Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

Experience with selective venous sampling in diagnosis of ACTH-dependent Cushing's syndrome.

Twenty-three patients with adrenocorticotrophic hormone-(ACTH)-dependent Cushing''s syndrome were subjected to selective venous catheterisation and sampling for ACTH on a total of 26 occasions. Out of 10 patients with pituitary-dependent disease, nine had raised ACTH concentrations in one or both high internal jugular vein samples. Eight patients had 11 proved sites of ectopic hormone production: of these, six were correctly identified by the sampling technique, and in four of them this was the only accurate method of localisation. The results of one catheterisation were misleading, and on 10 occasions they were inconclusive; five patients remained undiagnosed by any method. Overall, 15 of the 26 catheterisations provided diagnostically valuable information. Selective venous catheterisation and sampling for ACTH is effective in confirming a pituitary source of the hormone and may be valuable in locating the source of ectopic ACTH production in some cases.     

An assessment of the breeding range,colony sizes and population of the Westland petrel (Procellaria westlandica)

Abstract

The Westland petrel (Procellaria westlandica) is an endemic New Zealand species and one of the very few burrowing seabird species still breeding on mainland New Zealand. It nests only on a series of coastal ridgelines near to Punakaiki on the West Coast of the South Island. Between 2002 and 2005, surveys were undertaken at 28 of the 29 known colonies. The area occupied by the colonies was 73 ha; most colonies had fewer than 50 burrows, but six colonies had 201–500 burrows and four colonies had more than 1000 burrows. We find that the current breeding range of Westland petrel and the location of individual colonies are similar to those reported in both the 1950s and 1970s. Based on total burrow counts at 28 colonies and burrow occupancy rates determined by annual monitoring, the annual breeding population is estimated to be between 2954 and 5137 breeding pairs.     

Neural correlates of behavioral preference for culturally familiar drinks

Coca-Cola (Coke) and Pepsi are nearly identical in chemical composition, yet humans routinely display strong subjective preferences for one or the other. This simple observation raises the important question of how cultural messages combine with content to shape our perceptions; even to the point of modifying behavioral preferences for a primary reward like a sugared drink. We delivered Coke and Pepsi to human subjects in behavioral taste tests and also in passive experiments carried out during functional magnetic resonance imaging (fMRI). Two conditions were examined: (1) anonymous delivery of Coke and Pepsi and (2) brand-cued delivery of Coke and Pepsi. For the anonymous task, we report a consistent neural response in the ventromedial prefrontal cortex that correlated with subjects' behavioral preferences for these beverages. In the brand-cued experiment, brand knowledge for one of the drinks had a dramatic influence on expressed behavioral preferences and on the measured brain responses.     

Symbolic reachable set computation of piecewise affine hybrid automata and its application to biological modelling: Delta-Notch protein signalling

Hybrid automata are an eminently suitable modelling framework for biological protein regulatory networks, as the protein concentration dynamics inside each biological cell are modelled using linear differential equations; inputs activate or deactivate these continuous dynamics through discrete switches, which themselves are controlled by protein concentrations reaching given thresholds. This paper proposes an iterative refinement algorithm for computing discrete abstractions of a class of hybrid automata with piecewise affine continuous dynamics and forced discrete transitions, defined completely in terms of symbolic variables and parameters. Furthermore, these discrete abstractions are utilised to compute symbolic parametric backward reachable sets from the equilibria of the hybrid automata, that are guaranteed to be exact or conservative under-approximations. The algorithm is then implemented using MATLAB and QEPCAD, to compute reachable sets for the biologically observed equilibria of the multiple cell Delta-Notch protein signalling automaton with symbolic parameters. The results are analysed to show that novel, non-intuitive, and biologically interesting properties can be deduced from the reachability computation, thus demonstrating the utility of the algorithm.     

