Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages

In addition to its' established metabolic and cardioprotective effects, glucagon-like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP-1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4-12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80(++) macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4-treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting.

Systemic recruitment of osteoblastic cells in fracture healing

We hypothesise that following a bone fracture there is systemic recruitment of bone forming cells to a fracture site. A rabbit ulnar osteotomy model was adapted to trace the movement of osteogenic cells. Bone marrow mesenchymal stem cells from 41 NZW rabbits were isolated, culture-expanded and fluorescently labelled. The labelled cells were either re-implanted into the fracture gap (Group A); into a vein (Group B); or into a remote tibial bone marrow cavity 48 h after the osteotomy (Group C) or 4 weeks before the osteotomy was established (Group D), and a control group (Group E) had no labelled cells given. To quantify passive leakage of cells to an injury site, inert beads were also co-delivered in Group B. Samples of the fracture callus tissue and various organs were harvested at discrete sacrifice time-points to trace and quantify the labelled cells. At 3 weeks following osteotomy, the number of labelled cells identified in the callus of Group C, was significantly greater than following IV delivery, Group B, and there was no difference in the number of labelled cells in the callus tissues, between Groups C and A, indicating the labelled bone marrow cells were capable of migrating to the fracture sites from the remote bone marrow cavity. Significantly fewer inert beads than labelled cells were identified in Group B callus, suggesting some of the bone-forming cells were actively recruited and selectively chosen to the fracture site, rather than passively leaked into the circulation and to bone injury site. This investigation supports the hypothesis that some osteoblasts involved in fracture healing were systemically mobilised and recruited to the fracture from remote bone marrow sites. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Characterization of outward K(+) currents in isolated smooth muscle cells from sheep urethra.

The perforated-patch technique was used to measure membrane currents in smooth muscle cells from sheep urethra. Depolarizing pulses evoked large transient outward currents and several components of sustained current. The transient current and a component of sustained current were blocked by iberiotoxin, penitrem A, and nifedipine but were unaffected by apamin or 4-aminopyridine, suggesting that they were mediated by large-conductance Ca(2+)-activated K(+) (BK) channels. When the BK current was blocked by exposure to penitrem A (100 nM) and Ca(2+)-free bath solution, there remained a voltage-sensitive K(+) current that was moderately sensitive to blockade with tetraethylammonium (TEA; half-maximal effective dose = 3.0 +/- 0.8 mM) but not 4-aminopyridine. Penitrem A (100 nM) increased the spike amplitude and plateau potential in slow waves evoked in single cells, whereas addition of TEA (10 mM) further increased the plateau potential and duration. In conclusion, both Ca(2+)-activated and voltage-dependent K(+) currents were found in urethral myocytes. Both of these currents are capable of contributing to the slow wave in these cells, suggesting that they are likely to influence urethral tone under certain conditions.

The complex array of bradykinin-related peptides (BRPs) in the peptidome of pickerel frog (Rana palustris) skin secretion is the product of transcriptional economy.

Previous peptidomic analyses of the defensive skin secretion from the North American pickerel frog, Rana palustris, have established the presence of canonical bradykinin and multiple bradykinin-related peptides (BRPs). As a consequence of the multiplicity of peptides identified and their diverse primary structures, it was speculated that they must represent the products of expression of multiple genes. Here, we present unequivocal evidence that the majority of BRPs (11/13) identified in skin secretion by the peptidomic approach can be generated by differential site-specific protease cleavage from a single common precursor of 321 amino acid residues, named skin kininogen 1, whose primary structure was deduced from cloned skin secretion-derived cDNA. The organization of skin kininogen 1 consists of a hydrophobic signal peptide followed by eight non-identical domains each encoding a single copy of either canonical bradykinin or a BRP. Two additional splice variants, encoding precursors of 233 (skin kininogen 2) or 189 amino acid residues (skin kininogen 3), were also cloned and were found to lack BRP-encoding domains 5 and 6 or 4, 5 and 6, respectively. Thus, generation of peptidome diversity in amphibian defensive skin secretions can be achieved in part by differential protease cleavage of relatively large and multiple-encoding domain precursors reflecting a high degree of transcriptional economy.

Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization.

