key: cord-0009234-d1gm02ji
authors: Sellal, François; Stoll-Keller, Françoise
title: Rabies: ancient yet contemporary cause of encephalitis
date: 2005-03-11
journal: Lancet
DOI: 10.1016/s0140-6736(05)71060-6
sha: 55d5a4930204e858d6a980e0f268b7d3b60ff3a3
doc_id: 9234
cord_uid: d1gm02ji

nan

beyond regulation and involves defining in general terms what a doctor is and what a doctor does. In many respects, the GMC's standards constitute a social contract or compact with society on medical practice. 8 Arguments for a new compact that gives primacy to patients' interests allied to effective accountability have already been made, 9, 10 and the findings of the inquiry reinforce the case. In his discussion of the attack on professionalism and the decline in status of professions in the past 25 years, particularly medicine in the USA, Freidson has highlighted the weakened credibility of professional claims to be an independent principled moral voice. 11 He argues that if professionalism is to be restored, it must strengthen its moral voice-the most visible means of which would be by improving methods of adjudicating and correcting violations of ethical codes of practice. But forging a new compact and getting doctors to adopt it will demand a clear sense of purpose and strong leadership by the medical institutions, including the GMC. 12 The collective failure of these institutions to provide effective leadership on a fundamental principle of medical practice raises doubts about their ability to take up the challenge, and consequently creates concern about how they are currently constituted. The time has come to explore the need for major reform of the medical institutions to make them fit to sustain professionalism and respond to the changing expectations of society.

After a series of failures and scandals in recent years, culminating in the finding that expediency has taken precedence over principle, the medical profession in the UK now finds itself needing to defend professionalism and renegotiate its social contract. The contract that eventually emerges will be dictated by the degree of determination and leadership shown by the medical institutions, including the GMC. It is not too late for the most honourable of all professions to show that it can be trusted to define and defend its own standards, but time is very short.

Department of Health Sciences, University of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK rb14@le.ac.uk I was a witness to the Shipman Inquiry, prepared reports at its request, and was a member of several of its seminars. Christoph Schankin et al 1 recently reported a patient who developed rabies encephalitis on his return from India. This report provides an opportunity to recall that rabies is not only an old fatal disease, whose first description dates from the 23rd century BC, but also a re-emerging zoonosis. Although preventable by vaccination, rabies is still not effectively controlled and its true impact is largely underestimated. 2 Except in Australia, Japan, and Scandinavia, animal rabies occurs on all continents, with the dog as the principal vector and reservoir of Lyssavirus. In western Europe, control of stray dogs and campaigns of oral vaccination of dogs and wild animals, especially foxes, has led to a significant reduction in the number of rabies cases. Since 2001, France has been considered free of rabies, and the UK is said to never have had an indigenous case. These satisfactory results are questioned by recent data showing risks associated with illegally imported animals from infected countries, 3 and new reservoirs in Scotland in Rabies: ancient yet contemporary cause of encephalitis Comment indigenous insectivorous bats. 4 In North America, bats are the main vector of rabies, because 32 of the 35 most recent cases of human rabies were caused by bat strains of the virus. 5 Lyssaviruses are single-stranded RNA viruses. Because their genome is replicated by a polymerase devoid of a proof-reading mechanism, they are fast-evolving organisms capable of adapting to new hosts, which makes them among the most dangerous pathogens, like HIV, the coronavirus that causes severe acute respiratory syndrome, and influenza virus. Molecular studies have estimated that Lyssaviruses have already switched from the Chiroptera to the Carnivora order, probably between 888 and 1459 years ago. 6 The usual mode of transmission is through the bite of an infected animal or, more rarely, scratching and licking, as in Schankin et al's case. The reality is less straightforward: in 32 US cases caused by bat strains of virus, only 12 had physical contact with a bat. 5 The silver-haired bat variant, responsible for some of these newly emerging cases in North America, is not associated with any known history of conventional exposure. This variant has a unique cellular tropism and can replicate in epidermal cells and then penetrate a nerve. Hence, only a small superficially administered quantity of this virus is sufficient to cause infection and death. 7

More puzzling are the recent rabies cases in four transplant patients. 8 They all received various organs (lung, liver, kidney) from the same donor, who was not diagnosed with rabies before death. These cases raise the question of the possible spread of virus variants into solid organs via blood vessels. This idea is supported by studies indicating that rabies virus can infect macrophages. 9 In human beings, one should consider rabies in the diagnosis of neuropsychiatric disorders in a patient who has been in contact with animals and has been in an infected country. The encephalitic presentation, as in Schankin et al's case, is unmistakable, but the paralytic presentation, present in about 20% of cases, might mimic other diseases, such as acute disseminated encephalopathy. The organ donor mentioned above had a clinical picture mimicking subarachnoid haemorrhage. 8 Moreover, rabies virus variants might be responsible for cryptic forms of the disease.

