Referencias científicas

  

Artículos copiados de diversas fuentes 

 
 

http://www.sciencedirect.com/science/article/pii/
S193459091500315X
Patient-Funded Trials: Opportunity or Liability?
Danielle Marie Wenner1,
Jonathan Kimmelman
2,
Alex John London
1,
Patient-funded trials (PFTs) are gaining traction as a means of accelerating clinical translation. However, such trials sidestep mechanisms that promote rigor, relevance, efficiency, and fairness. We recommend that funding bodies or research institutions establish mechanisms for merit review of patient-funded trials, and we offer some basic criteria for evaluating PFT protocols
 


http://jnnp.bmj.com/content/86/11/e4.167.short?rss=1
URINARY, BOWEL AND SEXUAL FUNCTION IN PATIENTS WITH FRIEDREICH'S ATAXIA
Meher Lad1,
Michael Parkinson
2,
Myriam Rai
3,
Massimo Pandolfo
3,
Sinead Murphy
3,
Anton Emmanuel
5,
Jalesh Panicker
6,
Paola Giunti
2
Abstract
Background Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder leading to ataxia, weakness, peripheral neuropathy, diabetes and cardiomyopathy. Although patients also report urinary, bowel and sexual symptoms these have barely been described in the literature.
Methods 59 Patients seen in a research clinic in a year were included. Questionnaire scores measuring urinary, bowel and sexual symptoms were compared with validated measures of disease severity.
Results Urinary symptom scores correlated significantly (p=0.021) with duration of disease symptoms and spasticity scores (p=0.045). Quality of life measures of patients with urinary symptoms correlated with ataxia rating scales (SARA) (p=0.036) and non-ataxic symptoms (INAS) (p=0.003). Neurogenic Bowel Disease scores correlated with severity of ataxic symptoms (SARA) (p=0.024) and activities of daily living (ADLs) (p=0.001). Sexual symptom scores did not correlate with any established measures of disease severity and disease duration.
Conclusions Urinary and lower gastro-intestinal symptoms can have a severe impact on patients with FRDA although they are under-recognised. They impact on quality of life and correlate with established measures of disease severity.
  



http://onlinelibrary.wiley.com/doi/10.1002/hbm.23034/abstract
Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE-FRDA study
Ian H. Harding1,*,
Louise A. Corben1,2,3,
Elsdon Storey4,
Gary F. Egan5,
Monique R. Stagnitti1,
Govinda R. Poudel1,
Martin B. Delatycki1,2,6 and
Nellie Georgiou-Karistianis1

Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello-cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n-back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello-cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto-cerebellar networks. These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar
 



http://content.onlinejacc.org/article.aspx?articleID=2449108#topLocation
Pathology of Intercalated Discs in Friedreich Cardiomyopathy 
R. Liane Ramirez, MS; Alyssa B. Becker, BA; Joseph E. Mazurkiewicz, PhD; Paul J. Feustel, PhD; Benjamin B. Gelman, MD, PhD; Arnulf H. Koeppen, MD
 
Friedreich ataxia (FA) is best known for its neurological phenotype, but the most common cause of death is heart disease (1). The pathogenesis of FA cardiomyopathy includes failure to clear iron from myocytes, chronic inflammation, fiber necrosis, and scarring (2). On cross section, heart fibers are significantly enlarged and excessively lobulated (2). In the longitudinal dimension, the pathogenesis also involves modifications of intercalated discs (ICDs), the plasma membrane specializations that connect heart fibers end-to-end. Many proteins participate in the assembly of fascia adherens junctions, desmosomes, and gap junctions (GJs) within or near ICDs (3). 



 
http://www.hindawi.com/journals/omcl/2015/565140/
A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency

Alexandra Seguin,1 Véronique Monnier,2 Amandine Palandri,2 Frédéric Bihel,3 Michael Rera,2 Martine Schmitt,3 Jean-Michel Camadro,1 Hervé Tricoire,2 and Emmanuel Lesuisse1

Abstract
Friedreich’s ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy.


