Wellcome Trust Centre for the History of Medicine

Hundreds of individual human cancer genome sequences are expected to be published in 2010, and thousands per year after that. The International Cancer Genome Consortium (ICGC) was launched with the aim of keeping track of the data relating to large-scale cancer genome studies of all major cancers in adults and children — a total of 50 different cancer types and/or subtypes. In this issue the ICGC team ( http://www.icgc.org ) spells out the policies and planning for the project. The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

PURPOSE: A new strain of H1N1 influenza, also known as swine flu was confirmed in the UK in May 2009 and has spread to over 100 countries around the world causing the World Health Organization to declare a global flu pandemic. The primary objectives of this review are to identify the key demographic and attitudinal determinants of three types of protective behaviour during a pandemic: preventive, avoidant, and management of illness behaviours, in order to describe conceptual frameworks in which to better understand these behaviours and to inform future communications and interventions in the current outbreak of swine flu and subsequent influenza pandemics. METHODS: Web of Science and PubMed databases were searched for references to papers on severe acute respiratory syndrome, avian influenza/flu, H5N1, swine influenza/flu, H1N1, and pandemics. Forward searching of the identified references was also carried out. In addition, references were gleaned from an expert panel of the Behaviour and Communications sub-group of the UK Scientific Pandemic Influenza Advisory Group. Papers were included if they reported associations between demographic factors, attitudes, and a behavioural measure (reported, intended, or actual behaviour). RESULTS: Twenty-six papers were identified that met the study inclusion criteria. The studies were of variable quality and most lacked an explicit theoretical framework. Most were cross-sectional in design and therefore not predictive over time. The research shows that there are demographic differences in behaviour: being older, female and more educated, or non-White, is associated with a higher chance of adopting the behaviours. There is evidence that greater levels of perceived susceptibility to and perceived severity of the diseases and greater belief in the effectiveness of recommended behaviours to protect against the disease are important predictors of behaviour. There is also evidence that greater levels of state anxiety and greater trust in authorities are associated with behaviour. CONCLUSIONS: The findings from this review can be broadly explained by theories of health behaviour. However, theoretically driven prospective studies are required to further clarify the relationship between demographic factors, attitudes, and behaviour. The findings suggest that intervention studies and communication strategies should focus on particular demographic groups and on raising levels of perceived threat of the pandemic disease and belief in the effectiveness of measures designed to protect against it.

The Human Genome Project has been the first major foray of the biological and medical research communities into “big science.” In this Viewpoint, we present some of our experiences in organizing and managing such a complicated, publicly funded, international effort. We believe that many of the lessons we learned will be applicable to future large-scale projects in biology.

Recent imaging studies show that the orbitofrontal cortex (OFC) is activated during a wide variety of paradigms, including guessing tasks, simple delayed matching tasks and sentence completion. We suggest that, as with other regions of the prefrontal cortex, activity in the OFC is most likely to be observed when there is insufficient information available to determine the appropriate course of action. In these circumstances the OFC, rather than other prefrontal regions, is more likely to be activated when the problem of what to do next is best solved by taking into account the likely reward value of stimuli and responses, rather than their identity or location. We suggest that selection of stimuli on the basis of their familiarity and responses on the basis of a feeling of 'rightness' are also examples of selection on the basis of reward value. Within the OFC, the lateral regions are more likely to be involved when the action selected requires the suppression of previously rewarded responses.

Activation likelihood estimation (ALE) has greatly advanced voxel-based meta-analysis research in the field of functional neuroimaging. We present two improvements to the ALE method. First, we evaluate the feasibility of two techniques for correcting for multiple comparisons: the single threshold test and a procedure that controls the false discovery rate (FDR). To test these techniques, foci from four different topics within the literature were analyzed: overt speech in stuttering subjects, the color-word Stroop task, picture-naming tasks, and painful stimulation. In addition, the performance of each thresholding method was tested on randomly generated foci. We found that the FDR method more effectively controls the rate of false positives in meta-analyses of small or large numbers of foci. Second, we propose a technique for making statistical comparisons of ALE meta-analyses and investigate its efficacy on different groups of foci divided by task or response type and random groups of similarly obtained foci. We then give an example of how comparisons of this sort may lead to advanced designs in future meta-analytic research.

