History of Dialysis in the UK: c.1950-1980

Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2009.©The Trustee of the Wellcome Trust, London, 2009.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 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Dialysis, the first technological substitution for organ function, is significant not only for the numbers of patients who have benefited. It contributed to the emergence of the field of medical ethics and the development of the nurse specialist, and transformed the relationship between physicians and patients by allowing patients to control their treatment. This seminar drew on participants’ recollections of dialysis from the early, practically experimental days after the Second World War, when resources for research were scant, until the 1980s when it had become an established treatment. Pioneers from the first UK dialysis units recalled the creation of the specialty of nephrology amid discouragement from renal physicians and the MRC, which felt that the artificial kidney was a gadget that would not last. International and interdisciplinary collaborations, and interactions between with industry and clinics in developing and utilising the specialist technology were emphasized. Patients, carers, nurses, technicians and doctors reminisced about their experiences of home dialysis, its complications and impact on family life, as well as the physical effects of surviving on long-term dialysis before transplantation became routine. The meeting was suggested and chaired by Dr John Turney and witnesses include Dr Rosemarie Baillod, Professor Christopher Blagg, Professor Stewart Cameron, Mr Eric Collins, Professor Robin Eady, Mrs Diana Garratt, Professor David Kerr, Professor Sir Netar Mallick, Dr Frank Marsh, Dr Jean Northover, Dr Chisholm Ogg, Dr Margaret Platts, Dr Stanley Rosen and Professor Stanley Shaldon. Two appendices contain reminiscences from Professor Kenneth Lowe and Sir Graham Bull. Crowther S M, Reynolds L A, Tansey E M. (eds) (2009) History of dialysis in the UK: c. 1950–2000, Wellcome Witnesses to Twentieth Century Medicine, vol. 37. London: The Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978 085484 1226The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

The Medicalization of Cannabis

Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.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 24 March 2009. Introduction by Professor Leslie Iversen.Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.Annotated and edited transcript of a Witness Seminar held on 24 March 2009. Introduction by Professor Leslie Iversen.Cannabis has been considered as both an illicit drug and a medicine throughout its history. Introduced to the UK as a medicine in the nineteenth century, its medical utility was limited and it was not until tetrahydrocannabinol (THC), one of the principal active components in cannabis, was isolated in 1964 by Raphael Mechoulam and his team in Israel that scientific research on the drug expanded. Further major developments came in the 1980s, when the cannabinoid receptors in the brain were discovered. Scientists, clinicians, policy makers and patients interested in exploring and utilizing cannabis as an orthodox medication attended this seminar. Several were involved with the early elucidation of the structures of the components of the cannabis plant, or with the two MRC-funded trials in the 1990s into the therapeutic effect of cannabis on multiple sclerosis (MS) and postoperative pain. The founding director of GW Pharmaceuticals discussed the problems of growing cannabis plants and standardizing extracts to produce a medicine that could gain regulatory approval. Two MS patients related their experiences of cannabinoid medications and the significance of patient activism and self-medication in renewing research interest in the potential medical benefits of cannabis, against the backdrop of increasing recreational use, was also considered. The meeting was suggested by Professor Virginia Berridge, who chaired the meeting jointly with Professor E. M. Tansey. Contributors include: Professor David Baker, Professor Virginia Berridge Dr Vincenzo Di Marzo, Professor Griffith Edwards, Professor John Galloway, Dr Edward Gill, Dr Geoffrey Guy, Dr Clare Hodges, Dr Anita Holdcroft, Ms Victoria Hutchins, Professor Raphael Mechoulam, Professor Anthony Moffat, Dr William Notcutt, Professor Roger Pertwee, Dr Philip Robson, Dr Ethan Russo, Professor Tilli Tansey, Ms Suzanne Taylor. One appendix gives diagrams of the structures of the major plant cannabinoids and structurally-related synthetic cannabinoids. Crowther S M, Reynolds L A, Tansey E M. (eds) (2010) The Medicalization of Cannabis, Wellcome Witnesses to Twentieth Century Medicine, vol. 40. London: The Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978 085484 129 5The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