Purpose: To investigate the association of cardiovascular risk factors and inflammatory markers with neovascular age-related macular degeneration (AMD). Design: Cross-sectional case-control study. Participants: Of the 410 of the =65-year-old community sample invited to attend, 205 participated (50% response rate). Of the 215 clinic attendees who were invited to participate, 212 agreed to take part (98% response rate). A diagnosis of neovascular AMD in at least one eye was made in 193 clinic attendees and 2 of the community sample. Methods: Clinic and community participants underwent a detailed ophthalmic examination with fundus imaging, were interviewed for assessment of putative risk factors, and provided a blood sample. Analysis included levels of serum lipids, intercellular adhesion molecule 1 (ICAM), vascular cellular adhesion molecule (VCAM), and C-reactive protein (CRP). All participants were classified by fundus image grading on the basis of the eye with more severe AMD features. Main Outcome Measure: Neovascular AMD. Results: There were 195 participants with choroidal neovascularization in at least one eye, 97 nonneovascular AMD participants, and 115 controls (no drusen or pigmentary irregularities in either eye). In confounder-adjusted logistic regression, a history of cardiovascular disease was strongly associated with neovascular AMD (odds ratio [OR], 7.53; 95% confidence interval [CI], 2.78-20.41). Cigarette smoking (OR, 3.71; 95% CI, 1.25-11.06), being in the highest quartile of body mass index (OR, 3.82; 95% CI, 1.22-12.01), stage 2 hypertension (OR, 3.21; 95% CI, 1.14-8.98), and being in the highest quartile of serum cholesterol (OR, 4.66; 95% CI, 1.35-16.13) were positively associated with neovascular AMD. There was no association between AMD status and serum CRP, ICAM, or VCAM. Conclusions: Our results suggest that cardiovascular disease plays an etiological role in the development of choroidal neovascularization in a proportion of older adults and highlight the importance of control of blood pressure and cholesterol, avoidance of smoking, and maintenance of a normal body weight. © 2008 American Academy of Ophthalmology.

Adrenomedullin Gene Delivery is Cardio-protective in a Model of Chronic Nitric Oxide Deficiency Combining Pressure Overload, Oxidative Stress and Cardiomyocyte Hypertrophy

BACKGROUND/AIMS:
Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of the vasodilator peptide, adrenomedullin (AM) and its receptors is augmented in cardiomyocytes, indicating that the myocardial AM system may be activated in response to pressure loading and ischemic insult to serve a counter-regulatory, cardio-protective role. The study examined the hypothesis that oxidative stress and hypertrophic remodeling in NO-deficient cardiomyocytes are attenuated by adenoviral vector-mediated delivery of the human adrenomedullin (hAM) gene in vivo.

METHODS:
The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 15mg . kg(-1) . day(-1)) was given to rats for 4 weeks following systemic administration via the tail vein of a single injection of either adenovirus harbouring hAM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM-4F2), or for comparison, adenovirus alone (Ad.Null) or saline. Cardiomyocytes were subsequently isolated for assessment of the influence of each intervention on parameters of oxidative stress and hypertrophic remodelling.

RESULTS: Cardiomyocyte expression of the transgene persisted for > or =4 weeks following systemic administration of adenoviral vector. In L-NAME treated rats, relative to Ad.Null or saline administration, Ad.CMV-hAM-4F2 (i) reduced augmented cardiomyocyte membrane protein oxidation and mRNA expression of pro-oxidant (p22phox) and anti-oxidant (SOD-3, GPx) genes; (ii) attenuated increased cardiomyocyte width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP) genes; (iii) did not attenuate hypertension.

CONCLUSIONS: Adenoviral vector mediated delivery of hAM resulted in attenuation of myocardial oxidative stress and hypertrophic remodelling in the absence of blood pressure reduction in this model of chronic NO-deficiency. These findings are consistent with a direct cardio-protective action in the myocardium of locally-derived hAM which is not dependant on NO generation.

Effectiveness of different footbath solutions in the treatment of digital dermatitis in dairy cows

Three experiments were conducted to test the effectiveness of different footbath solutions and regimens in the treatment of digital dermatitis (DD) in dairy cows. During the study, groups of cows walked through allocated footbath solutions after milking on 4 consecutive occasions. All cows were scored weekly for DD lesion stage on the hind feet during milking. A “transition grade” was assigned on the basis of whether the DD lesions improved (1) or deteriorated or did not improve (0) from week to week. This grade per cow was averaged for all cows in the group. In experiment 1, 118 cows were allocated to 1 of 3 footbath treatments for 5 wk: (1) 5% CuSO4 each week, (2) 2% ClO- each week, or (3) no footbath (control). The mean transition grade, and proportion of cows without DD lesions at the end of the trial were significantly higher for treatment 1 above (0.36, 0.13, and 0.11, respectively; standard error of the difference, SED=0.057). In experiment 2, 117 cows were allocated to 1 of 4 footbath treatment regimens for 8 wk: (1) 5% CuSO4 each week, (2) 2% CuSO4 each week, (3) 5% CuSO4 each fortnight, or (4) 2% CuSO4 each fortnight. For welfare reasons, cows allocated to the weekly and fortnightly footbath regimens had an average prevalence of >60% and =25% active DD at the start of the trial, respectively. Significantly more cows had no DD lesions (0.53 vs. 0.36, respectively; SED=0.049), and the mean transition grade of DD lesions was higher in the 5% compared with the 2% weekly CuSO4 treatment (0.52 vs. 0.38, respectively; SED=0.066). Similarly, significantly more cows had no DD lesions in the 5% compared with the 2% fortnightly CuSO4 treatments (0.64 vs. 0.47, respectively; SED=0.049). In experiment 3, 95 cows were allocated to 1 of 3 footbath treatments: (1) each week alternating 5% CuSO4 with 10% salt water, (2) each week alternating 5% CuSO4 with water, or (3) 5% CuSO4 each fortnight (control). After 10 wk, more cows had no DD in the salt water treatment than in the control treatment (0.35 vs. 0.26, respectively; SED=0.038), but levels of active lesions were higher for this treatment than in the other 2 treatments (0.17, 0.00, and 0.13, respectively; SED=0.029). Treatment did not affect mean transition grade of DD lesions. In conclusion, CuSO4 was the only footbath solution that was consistently effective for treatment of DD. In cases when DD prevalence was high, a footbath each week using 5% CuSO4 was the most effective treatment.

Occupation and Breast Cancer: a Canadian Case-Control Study

A local collaborative process was launched in Windsor, Ontario, Canada to explore the role of occupation as a risk factor for cancer. An initial hypothesis-generating study found an increased risk for breast cancer among women aged 55 years or younger who had ever worked in farming. On the basis of this result, a 2-year case–control study was undertaken to evaluate the lifetime occupational histories of women with breast cancer. The results indicate that women with breast cancer were nearly three times more likely to have worked in agriculture when compared to the controls (OR = 2.80 [95% CI, 1.6–4.8]). The risk for those who worked in agriculture and subsequently worked in automotive-related manufacturing was further elevated (OR = 4.0 [95% CI, 1.7–9.9]). The risk for those employed in agriculture and subsequently employed in health care was also elevated (OR = 2.3 [95% CI, 1.1–4.6]). Farming tended to be among the earlier jobs worked, often during adolescence. While this article has limitations including the small sample size and the lack of information regarding specific exposures, it does provide evidence of a possible association between farming and breast cancer. The findings indicate the need for further study to determine which aspects of farming may be of biological importance and to better understand the significance of timing of exposure in terms of cancer risk.

Restorative justice conferencing for reducing recidivism in young offenders (aged 7 to 21)

Background
Restorative justice is “a process whereby parties with a stake in a specific offence resolve collectively how to deal with the aftermath of the offence and its implications for the future” (Marshall 2003). Despite the increasing use of restorative justice programmes as an alternative to court proceedings, no systematic review has been undertaken of the available evidence on the effectiveness of these programmes with young offenders. Recidivism in young offenders is a particularly worrying problem, as recent surveys have indicated
the frequency of re-offences for young offenders has ranged from 40.2% in 2000 to 37.8% in 2007 (Ministry of Justice 2009)

Objectives
To evaluate the effects of restorative justice conferencing programmes for reducing recidivism in young offenders.

Search methods
We searched the following databases up to May 2012: CENTRAL, 2012 Issue 5, MEDLINE (1978 to current), Bibliography of Nordic Criminology (1999 to current), Index to Theses (1716 to current), PsycINFO (1887 to current), Social Sciences Citation Index (1970 to current), Sociological Abstracts (1952 to current), Social Care Online (1985 to current), Restorative Justice Online (1975 to current), Scopus (1823 to current), Science Direct (1823 to current), LILACS (1982 to current), ERIC (1966 to current), Restorative Justice Online (4May 2012),WorldCat (9May 2012), ClinicalTrials.gov (19May 2012) and ICTRP (19May 2012). ASSIA,National Criminal Justice Reference Service and Social Services Abstracts were searched up to May 2011. Relevant bibliographies, conference programmes and journals were also searched.

