The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lysosomal involvement

Lysosomotropic amines, such as ammonium chloride, are known to protect cells from the cytotoxic effects of diphtheria toxin. These drugs are believed to inhibit the transport of the toxin from a receptor at the cell exterior into the cytoplasm where a fragment of the toxin arrests protein synthesis. We studied the effects of lysosomotropic agents on the cytotoxic process to better understand how the toxin enters the cytoplasm. The cytotoxic effects of diphtheria toxin were not inhibited by antitoxin when cells were preincubated at 37 degrees C with toxin and ammonium chloride, exposed to antitoxin at 4 degrees C, washed to relieve the ammonium chloride inhibition, and finally warmed to 37 degrees C. The antigenic determinants of the toxin were, therefore, either altered or sheltered. It is likely that the combination of ammonium chloride and a low temperature trapped the toxin in an intracellular vesicle from which the toxin could proceed to the cytoplasm. Because lysosomotropic amines raise the pH within acidic intracellular vesicles, such as lysosomes, they could trap the toxin within such a vesicle if an acidic environment were necessary for the toxin to penetrate into the cytoplasm. We simulated acidic conditions which the toxin might encounter by exposing cells with toxin bound to their surface to acidic medium. We then measured the effects of lysosomotropic amines on the activity of the toxin to see if the acidic environment substituted for the function normally inhibited by the drugs. The drugs no longer protected the cells. This suggests that exposing the toxin to an acidic environment, such as that found within lysosomes, is an important step in the penetration of diphtheria toxin into the cytoplasm

Landscape, settlement and society: Wiltshire in the first millennium AD

This is a study of the county of Wiltshire from the Roman period toc. 11 00 AD, focusing on the key themes of landscape, settlement and society and using a combination of archaeological, topographical and historical evidence. Particular emphasis is given to place-names, which, it is argued, can help us to locate Romano-British settlements and inform us about the British survival in the post-Roman period. Early chapters tackle the transition between the Roman and Early Saxon periods, challenging current theories on the decline of Roman Britain and the Anglo-Saxon adventus. Subsequent chapters examine the evidence for early medieval territorial and ecclesiastical structure in Wiltshire, in addition to the AngloSaxon farming landscape. There is also detailed consideration of the origins of the medieval settlement pattern and a discussion of the relationship between settlements and the ranks of Anglo-Saxon society

Ethical challenges experienced by UK military medical personnel deployed to Sierra Leone (operation GRITROCK) during the 2014–2015 Ebola outbreak : a qualitative study

Background: As part of its response to the 2014 Ebola outbreak in west Africa, the United Kingdom (UK) government established an Ebola treatment unit in Sierra Leone, staffed by military personnel. Little is known about the ethical challenges experienced by military medical staff on humanitarian deployment. We designed a qualitative study to explore this further with those who worked in the treatment unit. Method: Semi-structured, face-to-face and telephone interviews were conducted with 20 UK military personnel deployed between October 2014 and April 2015 in one of three roles in the Ebola treatment unit: clinician; nursing and nursing assistant; and other medical support work, including infection control and laboratory and mortuary services. Results: Many participants reported feeling ethically motivated to volunteer for deployment, but for some personal interests were also a consideration. A small minority had negative feelings towards the deployment, others felt that this deployment like any other was part of military service. Almost all had initial concerns about personal safety but were reassured by their pre-deployment 'drills and skills', and personal protective equipment. Risk perceptions were related to perceptions about military service. Efforts to minimise infection risk were perceived to have made good patient care more difficult. Significantly, some thought the humanitarian nature of the mission justified tolerating greater risks to staff. Trust in the military institution and colleagues was expressed; many participants referred to the ethical obligation within the chain of command to protect those under their command. Participants expected resources to be overwhelmed and ‘empty beds’ presented a significant and pervasive ethical challenge. Most thought more patients could and should have been treated. Points of reference for participants’ ethical values were: previous deployment experience; previous UK/National Health Service experience; professional ethics; and, distinctly military values (that might not be shared with non-military workers). Conclusion: We report the first systematic exploration of the ethical challenges face by a Western medical military in the international response to the first major Ebola outbreak. We offer unique insights into the military healthcare workers’ experiences of humanitarian deployment. Many participants expressed motivations that gave them common purpose with civilian volunteers

Accelerating vaccine development and deployment: report of a Royal Society satellite meeting.

