Clinical Genetics in Britain: Origins and development

Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2010.©The Trustee of the Wellcome Trust, London, 2010.All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Clinical genetics has become a major medical specialty in Britain since its beginnings with Lionel Penrose’s work on mental handicap and phenylketonuria (PKU) and John Fraser Robert’s first genetic clinic in 1946. Subsequent advances in diagnosis and prediction have had key impacts on families with inherited disorders and prospective parents concerned about their unborn children. The Witness Seminar focused on the beginnings of British clinical genetics in London, Oxford, Liverpool and Manchester, the development of subspecialties, such as dysmorphology, and also the roles of the Royal College of Physicians, the Clinical Genetics Society and the Department of Health in the establishment of clinical genetics as a specialty in 1980. Specialist non-medical genetic counsellors, initially from the fields of nursing and social work, progressively became a more significant part of genetic services, while lay societies also developed an important influence on services. Prenatal diagnosis became possible with the introduction of new genetic tools in regional centres to identify fetal anomalies and chromosomal disorders. This volume complements the 2001 Witness Seminar on genetic testing which emphasizes laboratory aspects of medical genetics, with limited coverage of clinical genetics. Participants include: Ms Chris Barnes, Dr Caroline Berry, Professor Martin Bobrow (chair), Professor Sir John Burn, Dr Ian Lister Cheese, Professor Angus Clarke, Dr Clare Davison, Professor Joy Delhanty, Dr Nick Dennis, Professor Dian Donnai, Professor Alan Emery, Professor George Fraser, Mrs Margaret Fraser Roberts, Professor Peter Harper, Dr Hilary Harris, Professor Rodney Harris, Professor Shirley Hodgson, Dr Alan Johnston, Mrs Ann Kershaw, Mrs Lauren Kerzin-Storrar, Professor Michael Laurence, Professor Ursula Mittwoch, Professor Michael Modell, Professor Marcus Pembrey, Professor Sue Povey, Professor Heather Skirton, Professor Sir David Weatherall. Harper P A, Reynolds L A, Tansey E M. (eds) (2010) Clinical genetics in Britain: Origins and development. Wellcome Witnesses to Twentieth Century Medicine, vol. 39. London: The Wellcome Trust Centre for the History of Medicine at UCL.The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

Determinants of Alcohol, Khat, and Bhang Use in Rural Kenya

The study investigated local determinants of substance use in rural Kenya. Over the years, there has been a growing concern over increased use of substances across ages, gender, religious persuasions, and social class in Kenya. It is still unclear what psychosocial individual and/or community factors might be that offer some explanation for the high levels of alcohol and drug use. The study investigated community members’ social status in areas of gender, education, employment, self–esteem, and availability of substances. The sample was comprised of Kenyan rural participants, and included 153 men and 64 women with a mean age of 34.2 years. The participants completed a survey measuring possible psychosocial determinants of alcohol, khat and bhang (i.e., marijuana) use patterns. The sample evidenced high levels of substance use particularly involving the locally available substances (i.e., bottled beer, local brews, chewing khat, smoking bhang). Males in comparison to females were more likely to drink alcohol, chew khat, and smoke bhang. Women compared to men reported higher education and employment status, which were associated with less substance use. Females had higher self-esteem when they did not use bottled beer whereas males had higher self-esteem when they use bottled beer. The implications of these findings are discussed.Keywords: psychosocial determinants, substance use, rural, age, gender, social clas

Altered brain connectivity in sudden unexpected death in epilepsy (SUDEP) revealed using resting-state fMRI.

The circumstances surrounding SUDEP suggest autonomic or respiratory collapse, implying central failure of regulation or recovery. Characterisation of the communication among brain areas mediating such processes may shed light on mechanisms and noninvasively indicate risk. We used rs-fMRI to examine network properties among brain structures in people with epilepsy who suffered SUDEP (n = 8) over an 8-year follow-up period, compared with matched high- and low-risk subjects (n = 16/group) who did not suffer SUDEP during that period, and a group of healthy controls (n = 16). Network analysis was employed to explore connectivity within a 'regulatory-subnetwork' of brain regions involved in autonomic and respiratory regulation, and over the whole-brain. Modularity, the extent of network organization into separate modules, was significantly reduced in the regulatory-subnetwork, and the whole-brain, in SUDEP and high-risk. Increased participation, a local measure of inter-modular belonging, was evident in SUDEP and high-risk groups, particularly among thalamic structures. The medial prefrontal thalamus was increased in SUDEP compared with all other control groups, including high-risk. Patterns of hub topology were similar in SUDEP and high-risk, but were more extensive in low-risk patients, who displayed greater hub prevalence and a radical reorganization of hubs in the subnetwork. SUDEP is associated with reduced functional organization among cortical and sub-cortical brain regions mediating autonomic and respiratory regulation. Living high-risk subjects demonstrated similar patterns, suggesting such network measures may provide prospective risk-indicating value, though a crucial difference between SUDEP and high-risk was altered connectivity of the medial thalamus in SUDEP, which was also elevated compared with all sub-groups. Disturbed thalamic connectivity may reflect a potential non-invasive marker of elevated SUDEP risk