The Resurgence of Breastfeeding, 1975-2000

Annotated and edited transcript of a Witness Seminar held on 24 April 2007. Introduction by Professor Rima Apple, University of Wisconsin-Madison.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2009.©The Trustee of the Wellcome Trust, London, 2009.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 24 April 2007. Introduction by Professor Rima Apple, University of Wisconsin-Madison.Annotated and edited transcript of a Witness Seminar held on 24 April 2007. Introduction by Professor Rima Apple, University of Wisconsin-Madison.Annotated and edited transcript of a Witness Seminar held on 24 April 2007. Introduction by Professor Rima Apple, University of Wisconsin-Madison.Annotated and edited transcript of a Witness Seminar held on 24 April 2007. Introduction by Professor Rima Apple, University of Wisconsin-Madison.As breast-milk substitutes became iAs breast-milk substitutes became increasingly sophisticated and heavily marketed in the mid-twentieth century, bottle-feeding became regarded worldwide as safe, convenient, normal and even preferable to breastfeeding. From 1975, research conducted in the developing world, particularly Gambia, began to converge with work on immunology and child psychology to reassert the value of mothers’ own milk. At the same time, growing understanding of physiology, reproductive and developmental biology shifted interest from the composition of infant formulae to the biology of infant feeding. Insights from comparative zoology, dairy science and animal husbandry, shared with research in human lactation and ‘naturalization’ of childbirth all helped to de-medicalize infant feeding. Chaired by Professor Lawrence Weaver, this Witness Seminar was attended by representatives from women’s groups, pressure groups and international organizations, including Baby Milk Action, IBFAN, La Leche League, the National Childbirth Trust, WHO and UNICEF, as well as paediatricians, obstetricians, physiologists, nutritional scientists, zoologists, psychologists and members of industry. The discussion addressed the critical events, scientific advances, and social and political steps that drove the resurgence of breastfeeding, focusing not only on the nutritional science but also on the social context in which the changes took place. Participants included: Mr James Akre, Professor Elizabeth Alder, Mrs Phyll Buchanan, Professor Forrester Cockburn, Ms Rosie Dodds, Mrs Jill Dye, Professor Fiona Dykes, Ms Hilary English, Miss Chloe Fisher, Professor Anna Glasier, Professor Lars Hanson, Dr Elisabet Helsing, Dr Edmund Hey, Professor Peter Howie, Professor Alan McNeilly, Professor Kim Michaelsen, Mrs Rachel O’Leary, Ms Gabrielle Palmer, Professor Malcolm Peaker, Dr Ann Prentice,Professor Mary Renfrew, Mrs Patti Rundall, Ms Ellena Salariya, Dr Felicity Savage, Professor Roger Short, Dr Mary Smale, Dr Alison Spiro, Dr Penny Stanway, Dr Tilli Tansey, Mrs Jenny Warren, Mr John Wells, Professor Brian Wharton, Professor Roger Whitehead, Dr Anthony Williams, Miss Carol Williams and Dr Michael Woolridge. Crowther S M, Reynolds L A, Tansey E M. (eds) (2009) The resurgence of breastfeeding, 1975–2000, Wellcome Witnesses to Twentieth Century Medicine, vol. 35. 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

Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.

Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation

Changing trends and the impact of alcohol on the HIV/AIDS epidemic in South Africa: Review

The association between increased HIV infection and alcohol use has been extensively studied and is established. South Africa is among one of the sub-Saharan African countries with the highest prevalence and number of people living with HIV/AIDS in the world. Although recent evidence suggests that the epidemic has stabilised, infection rates remain unacceptably high. Alcohol use is on the increase, particularly in the groups most susceptible to HIV infection, namely women and young adults, and informs poor choices with respect to safer sexual practices. This paper reviews the association between alcohol and HIV. More specifically, however, it aims to explore the potential socio-politico-biological and cultural explanations as to the factors that intersect to drive these two epidemic diseases: alcoholism and HIV/AIDS in South Africa. Understanding some of the underlying factors will provide a framework to implement public health measures to curb HIV.Keywords: HIV, AIDS, South Africa, alcohol, politics of South Africa.L’association entre l’augmentation du VIH et la consommation d’alcool fait l’objet d’une étude. L’Afrique du Sud reste l’un des pays Sub-Saharien les plus touché par un taux de prévalence élevé et par le nombre de personnes vivant avec le VIH/SIDA dans le monde. Bien que les dernières objectives fussent de stabiliser l’épidémie, néanmoins le taux d’infection reste inacceptable. L’utilisation de l’alcool, particulièrement chez les femmes et les jeunes, est susceptible d’augmenter l’infection du VIH, et le peu d’information qu’ils ont sur le respect des pratiques sexuels sûr. L’article examine le lien entre l’association de l’alcool et le VIH, plus spécifiquement, cependant elle vise à explorer des explications potentielles socio-politico-culturelles et biologiques sur les facteurs de ces maladies épidémiques alcoolisme et le VIH/SIDA en Afrique du Sud. Il faut comprendre que les facteurs sous-jacents fourniront un cadre pour mettre en oeuvre des mesures de santé publique pour lutter contre le VIH