Both clinical presentations detailed above of human rabies share similar imaging patterns-ie, mild hyperintensity changes in the brain stem, hippocampus, hypothalamus, deep subcortical white matter, and deep grey matter on T2-weighted MRI. Enhancement with gadolinium seems to show up on images only late, when the patient becomes comatose. 10 Rapid and accurate detection of rabies virus in specimens is required when rabies is suspected. RT-PCR can detect rabies virus RNA in central nervous system tissue, saliva, spinal fluid, tears, skin biopsy samples, and urine within 3 days after clinical onset, and should be developed for use even in the laboratory conditions prevailing in developing countries. 11, 12 Since 1970, there have been medical reports of five patients who survived rabies encephalitis. 5 However, they all had severe sequelae. Therefore, today, the recommendation remains treatment before any clinical sign. Wound soap-washing and postexposure vaccination are the only means of preventing human death, but the best prophylaxis would be the elimination of animal rabies. Rights were not granted to include this image in electronic media. Please refer to the printed journal. The concept of nanoscience arose in a lecture by the physicist Richard Feynman in 1959, 1 and the remarkable possibilities of nanotechnology in molecular manufacturing were discussed by Drexler in 1986. 2 Rapid developments in nanotechnology have led, like other technological advances, to predictions of great benefits and also great dangers to humanity and the ecosystem. In response to these, the Royal Society and the Royal Academy of Engineering have reported on the opportunities and uncertainties surrounding these technological developments across the range of materials science, metrology, electronics, and nanomedicine. 3 We discuss here some of the implications for toxicology and human health. There are realistic prospects of benefits to medicine from nanotechnology, in terms of earlier more accurate diagnosis, imaging, and drug delivery and in better communication systems; few nanotechnologies pose a direct threat to humanity or the environment. There are, however, some foreseeable hazards, especially from nanoparticles and nanotubes. Our understanding of two pathogenic inhaled particles illuminates possible problems with the development of these nanotechnologies and points to methods of risk reduction.

The medical problems associated with the exploitation of amphibole asbestos are well known. Accumulation in lung and thus hazard is explained by thinness, long needle-like shape, and insolubility. 4 This understanding allows us to predict hazard associated with exposure to carbon and other nanotubes-key new nanomaterials. Nanotubes are fibres a few nanometres in diameter but many microns in length, with many useful properties and potential applications. However, nanotubes might have three of the properties that dictate hazard in amphibole asbestos; thinness, length, and insolubility. Taking account of hazard, risk is determined by dose and so inhalation of a sufficient dose of long nanotubes into the lungs could initiate pathological processes leading to the same diseases that asbestos causes.

Modest rises in the mass of air-pollution particles are associated with excess deaths and episodes of illness, most of which are cardiovascular rather than respiratory. Traffic-derived nanoparticles are likely to be responsible for these cardiovascular effects, by three possible pathways. First, we have hypothesised 5,6 that inhaled nanoparticles cause inflammation, changes in blood coagulability, and increased risk of heart attack in people made vulnerable by coronary artery disease. Second, nanoparticles may translocate from the lungs to the blood, 7 where they might interact with endothelium to promote thrombosis or destabilise atheromatous plaques. Third, some of the cardiovascular effects of particulate pollution suggest an autonomic reflex, 8 giving rise to speculation that nanoparticles stimulate or even penetrate nerves. Penetration into nerves has been supported by observations that dogs in polluted Mexico City accumulate air-pollution metals in their brains 9 and that, in rats, nanoparticles pass via the olfactory nerve to the brain. 10 Investigation of air-pollution particles shows that nanoparticles have two characteristics setting them apart from larger particles and which promote their toxicity. First, surface activity is important in determining toxicity and, mass for mass, the smaller the particles, the greater the surface; second, particles tens

Nanoscience, nanotoxicology, and the need to think small of bat rabies virus responsible for newly emerging human rabies cases in North America

Rabies transmission from organ transplants in the USA

Rabies virus replication in primary murine bone marrow macrophages and in human and murine macrophage-like cell lines: implication for viral persistence

MR imaging in human rabies

Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges

Antemortem diagnosis of human rabies