Interdomain salt‐bridges in the Ebola virus protein VP40 and their role in domain association and plasma membrane localization

The Ebola virus protein VP40 is a transformer protein that possesses an extraordinary ability to accomplish multiple functions by transforming into various oligomeric conformations. The disengagement of the C‐terminal domain (CTD) from the N‐terminal domain (NTD) is a crucial step in the conformational transformations of VP40 from the dimeric form to the hexameric form or octameric ring structure. Here, we use various molecular dynamics (MD) simulations to investigate the dynamics of the VP40 protein and the roles of interdomain interactions that are important for the domain–domain association and dissociation, and report on experimental results of the behavior of mutant variants of VP40. The MD studies find that various salt‐bridge interactions modulate the VP40 domain dynamics by providing conformational specificity through interdomain interactions. The MD simulations reveal a novel salt‐bridge between D45‐K326 when the CTD participates in a latch‐like interaction with the NTD. The D45‐K326 salt‐bridge interaction is proposed to help domain–domain association, whereas the E76‐K291 interaction is important for stabilizing the closed‐form structure. The effects of the removal of important VP40 salt‐bridges on plasma membrane (PM) localization, VP40 oligomerization, and virus like particle (VLP) budding assays were investigated experimentally by live cell imaging using an EGFP‐tagged VP40 system. It is found that the mutations K291E and D45K show enhanced PM localization but D45K significantly reduced VLP formation.     

The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.     

Consensus decision-making: performance of heuristics and mental models

Consensus decision-making, found in settings ranging from formal institutions to ad hoc groups, represents a critical component of human social interaction. In such cases, decision-makers often must agree to a course of action with awareness of others' behavior (e.g., votes) but not group members' underlying motivations and strategies. How, then, should individual agents/decision-makers balance the payoffs of available options against the time it takes to reach consensus (ranging from quick consensus to stalemate)? In the current research, a novel, repeated consensus task was played by simulated agents. These agents differed in how they a) evaluated the available options and b) anticipated the choices of fellow group members. While intuition may suggest that intractably selfish agents will outcompete those willing to compromise, the data demonstrate that socially minded agents – i.e., one type that employed a simple heuristic and two types that employed sophisticated social cognition – were the only ones to exhibit evolutionarily stable strategies. However, sophisticated cognition did not guarantee good performance, suggesting that caution is warranted in trying to “outsmart” competing agents. While these agents were restricted to simple behaviors, the approach and models described here provide a potentially useful framework for studying consensus in humans.     

Bronchoabsorption; a novel bronchoscopic technique to improve biomarker sampling of the airway

Background

Current techniques used to obtain lung samples have significant limitations and do not provide reproducible biomarkers of inflammation. We have developed a novel technique that allows multiple sampling methods from the same area (or multiple areas) of the lung under direct bronchoscopic vision. It allows collection of mucosal lining fluid and bronchial brushing from the same site; biopsy samples may also be taken. The novel technique takes the same time as standard procedures and can be conducted safely.

Methods

Eight healthy smokers aged 40–65 years were included in this study. An absorptive filter paper was applied to the bronchial mucosa under direct vision using standard bronchoscopic techniques. Further samples were obtained from the same site using bronchial brushings. Bronchoalveolar lavage (BAL) was obtained using standard techniques. Chemokine (C-C Motif) Ligand 20 (CCL20), CCL4, CCL5, Chemokine (C-X-C Motif) Ligand 1 (CXCL1), CXCL8, CXCL9, CXCL10, CXCL11, Interleukin 1 beta (IL-1β), IL-6, Vascular endothelial growth factor (VEGF), Matrix metalloproteinase 8 (MMP-8) and MMP-9 were measured in exudate and BAL. mRNA was collected from the bronchial brushings for gene expression analysis.

Results

A greater than 10 fold concentration of all the biomarkers was detected in lung exudate in comparison to BAL. High yield of good quality RNA with RNA integrity numbers (RIN) between 7.6 and 9.3 were extracted from the bronchial brushings. The subset of genes measured were reproducible across the samples and corresponded to the inflammatory markers measured in exudate and BAL.

Conclusions

The bronchoabsorption technique as described offers the ability to sample lung fluid direct from the site of interest without the dilution effects caused by BAL. Using this method we were able to successfully measure the concentrations of biomarkers present in the lungs as well as collect high yield mRNA samples for gene expression analysis from the same site. This technique demonstrates superior sensitivity to standard BAL for the measurement of biomarkers of inflammation. It could replace BAL as the method of choice for these measurements. This method provides a systems biology approach to studying the inflammatory markers of respiratory disease progression.

Trial registration

NHS Health Research Authority (13/LO/0256).