Pharmacological treatments for Friedreich ataxia

BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012. OBJECTIVES: To assess the effects of pharmacological treatments for Friedreich ataxia. SEARCH METHODS: On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months. DATA COLLECTION AND ANALYSIS: Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion. In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence). The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low. There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. AUTHORS' CONCLUSIONS: low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration

Design Research Units and Small to Medium Enterprises (SMEs): An Approach for Advancing Technology and Competitive Strength in Australia

© 2018 Informa UK Limited, trading as Taylor & Francis Group. This paper makes the case that small to medium enterprises (SMEs) in the manufacturing sector have the potential to benefit from connections with design research units operating within universities. It points out some of the challenges associated with research and development for SMEs, and argues design research units can allow SMEs to better meet these challenges. Additive Manufacturing is used as an exemplary emerging technology that makes explicit the new possibilities and instability of the contemporary manufacturing landscape. A case study is used to articulate the potentials and limitations of industry and university partnerships in design. In conclusion, two alternative models are analysed in order to highlight different ends to which the practitioner-based research can be put

Marianne Brandt: designer of icons or ‘real’ industrial designer?

In 1923, under the slogan ‘Art into industry: a new unity’, the Bauhaus adopted a new direction. Previously, the emphasis was on engaging with craft as a way to liberate the imagination of the designer, whereas now the teaching of craft was to prepare design for mass production(Marcus, 2008, 346). As a result of this change, the Bauhaus produced an array of what have become design classics which continue to resonate with people a century later. By focusing on light fittings, a prolific and high-profile area of the Bauhaus, our paperwill argue that many of the lighting designs had an emphasis on expressing ideas about form and material in accordance with Bauhaus ideology. Yet, very few could be considered genuine pieces of industrial design which aimed to meet user expectations and match manufacturer’s needs. In our view, the Bedside Table Lamp designed by Marianne Brandt in collaboration with Hin Bredendiek, is one of few complete industrial design projects to emerge out of the Bauhaus. An analysis of this object reveals an attention to detail, sound technical understanding, an emphasis on user needs and a complexity of form that went beyond the symmetrical and basic geometries of many of the Bauhaus works. At a time when industrial design was emerging as a discipline, this is an example of actual engagement with industry and manufacturing processes. These factors combined to create an innovative light fitting, free of older forms and approaches, which enjoyed both commercial and critical success. This study contributes another layer of understanding to the beginning of the industrial design discipline, it positions Marianne Brandt alongside pioneer industrial designers who designed for manufacture such as Peter Behrens, and Christopher Dresser and it elevates the Bedside Table Lamp from just another Bauhaus light to a unique and important exemplar

Optimization of in-line semiconductor measurement rates : balancing cost and risk in a high mix, low volume environment

Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering; in conjunction with the Leaders for Manufacturing Program at MIT, 2004.Includes bibliographical references (p. 99-101).Due to a number of market development over the last decade, semiconductor manufacturing companies, including Intel Corporation, have added significant numbers of primarily high growth rate, high-mix, low-volume (HMLV) products to their portfolios. The rapid transition from high-volume manufacturing (HVM) to HMLV manufacturing has caused significant problems. Foremost, the needs of many HMLV customers are different from HVM customers and require different operational tradeoffs. Moreover, many of the HVM focused metrics, tools, systems and processes have proven ill-suited for managing the added complexities and more varied needs of HMLV customers. This thesis examines many of the problems caused by introducing HMLV products into an HVM wafer fabrication facility (commonly referred to as a fab), and explores potential solutions such as improved cultural and organizational alignment; capacity management and setup elimination; and scheduling and work-in-process management to name a few. Although the discussion focuses on semiconductor operations, the concepts easily generalize to other companies struggling with achieving operational excellence (OpX) in an HMLV environment. In addition to exploring the macroscopic HMLV issues, we also feature an in-depth analysis of one aspect of achieving OpX in the HMLV environment: the optimization of in-line metrology skip rates. Based on a review of the current methods, a new approach is suggested based on a Bayesian economic skip-lot model we call MOST/2. In general, MOST/2 suggests that significant cost savings can be realized with only modest increases in the material at risk per excursion if measurement rates are further reduced. Compared with the other methods analyzed, the data indicates that MOST/2(cont.) provides superior cost/risk balanced results. For the 27 operations analyzed, results include annual costs savings of over $95,000, cycle time savings of over 5.3 hours per lot, operator savings of over 4.2 people per year and metrology capacity utilization rate reductions of over 65%. Finally, a brief organizational study was conducted to identify political, cultural and strategic design changes that would bolster long-term operational excellence (OpX) in the HMLV environment. Suggested changes include better identification of customer needs, improved communication and linking between groups, modification and alignment of factory and performance metrics and the creation of a stand-alone HMLV organization.by Christopher R. Pandolfo.S.M.M.B.A

Rapid evolution of weedy traits during sunflower de-domestication: the importance of hybridization and standing genetic variation

