Markov, fractal, diffusion, and related models of ion channel gating. A comparison with experimental data from two ion channels

The gating kinetics of single-ion channels are generally modeled in terms of Markov processes with relatively small numbers of channel states. More recently, fractal (Liebovitch et al. 1987. Math. Biosci. 84:37–68) and diffusion (Millhauser et al. 1988. Proc. Natl. Acad. Sci. USA. 85:1502–1507) models of channel gating have been proposed. These models propose the existence of many similar conformational substrates of the channel protein, all of which contribute to the observed gating kinetics. It is important to determine whether or not Markov models provide the most accurate description of channel kinetics if progress is to be made in understanding the molecular events of channel gating. In this study six alternative classes of gating model are tested against experimental single-channel data. The single-channel data employed are from (a) delayed rectifier K+ channels of NG 108–15 cells and (b) locust muscle glutamate receptor channels. The models tested are (a) Markov, (b) fractal, (c) one-dimensional diffusion, (d) three-dimensional diffusion, (e) stretched exponential, and (f) expo-exponential. The models are compared by fitting the predicted distributions of channel open and closed times to those observed experimentally. The models are ranked in order of goodness-of-fit using a boot-strap resampling procedure. The results suggest that Markov models provide a markedly better description of the observed open and closed time distributions for both types of channel. This provides justification for the continued use of Markov models to explore channel gating mechanisms

PHL 1445: An eclipsing cataclysmic variable with a substellar donor near the period minimum

PublishedThis is a pre-copyedited, author-produced PDF of an article accepted for publication in Monthly Notices of the Royal Astronomical Society following peer review. The version of record is available online via the DOI in this record.We present high-speed, three-colour photometry of the eclipsing dwarf nova PHL 1445, which, with an orbital period of 76.3 min, lies just below the period minimum of ~82 min for cataclysmic variable stars (CVs). Averaging four eclipses reveals resolved eclipses of the white dwarf and bright spot. We determined the system parameters by fitting a parametrized eclipse model to the averaged light curve. We obtain a mass ratio of q = 0.087 ± 0.006 and inclination i = 85°.2 ± 0°.9. The primary and donor masses were found to be Mw = 0.73 ± 0.03 M⊙ and Md = 0.064 ± 0.005 M⊙, respectively. Through multicolour photometry a temperature of the white dwarf of Tw = 13 200 ± 700 K and a distance of 220 ± 50 pc were determined. The evolutionary state of PHL 1445 is uncertain. We are able to rule out a significantly evolved donor, but not one that is slightly evolved. Formation with a brown dwarf donor is plausible, though the brown dwarf would need to be no older than 600 Myr at the start of mass transfer, requiring an extremely low mass ratio (q = 0.025) progenitor system. PHL 1445 joins SDSS 1433 as a sub-period minimum CV with a substellar donor. The existence of two such systems raises an alternative possibility that current estimates for the intrinsic scatter and/or position of the period minimum may be in error.UK Science and Technology Facilities Council (STFC)FONDECY

Effect of denosumab on osteolytic lesion activity after total hip arthroplasty: a single-centre, randomised, double-blind, placebo-controlled, proof of concept trial

Background Osteolysis causes recurrent pain and disability after total hip arthroplasty. We investigated the effect of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision total hip arthroplasty surgery to show the biological proof of concept for a non-surgical treatment for the disease. Methods We did a phase 2, randomised, double-blind, placebo-controlled, proof of concept superiority trial at Sheffield Teaching Hospitals, Sheffield, UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiographically confirmed osteolysis were randomly allocated (1:1) to subcutaneous denosumab (60 mg single-dose) or placebo by an independent pharmacist using a random number table. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane–bone interface at surgery 8 weeks later, measured by quantitative histomorphometry in all patients who underwent revision surgery. Adverse events were analysed in all randomly assigned participants. This trial is registered with the EU Clinical Trials Register (EudraCT 2011-000541-20). Findings Between Dec 12, 2012, and June 24, 2018, 51 patients were assessed for eligibility, of whom 24 were randomly assigned to study treatment. Two patients had their revision surgery cancelled for unrelated reasons, leaving 22 patients (ten in the denosumab group) for analysis of the primary outcome. There were 83% fewer osteoclasts at the osteolysis membrane–bone interface in the denosumab versus the placebo group (median 0·05 per mm [IQR 0·11] vs 0·30 mm [0·40], p=0·011). No deaths or treatment-related serious adverse events occurred. Seven adverse events, including one severe adverse event, occurred in four (36%) of 11 patients in the denosumab group. In the placebo group ten adverse events, including three severe adverse events, occurred in five (38%) of 13 patients. Interpretation To our knowledge, this is the first clinical trial of an investigational drug for osteolysis that shows tissue-specific biological efficacy. These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery. Funding Amgen

At the borders of medical reasoning: Aetiological and ontological challenges of medically unexplained symptoms

Medically unexplained symptoms (MUS) remain recalcitrant to the medical profession, proving less suitable for homogenic treatment with respect to their aetiology, taxonomy and diagnosis. While the majority of existing medical research methods are designed for large scale population data and sufficiently homogenous groups, MUS are characterised by their heterogenic and complex nature. As a result, MUS seem to resist medical scrutiny in a way that other conditions do not. This paper approaches the problem of MUS from a philosophical point of view. The aim is to first consider the epistemological problem of MUS in a wider ontological and phenomenological context, particularly in relation to causation. Second, the paper links current medical practice to certain ontological assumptions. Finally, the outlines of an alternative ontology of causation are offered which place characteristic features of MUS, such as genuine complexity, context-sensitivity, holism and medical uniqueness at the centre of any causal set-up, and not only for MUS. This alternative ontology provides a framework in which to better understand complex medical conditions in relation to both their nature and their associated research activity

Causation in evidence-based medicine: In reply to Strand and Parkkinen

Strand and Parkkinen criticize our dispositional account of causation in evidence-based medicine for failing to provide a proper epistemology of causal knowledge. In particular, they claim that we do not explain how causal inferences should be drawn. In response, we point out that dispositionalism does indeed have an account of the epistemology of causation, including counterfactual dependence, intervention, prediction and clinical decision. Furthermore, we argue that this is an epistemology that fits better with the known fallibility of even our best-informed predictions. Predictions are made on the basis that causes dispose or tend towards their effects, rather than guarantee them. The ontology of causation remains a valuable study for, among other reasons, it tells us that powers do not always combine additively. This counts against the monocausality that is tested by randomized controlled trials