Selection criteria
Randomised controlled trials (RCTs) or quasi-RCTs of restorative justice conferencing versus management as usual, in young offenders.

Data collection and analysis
Two authors independently assessed the risk of bias of included trials and extracted the data. Where necessary, original investigators were contacted to obtain missing information.

Main results
Four trials including a total of 1447 young offenders were included in the review. Results failed to find a significant effect for restorative justice conferencing over normal court procedures for any of the main analyses, including number re-arrested (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.59 to 1.71; P = 0.99), monthly rate of reoffending (standardised mean difference (SMD) -0.06, 95% CI -0.28 to 0.16; P = 0.61), young person’s remorse following conference (OR 1.73, 95% CI 0.97 to 3.10; P = 0.06), young person’s recognition of wrongdoing following conference (OR 1.97, 95% CI 0.81 to 4.80; P = 0.14), young person’s self-perception following conference (OR 0.95, 95% CI 0.55 to 1.63; P = 0.85), young person’s satisfaction following conference (OR 0.42, 95% CI 0.04 to 4.07; P = 0.45) and victim’s satisfaction following conference (OR 4.05, 95%CI 0.56 to 29.04; P = 0.16). A small number of sensitivity analyses did indicate significant effects, although all are to be interpreted with caution.

Authors’ conclusions
There is currently a lack of high quality evidence regarding the effectiveness of restorative justice conferencing for young offenders. Caution is urged in interpreting the results of this review considering the small number of included studies, subsequent low power and high risk of bias. The effects may potentially be more evident for victims than offenders. The need for further research in this area is highlighted.

Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts

Bystander responses underlie some of the current efforts to develop gene therapy approaches for cancer treatment. Similarly, they may have a role in strategies to treat tumours with targeted radioisotopes. In this study we show direct evidence for the production of a radiation-induced bystander response in primary human fibroblasts, We utilize a novel approach of using a charged-particle microbeam, which allows individual cells within a population to be selected and targeted with counted charged particles. Individual primary human fibroblasts within a population of 600-800 cells were targeted with between 1 and 15 helium ions (effectively, alpha -particles). The charged particles were delivered through the centre of the nucleus with an accuracy of +/- 2 mum and a detection and counting efficiency of greater than 99%. When scored 3 days later, even though only a single cell had been targeted, typically an additional 80-100 damaged cells were observed in the surviving population of about 5000 cells. The yield of damaged cells was independent of the number of charged particles delivered to the targeted cell, Similar results of a 2-3-fold increase in the background level of damage present in the population were observed whether 1 or 4 cells were targeted within the dish. Also, when 200 cells within one quadrant of the dish were exposed to radiation, there was a 2-3-fold increase in the damage level in an unexposed quadrant of the dish, This effect was independent of the presence of serum in the culture medium and was only observed when a cell was targeted, but not when only the medium was exposed, confirming that a cell-mediated response is involved. (C) 2001 Cancer Research Campaign.

A transiting companion to the eclipsing binary KIC002856960

We present an early result from an automated search of Kepler eclipsing binary systems for circumbinary companions. An intriguing tertiary signal has been discovered in the short period eclipsing binary KIC002856960. This third body leads to transit-like features in the light curve occurring every 204.2 days, while the two other components of the system display eclipses on a 6.2 hour period. The variations due to the tertiary body last for a duration of \sim1.26 days, or 4.9 binary orbital periods. During each crossing of the binary orbit with the tertiary body, multiple individual transits are observed as the close binary stars repeatedly move in and out of alignment with the tertiary object. We are at this stage unable to distinguish between a planetary companion to a close eclipsing binary, or a hierarchical triply eclipsing system of three stars. Both possibilities are explored, and the light curves presented.

