The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity.

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1alpha, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.

Exploring the relationship between social deprivation and domestic radon levels in the East Midlands, UK.

The natural radioactive gas radon is widely present in the built environment and at high concentrations is associated with enhanced risk of lung-cancer. This risk is significantly enhanced for habitual smokers. Although populations with higher degrees of social deprivation are frequently exposed to higher levels of many health-impacting pollutants, a recent study suggests that social deprivation in the UK is associated with lower radon concentrations. The analysis reported here, based on published data on social deprivation and domestic radon in urban and rural settings in the English East Midlands, identifies a weak association between increasing deprivation and lower radon areas. This is attributed to the evolution of the major urban centres on low-permeability, clay-rich alluvial soils of low radon potential. In addition, the predominance of high-rise dwellings in towns and cities will further reduce average exposure to radon in populations in those areas.

Is environmental radon gas associated with the incidence of neurodegenerative conditions? A retrospective study of multiple sclerosis in radon affected areas in England and Wales.

To test whether an association exists between radon gas concentration in the home and increased multiple sclerosis (MS) incidence, a retrospective study was undertaken of MS incidence in known areas of raised domestic radon concentration in England and Wales, using The Health Improvement Network (THIN) clinical research database. The study population comprised 20,140,498 person-years of clinical monitoring (males: 10,056,628: 49.93%; females: 10,083,870: 50.07%), representing a mean annual population of 2.5 million individuals. To allow for the possible latency of MS initiation following exposure, data extraction was limited to patients with at least five years registration history with the same GP practice before first diagnosis. Patient records were allocated to one of nine radon concentration bands depending on the average radon level in their postcode sector. MS incidence was analysed by searching for patients with first MS diagnosis over the eight calendar years 2005-2012 inclusive. 1512 new MS cases were diagnosed, 1070 females, 442 males, equivalent to raw incidence rates of 7.51, 10.61 and 4.40 per 10(5) person-years respectively, comparable to previously reported results. Of these new cases, 115 could be allocated to one of the radon bands representing high radon areas. Standardising to the UK 2010 population, excess relative risk (ERR) figures for MS were calculated for each radon band. Linear regression of ERR against mean band radon concentration shows a positive gradient of 0.22 per 100 Bq·m(-3) (R(2) = 0.25, p = 0.0961) when forced through the origin to represent a linear-no-threshold response. The null hypothesis falls inside the 95% confidence interval for the linear fit and therefore this fit is not statistically significant. We conclude that, despite THIN sampling around 5% of the population, insufficient data was available to confirm or refute the hypothesised association between MS incidence and radon concentration.

Statin-associated myopathy with normal creatine kinase levels.

BACKGROUND: Muscle symptoms in patients who are treated with statins and have normal creatine kinase levels are not well understood. OBJECTIVE: To report biopsy-confirmed myopathy and normal creatine kinase levels associated with statin use. DESIGN: Case reports from preliminary analysis of an ongoing clinical trial. SETTING: Clinical research center in a community hospital. PATIENTS: Four patients with muscle symptoms that developed during statin therapy and reversed during placebo use. MEASUREMENTS: 1) Patients' ability to identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength. RESULTS: All four patients repeatedly distinguished blinded statin therapy from placebo. Strength testing confirmed weakness during statin therapy that reversed during placebo use. Muscle biopsies showed evidence of mitochondrial dysfunction, including abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy. CONCLUSION: Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum creatine kinase levels.

The effects of geology and the impact of seasonal correction factors on indoor radon levels: a case study approach.

Geology has been highlighted by a number of authors as a key factor in high indoor radon levels. In the light of this, this study examines the application of seasonal correction factors to indoor radon concentrations in the UK. This practice is based on an extensive database gathered by the National Radiological Protection Board over the years (small-scale surveys began in 1976 and continued with a larger scale survey in 1988) and reflects well known seasonal variations observed in indoor radon levels. However, due to the complexity of underlying geology (the UK arguably has the world's most complex solid and surficial geology over the shortest distances) and considerable variations in permeability of underlying materials it is clear that there are a significant number of occurrences where the application of a seasonal correction factor may give rise to over-estimated or under-estimated radon levels. Therefore, the practice of applying a seasonal correction should be one that is undertaken with caution, or not at all. This work is based on case studies taken from the Northamptonshire region and comparisons made to other permeable geologies in the UK.