 
http://embor.embopress.org/content/16/10/1246?etoc
Next generation partnerships in translational science and medicine
 
 
http://www.sciencedirect.com/science/article/pii/
S0167527315304873
Staging of cardiomyopathy in Friedreich ataxia
Roger E. Peverill
 
 
http://onlinelibrary.wiley.com/doi/10.1002/
mds.26382/abstrac
t;jsessionid=09621BD6E1B266F5A54380D2
8DA26003.f02t03?userIsAuthenticated=false&deniedAccessCustomisedMessage=
Delayed-onset Friedreich's ataxia revisited
Claire Lecocq MD1, Perrine Charles MD2, Jean-Philippe Azulay MD, PhD3, Wassilios Meissner MD, PhD4, Myriam Rai PhD5, Karine N'Guyen MD6, Yann Péréon MD, PhD7, Nelly Fabre MD8, Elsa Robin MD9, Sylvie Courtois MD10, Lucie Guyant-Maréchal MD11, Fabien Zagnoli MD, PhD12, Gabrielle Rudolf PhD13, Mathilde Renaud MD14, Mathieu Sévin-Allouet MD15, Fabien Lesne CRA16, Nick Alaerts CRA17, Cyril Goizet MD, PhD18, Patrick Calvas MD, PhD19, Alexandre Eusebio MD, PhD20, Claire Guissart MD21, Pascal Derkinderen MD, PhD22, Francois Tison MD, PhD23, Alexis Brice MD, PhD24, Michel Koenig Md, PhD25, Massimo Pandolfo Md, PhD26, Christine Tranchant MD, PhD27, Alexandra Dürr MD, PhD28 andMathieu Anheim MD, PhD29,


ABSTRACT
Background
Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia.


Methods
Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken.


Results
Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated.


Conclusion
Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.” As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.



http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138437 
FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia

Abstract
Background
Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.

Methodology / Principal Findings
The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.

Conclusions / Significance
Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.



http://www.nih.gov/news-events/news-releases

/scientists-test-new-gene-therapy-vision-loss-mitochondrial-disease 
Scientists test new gene therapy for vision loss from a mitochondrial disease
 
NIH-funded study shows success in targeting mitochondrial DNA in mice.
Dr. John Guy and colleagues added a homing signal to a virus in order to deliver the ND4 gene into mitochondria. A marker for the gene is shown in red and the ND4 protein is shown in green, inside retinal ganglion cells in the mouse eye. The nuclei of retinal ganglion cells are shown in blue. Dr. Hong Yu, Bascom Palmer.Researchers funded by the National Institutes of Health have developed a novel mouse model for the vision disorder Leber hereditary optic neuropathy (LHON), and found that they can use gene therapy to improve visual function in the mice. LHON is one of many diseases tied to gene mutations that damage the tiny energy factories that power our cells, called mitochondria.

“This study marks an important contribution to research on LHON, and in efforts toward an effective therapy. But the implications are even broader, because the approaches that the investigators used could aid therapy development for a vast array of other mitochondrial diseases,” said Maryann Redford, D.D.S, M.P.H., a program director in Collaborative Clinical Research at NIH’s National Eye Institute, which helped fund the study.

Mitochondria are as complex as any modern manufacturing facility, with specialized machinery for converting nutrients and oxygen into cellular energy. They even have their own DNA, and it is mutations within this mitochondrial DNA (mtDNA) that lead to LHON, as well as a host of other diseases. But the unique nature of mtDNA has presented challenges for developing and testing potential therapies for such diseases.

Until now, “there was no efficient way to get DNA into mitochondria,” said John Guy, M.D., professor of ophthalmology and director of the ocular gene therapy laboratory at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. Dr. Guy’s laboratory is among the first to develop an approach that can target mtDNA in living mice and people.

Their success in creating a mouse model of LHON and using it to test an investigational gene therapy is described today in the Proceedings of the National Academy of Sciences.

