Mechanisms of Phenotypic Variability in Myotonia Congenita

The severity of Myotonia Congenita varies not only across individuals with different CLCN1 genotypes, but also within a pedigree, and can even fluctuate over time within a single individual in response to environmental circumstances. The functional consequences of eight naturally occurring sequence variants in the skeletal muscle chloride channel gene, CLCN1, were examined by whole cell patch-clamp of HEK293T cells expressing the gene product, ClC-1, in order to investigate potential differences in their mechanisms of pathogenicity. G276D and G523D caused complete loss of function, while S289G produced altered kinetics and a marked depolarizing shift of voltage dependence. H369P, A566T and M646T all tested normal in the HEK293T assay despite strong clinical support for pathogenicity. Their mechanism of pathogenicity may rely on muscle-specific processes that are not faithfully recapitulated in HEK293T cells. W118G and P744T were selected as examples of variants for which pathogenicity is unclear from the clinical evidence. The former is present in controls, but over-represented in the Myotonia Congenita population. The latter is present in an individual who also harbours a large deletion in CLCN1. Both variants tested normal in the HEK293T assay. A potent trigger for worsening of myotonia in some female patients is pregnancy. In order to clarify the role of sex hormones in non-genomic modulation of skeletal muscle excitability, the effects of progesterone and oestrogen on endogenous chloride currents through the wildtype ClC-1 of mouse skeletal muscle were tested by whole cell patch clamp. Progesterone and oestrogen rapidly reduced the chloride conductance and shifted its voltage dependence, thus a non-genomic mechanism exists in skeletal muscle linking sex hormones to ClC-1. However the effect was only significant at 500 times the highest physiological concentration encountered in pregnancy. The macroscopic chloride conductance of a membrane expressing wildtype ClC-1 was simulated in Matlab. The simulation improves on published models by recapitulating both time-dependence and voltage-dependence of the channel through a method based on independent representations of the fast and the slow gates. The applicability of the model for the purposes of exploring the effects of specific mutations was assessed by attempting to simulate the currents through S289G channels; the effects of S289G could be mimicked by slowing and inverting the kinetics of the fast gate and shifting the fast gate opening probability to more depolarized potentials. The mechanism of low chloride conductance myotonia and electrical factors likely to impact on its severity are discussed in the context of experiments conducted in a model of myotonic muscle. Slowing of ClC-1 kinetics alone did not produce myotonia, but could lower the threshold for myotonia caused by shifts in voltage dependence. Muscle fibre diameter is an important factor in the propensity to myotonia, which can be driven by asynchrony between surface and t-tubular action potentials in large muscle fibres. Increasing muscle fibre diameter could underly the age-dependence of symptom onset in Myotonia Congenita, and differences in diameter could contribute to phenotypic variability, including male-female differences

Randomised, double-blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial study

Objectives To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Design Double blind, placebo controlled study. Setting Eighteen UK hospitals. Participants 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV1) 50% of predicted normal. Interventions Inhaled fluticasone propionate 500 ìg twice daily from a metered dose inhaler or identical placebo. Main outcome measures Efficacy measures: rate of decline in FEV1 after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. Results There was no significant difference in the annual rate of decline in FEV1 (P = 0.16). Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P < 0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P = 0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P = 0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v19%, P = 0.034). Conclusions Fluticasone propionate 500 ìg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1. Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease

Nongenomic actions of progesterone and 17β-estradiol on the chloride conductance of skeletal muscle.

Myotonia congenita, caused by mutations in ClC-1, tends to be more severe in men and is often exacerbated by pregnancy. We performed whole-cell patch clamp of mouse muscle chloride currents in the absence/presence of 100 μM progesterone or 17β-estradiol. 100 μM progesterone rapidly and reversibly shifted the ClC-1 activation curve of mouse skeletal muscle (V50 changed from -52.6 ± 9.3 to +35.5 ± 6.7; P < 0.01) and markedly reduced chloride currents at depolarized potentials. 17β-estradiol at the same concentration had a similar but smaller effect (V50 change from -57.2 ± 7.6 to -40.5 ± 9.8; P < 0.05). 1 μM progesterone produced no significant effect. Although the data support the existence of a nongenomic mechanism in mammalian skeletal muscle through which sex hormones at high concentration can rapidly modulate ClC-1, the influence of hormones on muscle excitability in vivo remains an open question. Copyright © 2013 Wiley Periodicals, Inc

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings

Extended Knowledge-How

According to reductive intellectualists about knowledge-how :147–190, 2008; Philos Phenomenol Res 78:439–467, 2009) knowledge-how is a kind of knowledge-that. To the extent that this is right, then insofar as we might conceive of ways knowledge could be extended with reference to active externalist :7–19, 1998; Clark in Supersizing the mind: embodiment, action, and cognitive extension: embodiment, action, and cognitive extension. Oxford University Press, Oxford, 2008) approaches in the philosophy of mind, we should expect no interesting difference between the two. However, insofar as anti-intellectualist approaches to knowledge-how are a viable option, there is an overlooked issue of how knowledge-how might be extended, via active externalism, in ways very differently from knowledge-that. This paper explores this overlooked space, and in doing so, illustrates how a novel form of extended knowledge-how emerges from a pairing of active externalism in the philosophy of mind with anti-intellectualism in the theory of knowledge. Crucial to our argument will be a new way of thinking about the extended mind thesis, as it pertains to the kinds of state one is in when one knows how to do something, and how this state connects with non-accidentally successful performanc

Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial.

BACKGROUND: Data on survival endpoints are usually summarised using either hazard ratio, cumulative number of events, or median survival statistics. Network meta-analysis, an extension of traditional pairwise meta-analysis, is typically based on a single statistic. In this case, studies which do not report the chosen statistic are excluded from the analysis which may introduce bias. METHODS: In this paper we present a tutorial illustrating how network meta-analyses of survival endpoints can combine count and hazard ratio statistics in a single analysis on the hazard ratio scale. We also describe methods for accounting for the correlations in relative treatment effects (such as hazard ratios) that arise in trials with more than two arms. Combination of count and hazard ratio data in a single analysis is achieved by estimating the cumulative hazard for each trial arm reporting count data. Correlation in relative treatment effects in multi-arm trials is preserved by converting the relative treatment effect estimates (the hazard ratios) to arm-specific outcomes (hazards). RESULTS: A worked example of an analysis of mortality data in chronic obstructive pulmonary disease (COPD) is used to illustrate the methods. The data set and WinBUGS code for fixed and random effects models are provided. CONCLUSIONS: By incorporating all data presentations in a single analysis, we avoid the potential selection bias associated with conducting an analysis for a single statistic and the potential difficulties of interpretation, misleading results and loss of available treatment comparisons associated with conducting separate analyses for different summary statistics

Prevalence study of genetically defined skeletal muscle channelopathies in England.

To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders