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Background: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. Methods: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. Findings: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: –27·7 [41·4] m; placebo: –30·3 [60·5] m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. Interpretation: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Funding: Minoryx Therapeutics.

Students with autism spectrum disorder often require social supports to function well in a mainstream class setting. Researchers have demonstrated the effects of social skills training for students...

espanolEl Endeavour, el primer barco ingles en circunnavegar el Globo en mision cientifica, hizo su primera parada en Funchal el 12 de agosto de 1768, en su camino hacia el Pacifico. No era un barco grande y navegaba en solitario. Ademas de su principal mision –observar y medir el transito de Venus en Tahiti–, debia observar y registrar la naturaleza de los lugares visitados. Pese a que el comandante de la nave, el teniente James Cook, tenia buenas razones para recalar en Funchal, las condiciones del mar, del todo impredecibles, le habrian podido forzar a recalar mas al sur, en Tenerife. De haber ocurrido esto, la historia botanica de Madeira hubiera sido bien diferente. Afortunadamente para los dos botanicos de a bordo, Joseph Banks y Daniel Solander, este ultimo el mejor discipulo de Linneo, el mar estaba en calma, lo que les posibilito conocer Madeira, y de esta manera recuperar las pioneras observaciones botanicas realizadas unos setenta anos antes de esta visita por Hans Sloane, para la modernidad. EnglishHMS Endeavour, the first British ship to circumnavigate the world on a scientific mission, had its first stop in Funchal on 12 August 1768 on the way to the Pacific. It was not a big ship and it sailed on its own. Not only was this a scientific voyage –initially making for Tahiti where Venus’s track across the sky could be accurately measured– but it had a remarkable and unique entourage dedicated to observing and recording the natural world. Though the ship’s commander, Lieutenant James Cook, had a good reason to call into the island’s principal port, it could have been otherwise: sea conditions, unpredictable at the best of times, might have forced him to head for Tenerife instead. Had this happened, the botanical history of Madeira might have been quite different. Fortunately for Joseph Banks and Daniel Solander, the ship’s botanists, the sea was kind and the two men, the latter Linnaeus’s best student, were able to bring Hans Sloane’s pioneering botanical observations, made more than seventy years earlier, into the modern age.

ObjectiveVitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD).MethodsIn this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.ResultsBetween October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood.ConclusionsOur weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period.Clinicaltrials.gov identifierNCT02595489Classification of EvidenceThis study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD.Sources of fundingNIH/NINDS K23NS087151

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare leukodystrophy with motor impairment due to biallelic mutations in DARS2, which encodes mitochondrial aspartyl tRNA synthetase. Progressive ataxia is the primary feature.The study objective is to determine the feasibility of remotely collecting quantitative gait and balance measures in LBSL.The study design uses wearable accelerometers and the scale for the assessment and rating of ataxia (SARA) scale to assess gait and postural sway in LBSL and control participants' homes through video conferencing.Lateral step variability (LSV), which indicates stride variability, and elevation of the step at mid-swing are increased for LBSL patients during brief walking tests. During stance with the eyes closed, LBSL participants show rapid accelerations and decelerations of body movement covering a large sway area and path. Both the LSV and sway area during stance with the feet together and eyes closed correlate strongly with the SARA.Wearable accelerometers are valid and sensitive for detecting ataxia in LBSL patients during remote assessments. The finding of large increases in the sway area during stance with the eyes closed is intriguing since dorsal column dysfunction is universally seen in LBSL. This approach can be applied to related rare diseases that feature ataxia.

In the last quarter of the 18th century, Joseph Banks came into possession of a set of botanically accurate, western‐influenced, drawings of Chinese plants, executed in Canton by a Chinese artist and supervised by John Bradby Blake, an East India Company supercargo. Banks realized that these drawings, now in the Natural History Museum, London, would help his collectors in Canton accurately identify the Chinese species he sought as living plants for the Royal Gardens at Kew. Banks commissioned a collector's manual whose illustrations were based on the Blake drawings. In the early 19th century, William Kerr used this manual (now unfortunately lost) to continue the Blake practice – these drawings are at the Royal Botanic Gardens, Kew. John Reeves, many of whose drawings are at the Royal Horticultural Society, used Kerr's commissions to produce the next generation of botanical art in Canton.