The global impact of LHON is unknown. In England, the estimated prevalence is about 1 in 30,000. Early symptoms include blurry vison and usually appear during the teens or early twenties. Eyesight tends to worsen over time, eventually leading to a severe loss of sharpness (acuity) and color vision. These problems are caused by a loss of retinal ganglion cells — the cells that carry visual signals from the retina through the optic nerve and into the brain.

The most common mutation behind LHON impairs a mitochondrial gene called ND4. Dr. Guy began to research a possible gene therapy approach for delivering a substitute copy of the gene into mitochondria about 15 years ago. In most studies and applications of gene therapy, viruses have become the preferred vessel for delivering genes into cells. But viruses evolved to invade the body’s cells and penetrate the nucleus, which contains the bulk of our DNA, comprising about 20,000 genes. Most viruses are poor at penetrating mitochondria.

To fix that, Dr. Guy and his team took advantage of the fact that mitochondria import cellular proteins that they cannot make themselves. By attaching a bit of one such protein to the outer shell of a virus — called an adeno-associated virus — he effectively gave the virus a homing signal and entry code into mitochondria.

This modified virus has been the key to creating a mouse that replicates LHON and to an investigational gene therapy for LHON that is currently in clinical trials.

To create a mouse model for LHON, the researchers loaded the virus with a defective copy of the ND4 gene carrying the same mutation that causes about 70 percent of LHON cases. They also included DNA coding for a red fluorescent protein, as a visible marker for the virus and its payload. Then they injected the virus into fertilized mouse egg cells, and grew the cells to maturity.

After breeding the mice through several generations, the researchers had their mouse model. The presence of the virally encoded ND4 mutation in the eye was confirmed by essentially doing an eye exam to look for the red fluorescent marker. Over time, the mice showed a loss of retinal ganglion cells, atrophy (shrinkage) of the optic nerve, and a decline in visual responses, as seen in a type of electrical recording from the retina known as an electroretinogram.

To develop a gene therapy for LHON, the team packaged the normal human ND4 gene into the same stealthy virus. This combination, when injected into the eye, led to improved visual function in the LHON mouse model. When injected into normal mice, the virus carrying ND4 did not cause any adverse effects on vision.

Prior to development of the new mouse model, Dr. Guy’s lab had shown that they could produce temporary signs of LHON in mice. They were able to prevent development of LHON in the mice, but not reverse it. “Now we’ve shown that we can improve visual function after it’s been lost,” he said.

The mouse research is helping inform an ongoing NEI-supported clinical trial, which is led by Dr. Guy and is testing the safety of the same gene therapy approach (without the red fluorescent protein) in people with LHON. The trial is recruiting LHON patients who fit into three categories — those with chronic vision loss in both eyes, with recent-onset vision loss in both eyes, or with recent-onset vision loss in one eye but no signs of abnormal vision in the other eye. For more information, visit http://www.clinicaltrials.gov and search for the trial identifier NCT02161380.


 
http://content.onlinejacc.org/article.aspx?articleID=2449108
Pathology of Intercalated Discs in Friedreich Cardiomyopathy

R. Liane Ramirez, MS; Alyssa B. Becker, BA; Joseph E. Mazurkiewicz, PhD; Paul J. Feustel, PhD; Benjamin B. Gelman, MD, PhD; Arnulf H. Koeppen, MD

Article
.Friedreich ataxia (FA) is best known for its neurological phenotype, but the most common cause of death is heart disease (1). The pathogenesis of FA cardiomyopathy includes failure to clear iron from myocytes, chronic inflammation, fiber necrosis, and scarring (2). On cross section, heart fibers are significantly enlarged and excessively lobulated (2). In the longitudinal dimension, the pathogenesis also involves modifications of intercalated discs (ICDs), the plasma membrane specializations that connect heart fibers end-to-end. Many proteins participate in the assembly of fascia adherens junctions, desmosomes, and gap junctions (GJs) within or near ICDs (3).



