeness during 43 years of a national birth cohort study. DESIGN: The study population is a class stratified random sample of all single, legitimate births that occurred during one single week in 1946; it has been studied at regular intervals, so far to 1989. MAIN RESULTS: Losses through death and emigration were comparable to those in the national population of the same age. Response rates from the population resident in Britain have remained high, and the responding population is in most respects representative of the native population born in the early postwar years. Response rates within some serious physical illnesses did not differ from those of the healthy population. CONCLUSIONS: The continuing high response rate and representativeness of this national birth cohort is likely to be the result of home based data collections and of the regular contact to provide feedback of information and to check addresses of the study population.