'Colour and communion': Exploring the influences of visual art-making as a leisure activity on older women's subjective well-being

This is the post-print version of the final paper published in Journal of Aging Studies. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2009 Elsevier B.V.Research into the subjective experience of art-making for older people is limited, and has focused mostly on professional artists rather than amateurs. This study examined older women's motives for visual art-making. Thirty-two participants aged 60-86 years old were interviewed. Twelve lived with chronic illness; twenty reported good health. Nearly all had taken up art after retirement; two had since become professional artists. Participants described their art-making as enriching their mental life, promoting enjoyment of the sensuality of colour and texture, presenting new challenges, playful experimentation, and fresh ambitions. Art also afforded participants valued connections with the world outside the home and immediate family. It encouraged attention to the aesthetics of the physical environment, preserved equal status relationships, and created opportunities for validation. Art-making protected the women's identities, helping them to resist the stereotypes and exclusions which are commonly encountered in later life.AHR

A Novel Hap1-Tsc1 interaction regulates neuronal mTORC1 signaling and morphogenesis in the brain

Tuberous sclerosis complex (TSC) is a leading genetic cause of autism. The TSC proteins Tsc1 and Tsc2 control the mTORC1 signaling pathway in diverse cells, but how the mTORC1 pathway is specifically regulated in neurons remains to be elucidated. Here, using an interaction proteomics approach in neural cells including neurons, we uncover the brain-enriched protein huntingtin-associated protein 1 (Hap1) as a novel functional partner of Tsc1. Knockdown of Hap1 promotes specification of supernumerary axons in primary hippocampal neurons and profoundly impairs the positioning of pyramidal neurons in the mouse hippocampus in vivo. The Hap1 knockdown-induced phenotypes in primary neurons and in vivo recapitulate the phenotypes induced by Tsc1 knockdown. We also find that Hap1 knockdown in hippocampal neurons induces the downregulation of Tsc1 and stimulates the activity of mTORC1, as reflected by phosphorylation of the ribosomal protein S6. Inhibition of mTORC1 activity suppresses the Hap1 knockdown-induced polarity phenotype in hippocampal neurons. Collectively, these findings define a novel link between Hap1 and Tsc1 that regulates neuronal mTORC1 signaling and neuronal morphogenesis, with implications for our understanding of developmental disorders of cognition

Altered brain connectivity in sudden unexpected death in epilepsy (SUDEP) revealed using resting-state fMRI

The circumstances surrounding SUDEP suggest autonomic or respiratory collapse, implying central failure of regulation or recovery. Characterisation of the communication among brain areas mediating such processes may shed light on mechanisms and noninvasively indicate risk. We used rs-fMRI to examine network properties among brain structures in people with epilepsy who suffered SUDEP (n = 8) over an 8-year follow-up period, compared with matched high- and low-risk subjects (n = 16/group) who did not suffer SUDEP during that period, and a group of healthy controls (n = 16). Network analysis was employed to explore connectivity within a ‘regulatory-subnetwork’ of brain regions involved in autonomic and respiratory regulation, and over the whole-brain. Modularity, the extent of network organization into separate modules, was significantly reduced in the regulatory-subnetwork, and the whole-brain, in SUDEP and high-risk. Increased participation, a local measure of inter-modular belonging, was evident in SUDEP and high-risk groups, particularly among thalamic structures. The medial prefrontal thalamus was increased in SUDEP compared with all other control groups, including high-risk. Patterns of hub topology were similar in SUDEP and high-risk, but were more extensive in low-risk patients, who displayed greater hub prevalence and a radical reorganization of hubs in the subnetwork. SUDEP is associated with reduced functional organization among cortical and sub-cortical brain regions mediating autonomic and respiratory regulation. Living high-risk subjects demonstrated similar patterns, suggesting such network measures may provide prospective risk-indicating value, though a crucial difference between SUDEP and high-risk was altered connectivity of the medial thalamus in SUDEP, which was also elevated compared with all sub-groups. Disturbed thalamic connectivity may reflect a potential non-invasive marker of elevated SUDEP risk

Altered cell cycle regulation helps stem-like carcinoma cells resist apoptosis

Reemergence of carcinomas following chemotherapy and/or radiotherapy is not well understood, but a recent study in BMC Cancer suggests that resistance to apoptosis resulting from altered cell cycle regulation is crucial