 http://www.sciencedirect.com/science/article/pii/
S1567724915001555
Protein replacement therapy for mitochondrial disorders
M. Rapoporta,
D. Marcus
a,
A. Saada
a,
T. Erlich
a,
R. Hadad
a,
H. Greif
b,
M. Lichtenstein
a,
H. Lorberboum-Galski
a
 
 
http://journals.lww.com/theneurologist/pages/
articleviewer.aspx?year=2015&issue=09000&article=00005&type=abstract 
Friedreich Ataxia: From the Eye of a Molecular Biologist
Muthuswamy, Srinivasan MSc; Agarwal, Sarita PhD

Abstract

Friedreich ataxia (FRDA) is caused by the expansion of a GAA triplet repeat in the first intron of the FXN gene. This disease was named after Nicholaus Friedreich, Germany, who depicted the essential finding. Among ataxias, FRDA is the most common hereditary ataxia. It has the autosomal recessive pattern of inheritance. The expansion of the GAA triplet repeat hinders the transcription, thereby reducing the level of the FXN transcript and consequently reducing the level of frataxin, a 210-amino acid protein. The disease pathogenesis is fundamentally due to a lack of frataxin, which is claimed to play a role in iron-sulfur cluster synthesis. Oxidative stress builds up as a result of Fe accumulation in the mitochondria, causing degeneration of the cells, which primarily occurs in the neurons and later in the cardiac tissues, and to some extent in the pancreas. The therapeutic interventions are at infancy; however, current treatments are targeted toward the reduction of iron overload and its effects. 


 
http://www.gaitposture.com/article/S0966-6362(15)00757-2/abstract?cc=y=
Does tandem walking discriminate better than normal walking among children with DCD, ataxia and healthy controls? A preliminary analysis performed with IMUs on the trunk
To view the full text, please login as a subscribed user or purchase a subscription. Click here to view the full text on ScienceDirect.
Boxplots of the subset of variables that were significantly different between pairs of groups (H, DCD, FRDA) in NW (grey background) and in TW (white background); p-values are reported.
Introduction: Developmental co-ordination disorder (DCD) is a condition affecting physical co-ordination in children. Friedreich's ataxia (FRDA) is an autosomal recessive disease that causes difficulty in balance (disequilibrium), impaired coordination of the legs or arms and impaired position sense. In some cases discriminating children with DCD from children with FRDA is difficult [1]. Diagnosis of FRDA and DCD is likely to be affected by the clinician's subjectivity since it includes the use of clinical scales and the visual observation of gait paradigms such as normal walking (NW) or tandem walking (TW). 



http://www.nature.com/nrg/journal/v16/n10/full/nrg3961.html 
R loops: new modulators of genome dynamics and function
José M. Santos-Pereira1,
Andrés Aguilera
1,
Abstract
R loops are nucleic acid structures composed of an RNA–DNA hybrid and a displaced single-stranded DNA. Recently, evidence has emerged that R loops occur more often in the genome and have greater physiological relevance, including roles in transcription and chromatin structure, than was previously predicted. Importantly, however, R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing, phenomena that are frequently associated with cancer and a number of genetic diseases. We review the current knowledge of the mechanisms controlling R loops and their putative relationship with disease.
 



http://www.sciencedirect.com/science/article/pii/
S2405580815000837
Characterization of the retinal pigment epithelium in Friedreich ataxia
Abstract
We assessed structural elements of the retina in individuals with Friedreich ataxia (FRDA) and in mouse models of FRDA, as well as functions of the retinal pigment epithelium (RPE) in FRDA using induced pluripotent stem cells (iPSCs). We analyzed the retina of the FRDA mouse models YG22R and YG8R containing a human FRATAXIN (FXN) transgene by histology. We complemented this work with post-mortem evaluation of eyes from FRDA patients. Finally, we derived RPE cells from patient FRDA-iPSCs to assess oxidative phosphorylation (OXPHOS) and phagocytosis. We showed that whilst the YG22R and YG8R mouse models display elements of retinal degeneration, they do not recapitulate the loss of retinal ganglion cells (RGCs) found in the human disease. Further, RPE cells differentiated from human FRDA-iPSCs showed normal OXPHOS and we did not observe functional impairment of the RPE in Humans.
 