Hybridization between crops and their wild relatives may promote the evolution of de-domesticated (feral) weeds. Wild sunflower is typically found in ruderal environments, but crop-wild hybridization may facilitate the evolution of weedy biotypes. Using one crop-specific mitochondrial marker (CMS-PET1) and 14 nuclear SSR markers, we studied the origin and genetic diversity of BRW, a recently discovered weedy biotype. Then, using a resurrection approach, we tested for rapid evolution of weedy traits (seed dormancy, herbicide resistance, and competitive ability) by sampling weedy and wild biotypes 10 years apart (2007 and 2017). All the weedy plants present the CMS-PET1 cytotype, confirming their feral origin. At the nuclear markers, BRW showed higher genetic diversity than the cultivated lines, as high genetic diversity as the most diverse wild biotypes, and low differentiation with one wild biotype, suggesting that wild hybridization increased the genetic diversity of the feral BRW. Regarding weedy trait evolution, we found support for rapid evolution towards higher seed dormancy, but not for higher competitive ability or herbicide resistance. Standing genetic variation probably facilitated the evolution of seed dormancy and limited the evolution of herbicide resistance, as no resistant alleles were found in the ancestral biotype. Our results demonstrate that natural crop-wild hybrids can evolve quickly in farmers? fields, leading to the establishment of weedy biotypes of cultivated origin. Although herbicide resistance did not evolve in BRW, management strategies aimed at preventing the evolution of resistance should be a priority in order to avoid the emergence and spread of herbicide resistant biotypes in Argentina.Fil: Hernández, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Vercellino, Román Boris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Pandolfo, Claudio Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Mandel, Jennifer R.. University of Memphis; Estados UnidosFil: Presotto, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; Argentin

Rapid Evolution of Seed Dormancy During Sunflower De-Domestication

Hybridization between crops and their wild relatives may promote the evolution of de-domesticated (feral) weeds. Wild sunflower (Helianthus annuus L.) is typically found in ruderal environments, but crop-wild hybridization may facilitate the evolution of weedy populations. Using one crop-specific mitochondrial marker (CMS-PET1) and 14 nuclear SSR markers, we studied the origin and genetic diversity of a recently discovered weedy population of sunflower (named BRW). Then, using a resurrection approach, we tested for rapid evolution of weedy traits (seed dormancy, herbicide resistance, and competitive ability) by sampling weedy and wild populations 10 years apart (2007 and 2017). All the weedy plants present the CMS-PET1 cytotype, confirming their feral origin. At the nuclear markers, BRW showed higher genetic diversity than the cultivated lines and low differentiation with one wild population, suggesting that wild hybridization increased their genetic diversity. We found support for rapid evolution towards higher seed dormancy, but not for higher competitive ability or herbicide resistance. Our results highlight the importance of seed dormancy during the earliest stages of adaptation and show that crop-wild hybrids can evolve quickly in agricultural environments.Fil: Hernández, Fernando. Universidad Nacional del Sur. Departamento de Agronomía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Vercellino, Román Boris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Pandolfo, Claudio Ezequiel. Universidad Nacional del Sur. Departamento de Agronomía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Mandel, Jennifer R.. University of Memphis; Estados UnidosFil: Presotto, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; Argentin

Abnormal illness behavior and Internet addiction severity: The role of disease conviction, irritability, and alexithymia

Background and aims: While the association between health anxiety and maladaptive Internet use is a well-established finding, no studies have been performed to examine the possible effect of abnormal illness behavior (AIB). AIB is a maladaptive manner of experiencing, evaluating, or acting in response to health and illness that is disproportionate to evident pathology. The aim of this study was to investigate the association between AIB and Internet addiction (IA) severity in a sample of Italian University students. The possible effect of alexithymia, anxiety, and depression was also taken into account. Methods: Participants were 115 men and 163 women (mean age = 23.62 - 4.38 years); AIB was measured via the Illness Behavior Questionnaire (IBQ), and IA severity by the Internet Addiction Test (IAT). Results: The most powerful IBQ factor predicting IA severity scores was disease conviction. Irritability was the only emotional IBQ factor associated with IA severity. Nevertheless, disease conviction and alexithymia remained the only significant predictors of IAT scores when hierarchical regression analysis was executed. Discussion and conclusions: Our results support previous findings showing that those characterized by health anxiety are more prone to an excessive and maladaptive use of Internet. Moreover, this study showed that irritability was the only emotional aspect of AIB predicting IA severity. This finding is consistent with the cognitive model of hypochondria, which states that cognitive factors (dysfunctional beliefs and assumptions) play a major role in the explanation of this psychopathological condition

Produtividade de milho inoculado com Azospirillum brasilense em diferentes doses de nitrogênio, em latossolo vermelho - safra 2012/13.

O objetivo desse trabalho foi avaliar a produtividade do milho cultivado em Latossolo Vermelho na safra 2012/13, na presença ou ausência de inoculação de sementes com A. brasilense, em diferentes doses de N em cobertura. A inoculação de sementes de milho com Azospirillum brasilense não proporcionou incrementos significativos na produtividade de grãos de milho cultivados na safra 2012/13, em Latossolo Vermelho de Campos Novos e de Papanduva. Em Papanduva, as doses de N aplicadas em cobertura aumentaram a produtividade de grãos de milho

Test–retest reliability of the Friedreich’s ataxia rating scale

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam-based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it’s validity in measuring disease progression, formal test–retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test–retest reliability of the mFARS, and it’s upright stability subscore.Fil: Rummey, Christian. Clinical Data Science Gmbh; SuizaFil: Zesiewicz, Theresa A.. University of South Florida; ArgentinaFil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Farmer, Jennifer M.. Friedreich Ataxia Research Alliance; Estados UnidosFil: Pandolfo, Massimo. Université Libre de Bruxelles; BélgicaFil: Lynch, David R.. Children’s Hospital of Philadelphia; Estados Unido