Doping of ZnO nanoparticles (NPs) is being used to increase their commercialization in the optical and semiconductor fields. This paper addresses whether doping with Al alters how ZnO NPs at nonlethal levels modifies the metabolism of soil-borne pseudomonads which are beneficial in performing bioremediation or promoting plant growth. The differences in X-ray diffraction (XRD) patterns, observed between commercial ZnO and Al-doped ZnO NPs indicated the aluminum was present as Al NPs. Both particles aggregated in the bacterial growth medium and formed colloids of different surface charges. They had similar effects on bacterial metabolism: rapid, dose-dependent loss in light output indicative of temporary toxicity in a biosensor constructed in Pseudomonas putida KT2440; increased production of a fluorescent pyoverdine-type siderophore, and decreased levels of indole acetic acid and phenazines in Pseudomonas chlororaphis O6. Solubilization of Zn and Al from the NPs contributed to these responses to different extents. These findings indicate that Al-doping of the ZnO NPs did not reduce the ability of the NPs to alter bacterial metabolism in ways that could influence performance of the pseudomonads in their soil environment.

It is well-known that when Roger Casement left the Putumayo in November 1910, he took with him several Barbadian men, two Huitoto youths and a bundle of depositions documenting in extraordinary detail the atrocities committed by the Peruvian Amazon Company. What is far less known (and we have to thank Angus Mitchell for directing our attention to it in his publications) is that he also had with him a camera and several rolls of film waiting to be developed. Unfortunately only a handful of the photographs Casement had developed have survived. They lie in a box in the National Photographic Archive in Dublin, dormant and seemingly historically inert. Thankfully, the historicity of these images can be reconstructed, for in March 1912, when it looked as though the American government was backsliding in its promise of putting political pressure on the Peruvian government to protect the Indians and to stop the brutal labour regime in the rubber lands of the Putumayo, Casement posted copies of a number of these photographs to George Young at the British Embassy in Washington to shock the American administration into action. All of these photographs (which are in the National Archives in Washington, DC) were personally annotated by Casement, in the manner of an atrocity narrative, and provide a rare insight into the political possibilities of the visual image.

This paper analyzes the emergence and evolution of taxol, the world's bestselling anti-cancer drug. Over the years taxol has changed its identity, its status as property, and its association with different places (from the old-growth forests of Washington State to the government agencies of Washington, D.C., to laboratories in France). Taxol is not only a profitable pharmaceutical commodity and a substance injected into women with breast and/or ovarian cancer; it is also a natural product found in the bark of Taxus brevifolia (the Pacific yew, which is native to the North American Pacific Northwest) and a chemical substance that was discovered and brought to the point of commercial production in the public sector. We explore its role in several controversies: the destruction of old-growth forests, public participation in policy making, and the privatization of intellectual property and its effect on the price of drugs.

Notes on contributors Preface Introduction: Culture, consumption and society Andrew Sherratt, University of Oxford 1. Alcohol and its alternatives: symbol and substance in pre-industrial cultures Andrew Sherratt 2. Coca, beer, cigars and yag'e: meals and anti-meals in an Amerindinian community Stephen Hugh-Jones, University of Cambridge 3. Nicotian Dreams: the prehistory and early history of tobacco in eastern North America Alexander von Gernet, University of Toronto 4. Efficacy and concentration: analogies in betel use among the Fuyage (Papua New Guinea) Eric Hirsch, Brunel University 5. Kola nuts: the 'coffee' of the central Sudan Paul E. Lovejoy, York University, Canada 6. EXCITANTIA: Or, how enlightenment Europe took to soft drugs Jordan Goodman, University of Manchester Institute of Science and Technology 7. From coffeehouse to parlour: the consumption of coffee, tea and sugar in northwestern Europe in the seventeenth and eighteenth centuries Woodruf D. Smith, University of Texas at San Antonio 8. Tobacco use and tobacco taxation: a battle of interests in early modern Europe Jacob M. Price, University of Michigan 9. Japan and the world narcotics traffic Kathryn Meyer, Lafayette College, Pennsylvania 10. The rise and fall and rise and fall of cocaine in the United States David T. Courtwright, University of North Florida Afterword Jordan Goodman and Paul E. Lovejoy Selected bibliography Index