 



http://www.ajnr.org/content/early/2015/09/10/
ajnr.A4455.abstract
MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia

T.A. Santos, C.E.B. Maistro, C.B. Silva, M.S. Oliveira, M.C. França Jr and G. Castellano+ Author Affiliations

From the Neurophysics Group (T.A.S., C.E.B.M., M.S.O., G.C.), Gleb Wataghin Physics Institute, and Department of Neurology (C.B.S., M.C.F.), Medical Sciences School, University of Campinas, Brazil; and Brazilian Institute of Neuroscience and Neurotechnology (BRAINN) (São Paulo Research Foundation) (T.A.S., C.E.B.M., C.B.S., M.S.O., M.C.F., G.C.), Campinas, São Paulo, Brazil. 
Please address correspondence to Gabriela Castellano, PhD, University of Campinas/IFGW, Rua Sergio Buarque de Holanda, 777, Cidade Universitária “Zeferino Vaz,” 13083-859-Campinas-São Paulo, Brazil; e-mail:

 gabriela@ifi.unicamp.br


Abstract
BACKGROUND AND PURPOSE: Texture analysis is an image processing technique that can be used to extract parameters able to describe meaningful features of an image or ROI. Texture analysis based on the gray level co-occurrence matrix gives a second-order statistical description of the image or ROI. In this work, the co-occurrence matrix texture approach was used to extract information from brain MR images of patients with Friedreich ataxia and a control group, to see whether texture parameters were different between these groups. A longitudinal analysis was also performed. 

MATERIALS AND METHODS: Twenty patients and 21 healthy controls participated in the study. Both groups had 2 sets of T1-weighted MR images obtained 1 year apart for every subject. ROIs chosen for analysis were the medulla oblongata and pons. Texture parameters were obtained for these ROIs for every subject, for the 2 sets of images. These parameters were compared longitudinally within groups and transversally between groups. 

RESULTS: The comparison between patients and the control group showed a significant differences for the medulla oblongata (t test, P < .05, Bonferroni-corrected) but did not show a statistically significant difference for the pons. Longitudinal comparison of images obtained 1 year apart did not show differences for either patients or for controls, in any of the analyzed structures. 

CONCLUSIONS: Gray level co-occurrence matrix–based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia. 

 



 
https://www.clinicalkey.es/#!/content/playConten

/1-s2.0-S0891842215000452?returnurl=

http:%2F%2Flinkinghub.elsevier.com%2

Fretrieve%2Fpii%2FS0891842215000452

%3Fshowall%3Dtrue&referrer=
Jones Tendon Transfer 
Richard Derner DPM, FACFAS
Jeffrey Holmes DPM
Clinics in Podiatric Medicine and Surgery, Copyright © 2015 Elsevier Inc.
Key points • Jones tendon transfer or Jones tenosuspension is a tendon transfer performed to remove the deforming force for hallux malleus deformity. It is most often performed with interphalangeal joint (IPJacrnm1) fusion of the hallux. • Indicat...
 
 



http://www.tandfonline.com/doi/abs/10.1517/
21678707.2015.1083854?journalCode=ieod20&
Prospects of gene and cell therapy for managing cardiac complications in Friedreich ataxia
 
Abstract
Introduction: Friedreich ataxia (FRDA) is a progressive neurodegenerative disease affecting ∼ 1/50,000 people. The disease is caused by guanine–adenine–adenine repeat expansions in the frataxin gene, which results in frataxin deficiency. Cardiac complications occur in a majority of patients and are the leading cause of death in FRDA. Presently, there are no therapeutic agents to slow the disease progression. Recently, gene and cell therapies have been proposed as future treatments for addressing the debilitating cardiac features of the disease.