Prenatal and early sucking influences on dietary preference in newborn, weaning, and young adult cats

Early experiences are of potential importance in shaping long-term behavior. This study examined the relative influence of prenatal and/or early postnatal experience of chemosensory stimuli on subsequent olfactory and dietary preferences of cats as newborns, at 9-10 weeks, and at 6 months. Cats were exposed to vanillin or 4-ethylguaiacol via their mother's diet either prenatally, postnatally, perinatally (prenatal and postnatal), or experienced no exposure to the stimuli (control). Newborns were given a two-choice olfactory test between the familiar "odor" and no odor; 9-10 week olds were tested for their preference between two food treats, one flavored with the familiar stimulus and the other unflavored; at 6 months, cats were given a choice of two bowls of food, one flavored with the familiar stimulus and the other unflavored. At all ages, cats preferred the familiar, and avoided the unfamiliar, stimulus. Perinatal exposure exerted the strongest influence on preference. Prenatal exposure influenced preference at all ages and postnatal exposure exerted a stronger effect as the cat aged. We conclude that long-term chemosensory and dietary preferences of cats are influenced by prenatal and early (nursing) postnatal experience, supporting a natural and biologically relevant mechanism for the safe transmission of diet from mother to young. © The Author 2012. Published by Oxford University Press. All rights reserved.

Help needed in medication self-management for people with visual impairment: case-control study

Background: Visual impairment (VI) is rising in prevalence and contributing to increasing morbidity, particularly among older people. Understanding patients' problems is fundamental to achieving optimal health outcomes but little is known about how VI impacts on self-management of medication.

Aim: To compare issues relating to medication self-management between older people with and without VI.

Design and setting: Case-control study with participants aged =65 years, prescribed at least two long-term oral medications daily, living within the community.

Method: The study recruited 156 patients with VI (best corrected visual acuity [BCVA] 6/18 to 3/60) at low-vision clinics; community optometrists identified 158 controls (BCVA 6/9 or better). Researchers visited participants in their homes, administered two validated questionnaires to assess medication adherence (Morisky; Medication Adherence Report Scale [MARS]), and asked questions about medication self-management, beliefs, and support.

Results: Approximately half of the participants in both groups reported perfect adherence on both questionnaires (52.5% Morisky; 43.3%, MARS). Despite using optical aids, few (3%) with VI could read medication information clearly; 24% had difficulty distinguishing different tablets. More people with VI (29%) than controls (13%) (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.6 to 5.0) needed help managing their medication, from friends (19% versus 10%) or pharmacists (10% versus 2.5%; OR = 4.4, 95% CI = 1.4 to 13.5); more received social service support (OR = 7.1; 95% CI = 3.9 to 12.9).

Conclusion: Compared to their peers without VI, older people with VI are more than twice as likely to need help in managing medication. In clinical practice in primary care, patients' needs for practical support in taking prescribed treatment must be recognised. Strategies for effective medication self-management should be explored.

Novel hapten synthesis for antibody production and development of an enzyme-linked immunosorbent assay for determination of furaltadone metabolite 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ)

A heterologous competitive indirect enzyme-linked immunosorbent assay (ciELISA) for the determination of the furaltadone metabolite 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ) was developed. AMOZ was derivatised with 2-(4-formylphenoxy) acetic acid or 2-(3-formylphenoxy) acetic acid to obtain two novel immunizing haptens. The ability of these haptens in producing specific polyclonal antibodies against the nitrophenyl derivative of AMOZ (NPAMOZ) was compared with that of traditional immunizing haptens (derivatised AMOZ with 3-carboxybenzaldehyle or 4-carboxybenzaldehyle). The results indicated that the novel immunizing haptens were able to produce antibodies with almost a two-fold improvement in sensitivity of the ciELISA for NPAMOZ in comparison with the existing antibody based ELISAs. The differences in sensitivity were explained by the molecular modeling of the lowest energy conformations of NPAMOZ and the haptens. Another novel hapten, derivatised AMOZ with 2-oxoacetic acid, was synthesized and used as a heterologous coating hapten. The results showed that this strategy of using only a partial structure of the target molecule as the coating hapten was able to obtain a two to three-fold improvement in sensitivity. This study provided a modern approach for the development of an immunoassay with improved sensitivity for the metabolites of nitrofuran antibiotics. © 2012 Elsevier B.V. All rights reserved.

Breast Cancer Risk in Relation to Occupations with Exposure to Carcinogens and Endocrine Disruptors:a Canadian Case-Control Study

Background

Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours.

Methods

1005 breast cancer cases referred by a regional cancer center and 1147 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case?control design, exposure effects were estimated using conditional logistic regression.

Results

Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5).

Conclusions

These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.