The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it

Driving New Zealand’s Economic Relationship With Asia: The Importance Of Growing Connections, Capacity And Confidence

How does New Zealand’s engagement across the Asia region affect New Zealand’s prosperity and security? New Zealand’s approach to developing economic, political and people-to-people connections across Asia has changed considerably over the last few decades. This article seeks to highlight some of those changes, including how the New Zealand public’s perceptions of Asia have changed over time and how this has shaped New Zealand foreign policy. The critical question is whether enough is being done – across public, private and community sectors – to help position New Zealand as a highvalue partner in Asia for the long term

Potential research participants’ use of information during the consent process : a qualitative pilot study of patients enrolled in a clinical trial

There is increasing evidence that clinical trial participants are uninformed about the trials in which they participate, raising ethical concerns regarding informed consent. The aim of this pilot study was to explore clinical trial participants’ use of consent discussions and information sheets when considering participating in clinical trials research. A qualitative, interview-based pilot study was designed in order to elicit, through dialogue, details of the reasons for participants’ use of, and preferences regarding, different modes of information provision. Semi-structured interviews were undertaken with two different groups of patients who were participants in the Reinforcement of Closure of Stoma Site trial. The first group comprised newly-consented trial participants, who had been recruited up to 72 hours before our interview; the second group comprised patients attending a follow-up clinic 12 months after joining the trial. Thirteen participants were recruited in total: three newly-consented patients, and ten follow-up patients. The study found that participants’ use of consent discussions to gain information about clinical trials was varied, and that they only minimally used information sheets after providing initial consent for the trial. Participants demonstrated varying degrees of knowledge about the trial, with some having forgotten that they were still involved in the trial. Participants reported a high level of trust in medical staff as a reason for not seeking more information about the trial. Some participants reported dissatisfaction with the timing of information provision. Some were amenable to novel ways of receiving trial information, such as web-based methods. The pilot study demonstrated the feasibility of a larger study into the provision of information to prospective clinical trial participants. The results suggest that considering alternative ways of providing information and the appropriateness of existing information provision may be acceptable to and useful for potential trial participants

Who gets the gametes? An argument for a points system for fertility patients

This paper argues that the convention of allocating donated gametes on a “first come, first served” basis should be replaced with an allocation sys-tem that takes into account more morally relevant criteria than waiting time. This conclusion was developed using an empirical bioethics method-ology, which involved a study of the views of eighteen staff members from seven UK fertility clinics, and twenty academics, policy-makers, representa-tives of patient groups, and other relevant professionals, on the allocation of donated sperm and eggs. Against these views, we consider some nu-anced ways of including criteria in a points allocation system. We argue that such a system is more ethically robust than “first come, first served”, but we acknowledge that our results suggest that a points system will meet with resistance from those working in the field. We conclude that criteria such as a patient’s age, potentially damaging substance use, and parental status should be used to allocate points and determine which patients re-ceive treatment and in what order. These and other factors should be ap-plied according to how they bear on considerations like child welfare, pa-tient welfare, and the effectiveness of the proposed treatment

Should We Reject Donated Organs on Moral Grounds or Permit Allocation Using Non-Medical Criteria?:A Qualitative Study

Conditional and directed deceased organ donations occur when donors (or often their next of kin) attempt to influence the allocation of their donated organs. This can include asking that the organs are given to or withheld from certain types of people, or that they are given to specified individuals. Donations of these types have raised ethical concerns, and have been prohibited in many countries, including the UK. In this article we report the findings from a qualitative study involving interviews with potential donors (n = 20), potential recipients (n = 9) and transplant staff (n = 11), and use these results as a springboard for further ethical commentary. We argue that although participants favoured unconditional donation, this preference was grounded in a false distinction between ‘medical’ and ‘non-medical’ allocation criteria. Although there are good reasons to maintain organ allocation based primarily upon the existing ‘medical’ criteria, it may be premature to reject all other potential criteria as being unacceptable. Part of participants' justification for allocating organs using ‘medical’ criteria was to make the best use of available organs and avoid wasting their potential benefit, but this can also justify accepting conditional donations in some circumstances. We draw a distinction between two types of waste – absolute and relative – and argue that accepting conditional donations may offer a balance between these forms of waste

Premonitory urges are associated with decreased grey matter thickness within the insula and sensorimotor cortex in young people with Tourette syndrome

Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics and is associated with cortical–striatal–thalamic–cortical circuit (CSTC) dysfunction and hyperexcitability of cortical limbic and motor regions, which are thought to lead to the occurrence of tics. Importantly, individuals with TS often report that their tics are preceded by ‘premonitory sensory phenomena’ (PSP) that are described as uncomfortable cognitive or bodily sensations that precede the execution of a tic, and are experienced as a strong urge for motor discharge. While the precise role played by PSP in the occurrence of tics is controversial, PSP are nonetheless of considerable theoretical and clinical importance in TS, not least because they form the core component in many of the behavioural therapies that are currently used in the treatment of tic disorders. In this study, we investigated the brain structure correlates of PSP. Specifically, we conducted a whole-brain analysis of cortical (grey matter) thickness in 29 children and young adults with TS and investigated the association between grey matter thickness and PSP. We demonstrate for the first time that PSP are inversely associated with grey matter thickness measurements within the insula and sensori-motor cortex. We also demonstrate that grey matter thickness is significantly reduced in these areas in individuals with TS relative to a closely age- and gender-matched group of typically developing individuals and that PSP ratings are significantly correlated with tic severity