Areas covered: This review describes potential gene and cell therapy approaches to treating cardiac complications in FRDA. Cell therapies include induced pluripotent stem cells and bone marrow-derived mesenchymal stem cells. Gene therapy options consist of lentiviral, herpes simplex virus and adeno-associated virus (AAV) vectors for gene transfer, with AAV-frataxin vectors reaching late preclinical stages of testing.


Expert opinion: Gene and cell therapies are progressing toward clinical trials, with encouraging outcomes noted for mesenchymal stem cell therapy and AAV gene therapy in mouse models. Current limitations are largely technical; issues of immunogenicity and duration of benefits suggest that any treatment consisting of gene or cell therapy will require combinations of other drugs. AAV gene therapy offers the prospect of improving cardiac outcomes for the patient population of FRDA.
 



http://www.oudaily.com/news/ouhsc-professor-researcher-gets-grant-for-research/article_b5c541e0-5729-11e5-99ee-9b43ded80097.html
OUHSC professor, researcher gets $300,000 grant for research
by Dayten Israel
An OU researcher secured a grant from the Muscular Dystrophy Association for research into potential therapies for a genetic disease.
Researcher Sanjay Bidichandani, the CMRI Claire Gordon Duncan Chair in Genetics at OUHSC, is a professor of pediatrics at the OU College of Medicine and has worked at OU in the field of genetic research since 2000.
The three-year grant of $300,000 will fund research into promising therapies for a neuromuscular disease known as Friedreich's ataxia, Bidichandani said.
Ataxia is the loss of control of voluntary bodily movement due to affected parts of the nervous system or an inherited defective gene, according to the Mayo Clinic website.
Friedreich's ataxia is a devastating, incurable condition and the most common inherited ataxia, Bidichandani said.
Bidichandani’s research will evaluate the effectiveness of a new drug class known as HDAC inhibitors, Bidichandani said. HDAC inhibitors help genes that are packaged too tightly within cells, which is called an “epigenetic defect,” to loosen up so that the genes can be read.
Geneticists discovered the Friedreich's ataxia gene 20 years ago, and now that the cause of this condition is known, geneticists are at a point where they can actually work on potential therapies, Bidichandani said.
 
Bidichandani will test pre-existing HDAC inhibitors in reversing the specific epigenetic defect in Friedreich's ataxia and compare their effects to the more efficient versions being developed by his collaborators, Bidichandani said.
“We hope to find a drug or several drugs that can eventually become approved therapies for this disease,” Bidichandani said. “This research has the potential for other therapies to combat this incurable condition.”
The MDA received 350 grant applications this year, and Bidichandani’s research was one of 36 new grants funded and the only one in Oklahoma, Bidichandani said.
The grant is given to leaders in muscular dystrophy who offer therapeutic potential to fight these neuromuscular disorders, Bidichandani said.
 



http://link.springer.com/article/10.1007/s00204-015-1579-5?no-access=true
Redox- and non-redox-metal-induced formation of free radicals and their role in human disease
Marian ValkoAffiliated withFaculty of Chemical and Food Technology, Slovak University of TechnologyThe Center for Basic and Applied Research, University Hradec Kralove Email author 
, Klaudia JomovaAffiliated withDepartment of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University
, Christopher J. RhodesAffiliated withFresh Lands
, Kamil KučaAffiliated withThe Center for Basic and Applied Research, University Hradec KraloveBiomedical Research Center, University Hospital Hradec Kralove
, Kamil MusílekAffiliated withBiomedical Research Center, University Hospital Hradec KraloveDepartment of Chemistry, Faculty of Science, University Hradec Kralove