A critical analysis of climatic influences on indoor radon concentrations: Implications for seasonal correction.

Although statistically-derived national Seasonal Correction Factors (SCFs) are conventionally used to convert sub-year radon concentration measurements to an annual mean, it has recently been suggested that external temperature could be used to derive local SCFs for short-term domestic measurements. To validate this approach, hitherto unanalysed radon and temperature data from an environmentally-stable location were analysed. Radon concentration and internal temperature were measured over periods totalling 1025 days during an overall period of 1762 days, the greatest continuous sampling period being 334 days, with corresponding meteorological data collected at a weather station 10 km distant. Mean daily, monthly and annual radon concentrations and internal temperatures were calculated. SCFs derived using monthly mean radon concentration, external temperature and internal-external temperature-difference were cross-correlated with each other and with published UK domestic SCF sets. Relatively good correlation exists between SCFs derived from radon concentration and internal-external temperature difference but correlation with external temperature, was markedly poorer. SCFs derived from external temperature correlate very well with published SCF tabulations, confirming that the complexity of deriving SCFs from temperature data may be outweighed by the convenience of using either of the existing domestic SCF tabulations. Mean monthly radon data fitted to a 12-month sinusoid showed reasonable correlation with many of the annual climatic parameter profiles, exceptions being atmospheric pressure, rainfall and internal temperature. Introducing an additional 6-month sinusoid enhanced correlation with these three parameters, the other correlations remaining essentially unchanged. Radon latency of the order of months in moisture-related parameters suggests that the principal driver for radon is total atmospheric moisture content rather than relative humidity.

Future initiatives to reduce lung cancer incidence in the United Kingdom: smoking cessation, radon remediation and the impact of social change.

AIMS: Smoking and radon cause lung cancer, with smoking being the more significant risk factor. Although programmes to identify UK houses with raised radon levels and to encourage remedial action started in 1990, uptake has been limited and those most at risk, smokers and young families, are not being reached. The risks from smoking and radon are multiplicative. Public health campaigns have reduced smoking prevalence significantly. Since most radon-induced lung cancers occur in smokers, reducing the number of smokers will reduce the number of radon-induced lung cancers. This article considers the impact of reducing smoking prevalence on the effectiveness of radon remediation programmes, combining this with demographic trends and regional variations to assess implications for future public health. METHODS: Results on cost-effectiveness of smoking cessation and radon remediation programmes were combined with government figures for smoking prevalence to estimate the number of cancers averted and the cost-effectiveness of such programmes, taking into account demographic changes, including increasing life expectancy. Regional variations in smoking prevalence and smoking cessation programmes were reviewed, comparing these to the geographic variation of radon. RESULTS: The continuing impact of smoking cessation programmes in reducing smoking prevalence will reduce the number of radon-induced lung cancers, but with a lag. Smoking cessation programmes are more cost-effective than radon remediation programmes, presenting an additional opportunity to reduce radon risk to smokers. Regional data show no correlation between smoking prevalence and radon levels. CONCLUSIONS: Reduced smoking prevalence reduces the effectiveness of radon remediation programmes. This, coupled with limited uptake of radon remediation, suggests that radon remediation programmes should be targeted, and that an integrated public health policy for smoking and radon is appropriate. Lack of correlation between smoking prevalence and radon suggests that local assessment of relative priorities for public health strategies, such as the 'Total Place' initiative, is appropriate.

Small area mapping of domestic radon, smoking prevalence and lung cancer incidence--A case study in Northamptonshire, UK.

Smoking and radon both cause lung cancer, and together the risk is significantly higher. UK public health campaigns continue to reduce smoking prevalence, and other initiatives identify houses with raised radon (radon-222) levels and encourage remedial action. Smoking prevalence and radon levels in the UK have been mapped at Primary Care Trust level. This paper extends that work, using a commercial socio-demographic database to estimate smoking prevalence at the postcode sector level, and to predict the population characteristics at postcode sector level for 87 postcode sectors in Northamptonshire. Likely smoking prevalence in each postcode sector is then modelled from estimates of the smoking prevalence in the different socio-economic groups used by the database. Mapping estimated smoking prevalence, radon potential and average lung cancer incidence for each postcode sector suggested that there was little correlation between smoking prevalence and radon levels, as radon potential was generally lower in urban areas in Northamptonshire, where the estimates of smoking prevalence were highest. However, the analysis demonstrated some sectors where both radon potential and smoking prevalence were moderately raised. This study showed the potential of this methodology to map estimated smoking prevalence and radon levels to inform locally targeted public health campaigns to reduce lung cancer incidence.