The voyage of the HMS Rattlesnake to New Guinea and the archipelago to the east of it could have achieved so much for science. 'Make sure of what you do', enthused British hydrographer Francis Beaufort to the Rattlesnake's commander Owen Stanley in 1848. 'Do not leave interesting questions to be answered at the next visit - give names to Capes and Islands...and bring yourself and your people back without quarrels'. But for some reason Stanley wavered. There were several scientists on board the Rattlesnake desperate to ask interesting questions of these uncharted islands. But these natural historians, and in particular a young Thomas Henry Huxley, found their ambitions thwarted by their increasingly edgy captain.

The drug taxol has been hailed by many in the cancer community as a major breakthrough in the treatment of cancer. It has already been approved in use against ovarian and advanced breast cancer in many countries worldwide. Taxol has also promoted profound debates in the policy arena not, as one might expect, because of the characteristics or purposes of the drug itself, but because of other far-reaching effects. Taxol is a complex compound found in the bark of the Pacific yew tree, primarily in Oregon and Washington in the USA. The bark was first collected in 1962 and cytotoxicity demonstrated in 1964. Yet it was not until 1989 that the first results of clinical trials were reported. In the US taxol was then rushed through the Food and Drug Administration's regulatory procedures, approval being granted for use in refractory ovarian cancer in 1992. The controversies surrounding taxol surfaced in 1989 and grew substantially over the next few years. In this paper we examine two principal controversies concerning taxol, the first of which focused on apparent conflicts between the needs of environmental protection and those of cancer chemotherapy. Although the media portrayed this as a clash of interests between the environment and people with cancer, we argue that it was an attempt to increase lay participation in biomedical decision making and policy formulation. The second controversy was between health policy and the transfer of public scientific property to the corporate sector. The pharmaceutical company Bristol-Myers Squibb was given exclusive rights to provide taxol from Pacific yew trees under a Co-operative Research and Development Agreement signed in 1991. While this was seen to be in the US Government's (as well as the company's) interest, it provoked a public reaction questioning the terms and consequences of the transfer of publicly generated scientific knowledge to the private sector.

Review of Urban Orneholm (ed. and transl.), Four Eighteenth-century medical dissertations under the presidency of Nils Rosen

Social interactional theory posits that child behavior and parent behavior are inter-dependent. Interactions that encourage reciprocity and balanced turn-taking are considered most conducive to child communication development. Children who have impaired communication development often exhibit frustration and a variety of aberrant behaviors. These behaviors may be, at least in part, because of a breakdown or imbalance in parent-child turn-taking, a form of social reciprocity. Parent-child turn-taking was examined in children exhibiting a variety of neuropsychiatric symptoms, including developmental delays and behavioral problems. Preadmission videotapes of 43 children and their parents (43 mothers and 21 fathers) were coded with respect to initiating and responding behaviors. Twenty-seven of the children were prelinguistic, and 16 were linguistic. An imbalance in parent-child reciprocity and turn-taking was noted in this sample: Parents initiated more frequently than children, and children responded to approximately half of parent initiations. There was a greater imbalance in prelinguistic children, evidenced by a significantly higher rate of mother initiating (p.01) and responding behaviors (p.08) as well as a significantly lower rate of child initiating behaviors (p.02). Implications for interventions focusing on the parent-child dyad and including fathers are discussed, as well as directions for further research.