Abstract
Transition metal ions are key elements of various biological processes ranging from oxygen formation to hypoxia sensing, and therefore, their homeostasis is maintained within strict limits through tightly regulated mechanisms of uptake, storage and secretion. The breakdown of metal ion homeostasis can lead to an uncontrolled formation of reactive oxygen species, ROS (via the Fenton reaction, which produces hydroxyl radicals), and reactive nitrogen species, RNS, which may cause oxidative damage to biological macromolecules such as DNA, proteins and lipids. An imbalance between the formation of free radicals and their elimination by antioxidant defense systems is termed oxidative stress. Most vulnerable to free radical attack is the cell membrane which may undergo enhanced lipid peroxidation, finally producing mutagenic and carcinogenic malondialdehyde and 4-hydroxynonenal and other exocyclic DNA adducts. While redox-active iron (Fe) and copper (Cu) undergo redox-cycling reactions, for a second group of redox-inactive metals such as arsenic (As) and cadmium (Cd), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. While arsenic is known to bind directly to critical thiols, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. Redox-inert zinc (Zn) is the most abundant metal in the brain and an essential component of numerous proteins involved in biological defense mechanisms against oxidative stress. The depletion of zinc may enhance DNA damage by impairing DNA repair mechanisms. Intoxication of an organism by arsenic and cadmium may lead to metabolic disturbances of redox-active copper and iron, with the occurrence of oxidative stress induced by the enhanced formation of ROS/RNS. Oxidative stress occurs when excessive formation of ROS overwhelms the antioxidant defense system, as is maintained by antioxidants such as ascorbic acid, alpha-tocopherol, glutathione (GSH), carotenoids, flavonoids and antioxidant enzymes which include SOD, catalase and glutathione peroxidase. This review summarizes current views regarding the role of redox-active/inactive metal-induced formation of ROS, and modifications to biomolecules in human disease such as cancer, cardiovascular disease, metabolic disease, Alzheimer’s disease, Parkinson’s disease, renal disease, blood disorders and other disease. The involvement of metals in DNA repair mechanisms, tumor suppressor functions and interference with signal transduction pathways are also discussed.


Keywords
Metals Toxicity Oxidative stress Human disease Reactive oxygen species
 



http://www.ojrd.com/content/10/1/108/abstract
Friedreich ataxia in Norway – an epidemiological, molecular and clinical study
Iselin Marie Wedding13*, Mette Kroken2, Sandra Pilar Henriksen1, Kaja Kristine Selmer23, Torunn Fiskerstrand45, Per Morten Knappskog45, Tone Berge1 and Chantal ME Tallaksen13
 
Abstract
Background
Friedreich ataxia is an autosomal recessive hereditary spinocerebellar disorder, characterized by progressive limb and gait ataxia due to proprioceptive loss, often complicated by cardiomyopathy, diabetes and skeletal deformities. Friedreich ataxia is the most common hereditary ataxia, with a reported prevalence of 1:20 000 – 1:50 000 in Central Europe. Previous reports from south Norway have found a prevalence varying from 1:100 000 – 1:1 350 000; no studies are previously done in the rest of the country.


Methods
In this cross-sectional study, Friedreich ataxia patients were identified through colleagues in neurological, pediatric and genetic departments, hospital archives searches, patients’ associations, and National Centre for Rare Disorders. All included patients, carriers and controls were investigated clinically and molecularly with genotype characterization including size determination of GAA repeat expansions and frataxin measurements. 1376 healthy blood donors were tested for GAA repeat expansion for carrier frequency analysis.


Results
Twenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752–1:112]) was found. Homozygous GAA repeat expansions in the FXN gene were found in 27/29, while two patients were compound heterozygous with c.467 T < C, L157P and the deletion (g.120032_122808del) including exon 5a. Two additional patients were heterozygous for GAA repeat expansions only. Significant differences in the level of frataxin were found between the included patients (N = 27), carriers (N = 37) and controls (N = 27).


Conclusions
In this first thorough study of a complete national cohort of Friedreich ataxia patients, and first nation-wide study of Friedreich ataxia in Norway, the prevalence of Friedreich ataxia in Norway is lower than in Central Europe, but higher than in the last Norwegian report, and as expected from migration studies. A south–north prevalence gradient is present. Based on Hardy Weinberg’s equilibrium, the carrier frequency of 1:196 is consistent with the observed prevalence. All genotypes, and typical and atypical phenotypes were present in the Norwegian population. The patients were phenotypically similar to European cohorts. Frataxin was useful in the diagnostic work-up of heterozygous symptomatic cases.
 