Surface calcification of silicone plate intraocular lenses in patients with asteroid hyalosis.

PURPOSE: To report three cases in which a silicone-plate lens was explanted because of whitish deposits on the posterior optic surface. DESIGN: Observational case series with clinicopathological correlation. PATIENTS AND METHODS: In the three instances, the deposits were observed at least 2 years after uneventful cataract surgery. All of the patients had unilateral mild asteroid hyalosis in the concerned eye. After explantation of the lenses, gross and light microscopic analyses were performed. The posterior optic surfaces of the lenses also underwent scanning electron microscopy coupled with energy dispersive x-ray spectroscopy for analysis of the elemental composition of the deposits. RESULTS: Gross and light microscopic analyses revealed well-demarcated areas of whitish deposits on the posterior optic surface of the lenses, as well as multiple pits caused by Neodymium:yttrium aluminum garnet laser treatments. The deposits formed an amorphous layer with a "crustlike" appearance, which was confirmed by scanning electron microscopy. X-ray spectroscopy analyses demonstrated the composition of the deposits to be similar to hydroxyapatite. CONCLUSIONS: The material opacifying the lenses was probably derived from the asteroid bodies or from a similar process that results in this vitreous condition. We were unaware of this association between asteroid hyalosis and late postoperative dystrophic calcification of silicone lenses.

A critical comparison of the cost-effectiveness of domestic radon remediation programmes in three counties of England.

Radon remediation programmes in domestic dwellings were carried out in five areas, from three counties of England, and the total costs obtained. A single company, which abided by the Code of Practice of the Radon Council of Great Britain, carried out the remediation. The dose savings from the programmes were calculated and used to estimate the number of lung cancers averted. The data obtained allowed the cost-effectiveness of the remediation programmes in each area to be calculated. The remediation programmes in three areas (Northants 2, 3 and North Oxfordshire) were cost-effective whereas those in two areas (Northants 1 and North Somerset) were not. To be cost-effective, the Northants I and North Somerset areas would need to increase the number of householders that carried out remediation, if they were over the UK Action Level. Health policy makers should concentrate their resources on communities in areas where there is a significant proportion of dwellings above the UK Action Level and where the number of properties being remediated is low.

The cost-effectiveness of residential radon remediation programmes: assumptions about benefits stream profiles over time.

A recent cost-effectiveness analysis of a residential radon remediation programme considered and highlighted many areas of uncertainty in the parameters chosen for the analysis. One assumption not challenged in the study was the benefits stream profile adopted. There are several different ways of loading the benefits in terms of life years into the cost-effectiveness model and several of these are explored and the results are reported in this study. The benefits profile depends upon the lead-time to cancer manifestation post environmental carcinogen (radon) exposure. The literature reviewed suggests that there are many options for loading benefits to radon-induced lung cancer prevention programmes. In this study, the alternative benefits stream profiles are explored and their implications for the cost-effectiveness ratio are examined. Adopting different benefits stream profiles to the model results in a range of cost-effectiveness ratios from 14912.90 pounds per life year gained to 52416.27 pounds per life year gained. The preferred model is reported where the life years gained are assumed to be equally distributed over the last 15 years of the 40-year time horizon of the analysis (Y25-40) and the corresponding cost-effectiveness ratio is 37,943 pounds per life year gained.

Influences motivating smokers in a radon-affected area to quit smoking.