Body ownership refers to the special perceptual status of one's own body, which makes bodily sensations seem unique to oneself. We studied the neural correlates of body ownership by controlling whether an external object was accepted as part of the body or not. In the rubber hand illusion (RHI), correlated visuotactile stimulation causes a fake hand to be perceived as part of one's own body. In the present study, we distinguished between the causes (i.e., multisensory stimulation) and the effect (i.e., the feeling of ownership) of the RHI. Participants watched a right or a left rubber hand being touched either synchronously or asynchronously with respect to their own unseen right hand. A quantifiable correlate of the RHI is a shift in the perceived position of the subject's hand toward the rubber hand. We used positron emission tomography to identify brain areas whose activity correlated with this proprioceptive measure of body ownership. Body ownership was related to activity in the right posterior insula and the right frontal operculum. Conversely, when the rubber hand was not attributed to the self, activity was observed in the contralateral parietal cortex, particularly the somatosensory cortex. These structures form a network that plays a fundamental role in linking current sensory stimuli to one's own body and thus also in self-consciousness.

Age-related neurodegenerative and neurochemical changes are thought to underlie decline in motor and cognitive functions, but compensatory processes in cortical and subcortical function may allow maintenance of performance level in some people. Our objective was to investigate age-related changes in the motor system of the human brain using functional MRI. Twenty six right handed volunteers were scanned whilst performing an isometric, dynamic, visually paced hand grip task, using dominant (right) and non-dominant (left) hands in separate sessions. Hand grip with visual feedback activated a network of cortical and subcortical regions known to be involved in the generation of simple motor acts. In addition, activation was seen in a putative human 'grasping circuit', involving rostral ventral premotor cortex (Brodmann area 44) and intraparietal sulcus. Within this network, a number of regions were more likely to be activated the older the subject. In particular, age-related changes in task- specific activations were demonstrated in left deep anterior central sulcus when using the dominant or non-dominant hand. Additional age-related increases were seen in caudal dorsal premotor cortex, caudal cingulate sulcus, intraparietal sulcus, insula, frontal operculum and cerebellar vermis. We have demonstrated a clear age-related effect in the neural correlates of motor performance, and furthermore suggest that these changes are non-linear. These results support the notion that an adaptable and plastic motor network is able to respond to age-related degenerative changes in order to maintain performance levels.

Decision making under risk is central to human behavior. Economic decision theory suggests that value, risk, and risk aversion influence choice behavior. Although previous studies identified neural correlates of decision parameters, the contribution of these correlates to actual choices is unknown. In two different experiments, participants chose between risky and safe options. We identified discrete blood oxygen level-dependent (BOLD) correlates of value and risk in the ventral striatum and anterior cingulate, respectively. Notably, increasing inferior frontal gyrus activity to low risk and safe options correlated with higher risk aversion. Importantly, the combination of these BOLD responses effectively decoded the behavioral choice. Striatal value and cingulate risk responses increased the probability of a risky choice, whereas inferior frontal gyrus responses showed the inverse relationship. These findings suggest that the BOLD correlates of decision factors are appropriate for an ideal observer to detect behavioral choices. More generally, these biological data contribute to the validity of the theoretical decision parameters for actual decisions under risk.

Social relations between humans critically depend on our affective experiences of others. Oxytocin enhances prosocial behavior, but its effect on humans' affective experience of others is not known. We tested whether oxytocin influences affective ratings, and underlying brain activity, of faces that have been aversively conditioned. Using a standard conditioning procedure, we induced differential negative affective ratings in faces exposed to an aversive conditioning compared with nonconditioning manipulation. This differential negative evaluative effect was abolished by treatment with oxytocin, an effect associated with an attenuation of activity in anterior medial temporal and anterior cingulate cortices. In amygdala and fusiform gyrus, this modulation was stronger for faces with direct gaze, relative to averted gaze, consistent with a relative specificity for socially relevant cues. The data suggest that oxytocin modulates the expression of evaluative conditioning for socially relevant faces via influences on amygdala and fusiform gyrus, an effect that may explain its prosocial effects.

