Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Molecular imaging probes derived from natural peptides.

Covering: up to the end of 2015.Peptides are naturally occurring compounds that play an important role in all living systems and are responsible for a range of essential functions. Peptide receptors have been implicated in disease states such as oncology, metabolic disorders and cardiovascular disease. Therefore, natural peptides have been exploited as diagnostic and therapeutic agents due to the unique target specificity for their endogenous receptors. This review discusses a variety of natural peptides highlighting their discovery, endogenous receptors, as well as their derivatization to create molecular imaging agents, with an emphasis on the design of radiolabelled peptides. This review also highlights methods for discovering new and novel peptides when knowledge of specific targets and endogenous ligands are not available.

Estimating the potential disease rate reduction under varying conditions of combined effects.

The disease rate difference between people exposed and not exposed to some factor is the familiar estimate of attributable risk. When there are two or more causal exposures which demonstrate joint effects and are independently distributed, partitioning a population's overall rate between factors requires estimates of the marginal distributions of exposures and the independent (unconditional) and combined rate ratios for each exposure factor. The net potential reduction in the overall disease rate resulting from elimination of one of the exposures depends on these parameters and on the model of combined effect assumed, additive, multiplicative or some departure therefrom. In this paper the authors illustrate the extent to which the assumed model of combined effect of exposures determines which parameters need to be specified to estimate disease rate reductions. The concepts presented are demonstrated algebraically and with simulated hypothetical data. An application of the method is given with data from a case-control study of smoking, asbestos exposure and lung cancer.

Latency analysis in occupational epidemiology.

Allowance for prolonged disease induction and latency times is an important consideration in occupational epidemiology studies of cancer and other delayed effects of exposure. Two useful approaches for assessing prolonged induction and latency periods are (1) exposure lagging and (2) considering exposures only within moving time windows. The exposure weighting scheme proposed by Jahr2 to assess exposure burdens is another method that accounts for induction and latency, although not explicitly. These three approaches, which are shown to be special cases of exposure weighting, are illustrated with an analysis of lung cancer mortality among a cohort of workers from an asbestos textile plant.

X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder.

Biometals such as zinc, iron, copper and calcium play key roles in diverse physiological processes in the brain, but can be toxic in excess. A hallmark of neurodegeneration is a failure of homeostatic mechanisms controlling the concentration and distribution of these elements, resulting in overload, deficiency or mislocalization. A major roadblock to understanding the impact of altered biometal homeostasis in neurodegenerative disease is the lack of rapid, specific and sensitive techniques capable of providing quantitative subcellular information on biometal homeostasis in situ. Recent advances in X-ray fluorescence detectors have provided an opportunity to rapidly measure biometal content at subcellular resolution in cell populations using X-ray Fluorescence Microscopy (XFM). We applied this approach to investigate subcellular biometal homeostasis in a cerebellar cell line isolated from a natural mouse model of a childhood neurodegenerative disorder, the CLN6 form of neuronal ceroid lipofuscinosis, commonly known as Batten disease. Despite no global changes to whole cell concentrations of zinc or calcium, XFM revealed significant subcellular mislocalization of these important biological second messengers in cerebellar Cln6nclf (CbCln6nclf ) cells. XFM revealed that nuclear-to-cytoplasmic trafficking of zinc was severely perturbed in diseased cells and the subcellular distribution of calcium was drastically altered in CbCln6nclf cells. Subtle differences in the zinc K-edge X-ray Absorption Near Edge Structure (XANES) spectra of control and CbCln6nclf cells suggested that impaired zinc homeostasis may be associated with an altered ligand set in CbCln6nclf cells. Importantly, a zinc-complex, ZnII(atsm), restored the nuclear-to-cytoplasmic zinc ratios in CbCln6nclf cells via nuclear zinc delivery, and restored the relationship between subcellular zinc and calcium levels to that observed in healthy control cells. ZnII(atsm) treatment also resulted in a reduction in the number of calcium-rich puncta observed in CbCln6nclf cells. This study highlights the complementarities of bulk and single cell analysis of metal content for understanding disease states. We demonstrate the utility and broad applicability of XFM for subcellular analysis of perturbed biometal metabolism and mechanism of action studies for novel therapeutics to target neurodegeneration.

Adjustment of occupational exposure limits for seasonal occupations.

A previously reported model for predicting adjustments to permissible exposure limits has been extended to include adjustments for seasonal occupations. On the basis of the model, no "credit" (i.e., increase in exposure limits) may be allowed for a short work season unless the biological half-life in hours of the agent of concern is greater than 38 W, in which W is the number of weeks in the work season. Modifications to PELs due to the longer work-days and work-weeks often associated with seasonal occupations are incorporated into a general equation for estimating PEL adjustments. The adjustments assume no additional exposures the remainder of the year, and so do not apply to workers who merely move to other parts of the country and continue in a similar "seasonal" job.