AIMS: Domestic radon gas concentrations in parts of the UK are sufficiently high to increase lung cancer risk among residents, and recent studies have confirmed that the risk of smokers developing lung cancer is significantly enhanced by the presence of radon. Despite campaigns encouraging residents of radon-affected areas (RAEs) to test and remediate their homes, public response to the risks posed by radon remains relatively modest, particularly among smokers and young families, limiting the health benefits and cost-effectiveness achievable by remediation. The observation that smokers, who are most at risk from radon, are not explicitly targeted by current radon remediation campaigns prompted an assessment of the value of smoking-cessation initiatives in reducing radon-induced lung cancers by reaching at-risk subgroups of the population hitherto uninfluenced by radon-awareness programmes. This study addresses the motivation of current quitters in a designated RAE using a postal questionnaire administered around one year after the cessation attempt. METHODS: Residents of the Northamptonshire RAE who had joined the smoking-cessation programme between July and September 2006 and who remained verifiably tobacco free at four weeks, were subsequently invited to participate in a questionnaire-based investigation into factors affecting their decision to cease smoking. From an initial population of 445 eligible individuals, 205 of those contacted by telephone after 12 months agreed to complete postal questionnaires, and unsolicited questionnaires were sent to a further 112 participants for whom telephone contact had proved impossible. One hundred and three completed questionnaires were returned and analysed, the principal tools being χ(2) , Mann-Whitney and Kruskal-Wallis tests. RESULTS: Individuals decide to quit smoking from self-interest, principally on health grounds, and regard the effects of their smoke on others, particularly children and unborn babies, as less significant. The risk of developing respiratory, coronary/cardiac or cancerous conditions provides the greatest motivation to the decision to quit, with knowledge of radon among the lowest-ranked influences. CONCLUSIONS: This study confirms that quitters place risks to their personal health as the highest factors influencing their decision to quit, and health professionals should be aware of this when designing smoking-cessation initiatives. As radon risk is ranked very low by quitters, there would appear to be the potential to raise radon awareness through smoking-cessation programmes, with the objective of increasing the uptake and success rate of such programmes and encouraging participation in radon-remediation programmes.

Statin myopathy: a common dilemma not reflected in clinical trials.

Although statins are remarkably effective, they are still underprescribed because of concerns about muscle toxicity. We review the aspects of statin myopathy that are important to the primary care physician and provide a guide for evaluating patients on statins who present with muscle complaints. We outline the differential diagnosis, the risks and benefits of statin therapy in patients with possible toxicity, and the subsequent treatment options.

The modern spectrum of rhabdomyolysis: drug toxicity revealed by creatine kinase screening.

PURPOSE: This study describes the current etiologies, demographic characteristics, incidence of acute renal insufficiency and correlation between peak creatine kinase (CK) and peak creatinine in hospitalized patients with rhabdomyolysis. METHODS: A retrospective chart review of patients with creatine kinase (CK) values greater than 5000 IU/L during a nine month period identified 106 cases of rhabdomyolysis. RESULTS: The most common contributing etiologies were recreational drug and/or alcohol use in 28%, trauma in 23%, compression in 19%, shock in 17%, statin-use in 13%, seizure in 8% and quetiapine-use in 8%. 37% of cases involved multiple etiologies. Renal insufficiency occurred in 49% of cases and modestly but significantly correlated with CK (R(2) = 0.41, p < 0.0001). Myoglobinuria and a pre-renal state were associated with renal insufficiency in 49% and 52% of cases, respectively. CONCLUSIONS: Rhabdomyolysis should be defined with CK values exceeding 10-25 times the upper limit of normal irrespective of renal function. Using a laboratory marker such as CK can aid diagnosis of rhabdomyolysis and identify adverse drug events.

Myotoxic reactions to lipid-lowering therapy are associated with altered oxidation of fatty acids.

Despite exceptional efficacy and safety, fear of muscle toxicity remains a major reason statins are underutilized. Evidence suggests that statin muscle toxicity may be mediated by abnormalities in lipid metabolism. To test the hypothesis that myotubes from patients intolerant of lipid-lowering therapies have abnormal fatty acid oxidation (FAO) responses we compared muscle from 11 subjects with statin intolerance (Intolerant) with muscle from seven statin-naive volunteers undergoing knee arthroplasty (Comparator). Gross muscle pathology was graded and skeletal muscle cell cultures were produced from each subject. FAO was assessed following treatment with increasing statin concentrations. There was no difference in muscle biopsy myopathy scores between the groups. Basal octanoate oxidation was greater in Intolerant than in Comparator subjects (P = 0.03). Lovastatin-stimulated palmitate oxidation tended to be greater for Intolerant compared to Control subjects' myotubes (P = 0.07 for 5 microM and P = 0.06 for 20 microM lovastatin). In conclusion abnormalities in FAO of Intolerant subjects appear to be an intrinsic characteristic of these subjects that can be measured in their cultured myotubes.