The purpose of the Medical Termination of Pregnancy Bill, published on 15 June 1966, was to amend and clarify the law relating to termination of pregnancy by a registered medical practitioner. When David Steel, a young Liberal MP from the Scottish Borders, put this bill forward, some suggested that a Scottish politician had no need to introduce abortion reform since Scots law was already satisfactory in this regard. Certainly, abortion law in Scotland was more flexible than its English counterpart, and the number of prosecutions few. The line between criminal and non-criminal abortion was, however, just as indistinct, with great medical uncertainty in this area. On becoming law, the 1967 Abortion Act was the first piece of abortion-related legislation to cover Scotland, England and Wales collectively. None the less, for a variety of legal and moral reasons, abortion policy and practice continued to differ on either side of the Border.

We investigated whether the proinflammatory T cell cytokines IL-17 and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4(+) T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17- and IL-22-producing CD4(+) T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, whereas bronchoalveolar lavage fluid contained higher levels of IL-22 protein compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-gamma in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17- and IL-22-producing CD4(+) T cells may play important roles in the human immune response to mycobacteria.

short illness, and Wellcome became the proprietor of the company.Although disputes with Burroughs' widow caused some

In the 1830s the obstetrician Robert Lee made a series of observations on the gravid uterus that ran counter to received wisdom. This paper recounts the way in which Lee's work was handled by the premier scientific institution of the day, the Royal Society.

While he was working at the Royal Postgraduate Medical School, Ian Donald (later Regius Professor of Midwifery, University of Glasgow and a pioneer of diagnostic ultrasound) collaborated with Albert Claireaux and Robert Steiner on histological and radiological studies of hyaline membrane disease. In 1953, Donald and Steiner published thefirst radiological study of a series of cases. The success of this research stimulated Donald's interest in imaging technologies.

Event-related functional MRI (fMRI) was used to investigate the neural correlates of memory encoding as a function of age. While fMRI data were obtained, 14 younger (mean age 21 years) and 14 older subjects (mean age 68 years) made animacy decisions about words. Recognition memory for these words was tested at two delays such that older subjects' performance at the short delay was comparable to that of the young subjects at the long delay. This allowed age-associated changes in the neural correlates of encoding to be dissociated from the correlates of differential recognition performance. Activity in left inferior prefrontal cortex and the left hippocampal formation was greater for subsequently recognized words in both age groups, consistent with the findings of previous studies in young adults. In the prefrontal cortex, these 'subsequent memory effects' were, however, left-lateralized in the younger group but bilateral in the older subjects. In addition, for the younger group only, greater activity for remembered words was observed in anterior inferior temporal cortex, as were reversed effects ('subsequent forgetting' effects) in anterior prefrontal regions. The data indicate that older subjects engage much of the same neural circuitry as younger subjects when encoding new memories. However, the findings also point to age-related differences in both prefrontal and temporal activity during successful episodic encoding.

Grey matter volume in the posterior hippocampus of London taxi drivers is greater than in age-matched controls, and the size of this increase correlates positively with time spent taxi driving (E.A. Maguire et al., 2000. Proc Natl Acad Sci USA 97: 4398-4403). This change suggests that increased posterior hippocampal grey matter volume is acquired in response to increased taxi driving experience, perhaps reflecting their detailed representation of the city. However, an alternate hypothesis is that the difference in hippocampal volume is instead associated with innate navigational expertise, leading to an increased likelihood of becoming a taxi driver. To investigate this possibility, we used structural brain imaging and voxel-based morphometry (VBM) to examine a group of subjects who were not taxi drivers. Despite this group showing a wide range of navigational expertise, there was no association between expertise and posterior hippocampal grey matter volume (or, indeed, grey matter volume throughout the brain). This failure to find an association between hippocampal volume and navigational expertise thus suggests that structural differences in the human hippocampus reflect the detail and/or duration of use of the spatial representation acquired, and not innate navigational expertise per se.

Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.

The ability to identify and react to novelty within the environment is fundamental to survival. Computational models emphasize the potential role of the hippocampus in novelty detection, its unique anatomical circuitry making it ideally suited to act as a comparator between past and present experience. The hippocampus, therefore, is viewed to detect associative mismatches between what is expected based on retrieval of past experience and current sensory input. However, direct evidence that the human hippocampus performs such operations is lacking. We explored brain responses to novel sequences of objects using functional magnetic resonance imaging (fMRI), while subjects performed an incidental target detection task. Our results demonstrate that hippocampal activation was maximal when prior predictions concerning which object would appear next in a sequence were violated by sensory reality. In so doing, we establish the biological reality of associative match-mismatch computations within the human hippocampus, a process widely held to play a cardinal role in novelty detection. Our results also suggest that the hippocampus may generate predictions about how future events will unfold, and critically detect when these expectancies are violated, even when task demands do not require it. The present study also offers broader insights into the nature of essential computations carried out by the hippocampus, which may also underpin its unique contribution to episodic memory.

The time-scale of hippocampal involvement in supporting episodic memory remains a keenly debated topic, with disagreement over whether its role is temporary or permanent. Recently, there has been interest in how navigation by hippocampally-compromised patients in environments learned long ago speaks to this issue. However, identifying patients with damage that is primarily hippocampal, control subjects matched for navigation experience, and testing their in situ navigation, present substantial problems. We met these challenges by using a highly accurate and interactive virtual reality simulation of central London (UK) to assess the navigation ability of a licensed London taxi driver who had sustained bilateral hippocampal damage. In this test, patient TT and matched control taxi drivers drove a virtual London taxi along the streets they had first learned 40 years before. We found that the hippocampus is not required for general orientation in the city either in first person or survey perspectives, detailed topographical knowledge of landmarks and their spatial relationships, or even for active navigation along some routes. However, in his navigation TT was very reliant on main artery or 'A' roads, and became lost when navigation depended instead on non-A roads. We conclude that the hippocampus in humans is necessary for facilitating navigation in places learned long ago, particularly where complex large-scale spaces are concerned, and successful navigation requires access to detailed spatial representations.

AN interesting problem, to which I hope to return."Thus, in 1915, Karl Sudhoff ended a brief note on Galen's views on "seeds of plague", but the hope was never fulfilled, and, despite citation in bibliographies, Sudhoff's little article, buried deep in the wartime pages of the Mitteilungen zur Geschichte der Medizin, excited no scholarly attention whatsoever.'This was hardly surprising, for Sudhoff himself appeared to distrust his own conclusion that Galen had in fact prefigured Fracastoro's celebrated theory of seeds of diseases and was prepared to countenance, at least briefly, the idea that some diseases were specific entities which propagated by means of their seeds.But Galenic scholarship has moved on, albeit slowly, since Sudhoff's day, and the modern picture of Galen is of a doctor far less logical, systematic and consistent than he once appeared, and more ready to accept for his own immediate purposes ideas and examples from others that did not always fit with his overall schema of humoral medicine.Thus, while supporting Sudhoff's observations, I shall also show in this paper how Galen's (and, indeed, the Hippocratics') general philosophical views militated against the further development of any ontological theory of disease.Galen wrote of seeds of disease in a context of contagion and communicable diseases, and this paper will also have to concern itself, although not at great length, with ancient ideas and perceptions of contagion.Historians have occasionally denied to the doctors of antiquity a knowledge of contagion on the grounds that they had no theory of seeds of disease or of germs, but this is to confuse an appreciation of conta- gion qua contagiousness with one explanation of its mechanics.A belief in a theory of seeds presupposes a belief in contagious (or communicable) diseases, but the reverse is not true, for there were always other possible hypotheses, like that of putrid air, to explain why, for instance, phthisis was easily caught.Usually, contagion was