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BackgroundA previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.MethodsIn order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).ResultsOf the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.ConclusionOff-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies

A survey of farmers’ perceptions and management strategies of the sweet potato weevil in Homa bay county, Kenya

Sweet potato (Ipomoea batatas L.) is one of the most widely grown root cropsworldwide. In Africa, it is grown in small plots by poorer farmers. Production of thecrop is extremely low in Kenya as compared to other African countries due to theexistence of common insect pests. Sweet potato weevil (Cylas spp.) is known as thebiggest pit fall for production and productivity of the crop in the country. This studysought to determine the opinion of sweet potato farmers concerning sweet potatoresistance to Cylas spp. and determine control strategies employed by sweet potatofarmers in managing the pest. The study also sought to determine the sweet potatoproduction constraints faced by the farmers in Homa Bay County, Kenya. The studywas conducted using a Participatory Rural Appraisal approach in which 269 farmers inthe County were interviewed on the sweet potato varieties with field resistance to Cylasspp., the crops’ production constraints (with emphasis on damage by Cylas spp.) andfarmers’ control strategies in regard to the weevil. Data were also collected from thefarmers whose sample size was determined using the table on sample size selection andstandardization equation. Data were analysed using descriptive statistical techniquesthat were frequencies, percentages and standard errors. The study established thatmajority of the farmers from Rachuonyo (89.7%) and Ndhiwa (91.9%) were not awareof any variety that had field resistance to Cylas spp. However, 10.5% of the farmers inRachuonyo and 8.1% of the farmers in Ndhiwa identified nine varieties which haveshown relative field resistance to root damage by Cylas spp. The varieties that wereidentified to be resistant to Cylas spp. by farmers in Rachuonyo were Kalamb Nyerere,Tombra, Sinia, Odinga, Kemb 10, Wera and Zapallo. However, the varieties that wereidentified to be resistant to Cylas spp. by farmers in Ndhiwa were Amina, Mugandeand Ndege Oyiejo. Further, the findings revealed that Cylas spp. was the mostproblematic pest by 90.3% and 96.8% of households in Rachuonyo and Ndhiwa,respectively. Majority (64.5%) of the farmers in Ndhiwa did not use any methods tomanage Cylas spp. However, farmers in Rachuonyo (26.2%) and Ndhiwa (15.3%)preferred re-ridging during weeding as a management strategy in regard to Cylas spp.These findings reiterate the importance of the sweet potato weevil in rural sweet potatofarming systems and thus innovative management strategies are necessary.Key words: Sweet potato, control strategies, Cylas spp., resistance, pest, variety,constraint

Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

INFLUENCE OF ANKLE PASSIVE RANGE OF MOTION ON THE PERFORMANCE OF THE STAR EXCURSION BALANCE TEST

The purpose of this study was to measure the association between ankle passive range of motion (PROM) and the horizontal distance reached during the Star Excursion Balance Test (SEBT). Nineteen participants without any musculoskeletal and neurological injury performed the SEBT on eight directions proposed in the original protocol. The ankle PROM was measured with a manual goniometric device prior to the performance of the test. To determine the association between the distance reached during SEBT and the ankle PROM, we used the Pearson Correlation Coefficient Test (“r”). All directions of SEBT showed low correlation with the ankle PROM without significant differences for any variable. We concluded that the ankle PROM is not a confounding variable that should be monitored for use the SEBT for healthy individuals