The "TWAp" in the lead standard.

This paper analyzes current OSHA practice for adjusting the permissible exposure limit (PEL) for inorganic lead to accommodate unusual work schedules. Depending on the work schedule, the PEL adjustment procedure can allow substantially higher exposure or require substantially lower exposure, as compared to the exposure permitted by the lead standard for a normal work schedule. In addition, the procedure allows compliance with the standard by manipulation of the work schedule alone, without reduction in lead exposure. The paper describes how calculating exposure on a weekly basis using the procedure outlined in the OSHA Field Operations Manual would eliminate the seven-fold range of allowed exposure.

Adjusting occupational exposure limits for moonlighting, overtime, and environmental exposures.

A mathematical model is used to predict relative body burdens of inhaled contaminants in workers who work two jobs or overtime, or who experience off-the-job exposure to air contaminants. Expected "peak" or maximum body burdens from multiple exposures are compared to those expected from the "normal" occupational exposure on which TLVs and Permissible Exposure Limits (PELs) arebased (five 8-hour days per week with zero off-the-job exposure). The model is designed to predict what adjustments to the TLVs and PELs are necessary to avoid accumulation of excess peak body burdens of contaminants from the additional exposures incurred. The general application of models to determine occupational exposure limits is reviewed, and several models are compared.

Application of occupational exposure limits to unusual work schedules.

A one-compartment exponential models is described which predicts "equal protection", based on biological uptake rates, for unusual air contaminant exposure situations as compared to a "normal" exposure of five 8-hour days per week. This is done by equating peak body burdens resulting from a normal and an unusual exposure, in terms of an adjustment factor applied to the normal exposure limit for an air contaminant. This factor predicts the highest allowable concentration in an unusual exposure situation which will not result in a higher-than normal body accumulation of the inhaled substance. Graphs and formulae are provided for determining adjustment factors for anticipated unusual exposure schedules. The model's predictions and published data are compared.

Mortality among workers at a nuclear fuels production facility.

A retrospective cohort mortality study was conducted in a population of workers employed at a facility with the primary task of production of nuclear fuels and other materials. Data for hourly and salaried employees were analyzed separately by time period of first employment and length of employment. The hourly (N = 6,687 with 728 deaths) and salaried (N = 2,745 with 294 deaths) employees had a mortality experience comparable to that of the United States and, in fact, exhibited significant fewer deaths in many categories of diseases that are traditionally associated with the healthy worker effect. Specifically, fewer deaths were noted in the categories of all causes, all cancers, cancer of the digestive organs, lung cancer, brain cancer (hourly workers only), diabetes, all diseases of the circulatory system, all respiratory diseases, all digestive system diseases, all diseases of the genitourinary system (hourly only), and all external causes of death. A statistically significant, and as yet unexplained increase in leukemia mortality (6 observed vs. 2.18 expected) appeared among a subset of the hourly employees, first hired before 1955, and employed between 5-15 years.

Mortality among workers in the Florida phosphate industry. I. Industry-wide cause-specific mortality patterns.

A retrospective cohort mortality study was conducted on 17,601 white and 4,722 nonwhite male workers in the Florida phosphate mining and chemical processing industry. Concerns about potential risks from naturally-occurring sources of ionizing radiation and anecdotal reports of lung cancer among workers prompted this investigation. Historical follow-up was conducted for the years 1949 to 1978. In comparison with U.S. rates, small excess of mortality rates of lung cancer were observed for white (standardized mortality ratio [SMR] equals 1.22) and nonwhite workers (SMR = 1.24); however, these excesses disappeared when contrasts were made with prevailing rates in Florida. Emphysema mortality was also slightly elevated in comparison with U.S. rates; the SMRs were 1.48 and 1.73 for white and nonwhite workers, respectively. Neither disease was related to overall length of employment. Detailed analyses of mortality in relation to work assignments are presented in the companion article.

Mortality among workers in the Florida phosphate industry. II. Cause-specific mortality relationships with work areas and exposures.

Small excesses of lung cancer and emphysema mortality had been detected among an historical cohort of 17,601 white and 4,722 nonwhite Florida phosphate industry workers. Internal mortality rate comparisons were made between worker subcohorts classified according to length of employment in 16 work areas and according to employment duration in jobs grouped by potential exposures to 10 agents, including alpha radiation. The only consistent associations seen were increased lung cancer mortality rates among long-term workers in plant-wide services and skilled crafts jobs. There was no evidence to support causal associations with exposures characteristic of the phosphate industry.