 



http://www.medengphys.com/article/S1350-
4533(15)00176-9/abstract
Effect of power-assisted hand-rim wheelchair propulsion on shoulder load in experienced wheelchair users: A pilot study with an instrumented wheelchair

 

Fig. 1
Left: Schematic of the 6 degrees of freedom sensor mounted on the wheel and axis. The assisting motor was mounted in the axis itself. A mounting plate and amedium-density fiberboard (MDF) were placed between the motor and the 6 degrees of freedom (DOF) force and torque sensor. The hand-rim was mounted on the sensor via the sensor casing, sensor arm and center plate. Right: The instrumented wheel as implemented in the experimental wheelchair used in this study. The picture also shows the reflective markers and electrodes for surface electromyography.


Fig. 2
Left and mid: The local positive forces FX:anterior, FY: superior and FZ: lateral directed forces at point of force application at the point of force application on the rim (left) and the glenohumeral joint (mid). Right: Positive moments MX: adduction moment, MY: internal rotation and MZ: flexion moment at the glenohumeral joint.

Fig. 3
Maximum shoulder forces (N) and moments (N m) measured with and without power assist (n = 10). In each graph the box plot on the left is without power assist and on the right with power assist. The significant differences between the values with and without power assist are presented with a p-value. + : outlier.

Fig. 4


Three dimensional shoulder forces and moments during the push phase. The plotted line for each parameter represents the mean of 10 sequential strokes with standard deviation for 1 subject. FX, FY, FZ: force in respectively x, y and z direction; MX, MY, MZ, moment around respectively x, y and z axis. Left: during propulsion without power assist. Right: during propulsion with power assist.


Abstract
This study aims to compare hand-rim and power-assisted hand-rim propulsion on potential risk factors for shoulder overuse injuries: intensity and repetition of shoulder loading and force generation in the extremes of shoulder motion. Eleven experienced hand-rim wheelchair users propelled an instrumented wheelchair on a treadmill while upper-extremity kinematic, kinetic and surface electromyographical data was collected during propulsion with and without power-assist. As a result during power-assisted propulsion the peak resultant force exerted at the hand-rim decreased and was performed with significantly less abduction and internal rotation at the shoulder. At shoulder level the anterior directed force and internal rotation and flexion moments decreased significantly. In addition, posterior and the minimal inferior directed forces and the external rotation moment significantly increased. The stroke angle decreased significantly, as did maximum shoulder flexion, extension, abduction and internal rotation. Stroke-frequency significantly increased. Muscle activation in the anterior deltoid and pectoralis major also decreased significantly. In conclusion, compared to hand-rim propulsion power-assisted propulsion seems effective in reducing potential risk factors of overuse injuries with the highest gain on decreased range of motion of the shoulder joint, lower peak propulsion force on the rim and reduced muscle activity.
 



 
http://www.sciencedirect.com/science/article/pii/
S0022510X15020699
Quantitative evaluation of gait ataxia by accelerometers

Shinichi Shiraia, b, Ichiro Yabea, Masaaki Matsushimaa, Yoichi M. Itoc, Mitsuru Yoneyamad, Hidenao Sasakia, , a Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japanb Department of Neurology, Kushiro Rosai Hospital, Kushiro, Japanc Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japand MCHC R&D Synergy Center, Inc., Yokohama, Japan

Abstract
An appropriate biomarker for spinocerebellar degeneration (SCD) has not been identified. Here, we performed gait analysis on patients with pure cerebellar type SCD and assessed whether the obtained data could be used as a neurophysiological biomarker for cerebellar ataxia. We analyzed 25 SCD patients, 25 patients with Parkinson's disease as a disease control, and 25 healthy control individuals. Acceleration signals during 6 min of walking and 1 min of standing were measured by two sets of triaxial accelerometers that were secured with a fixation vest to the middle of the lower and upper back of each subject. We extracted two gait parameters, the average and the coefficient of variation of motion trajectory amplitude, from each acceleration component. Then, each component was analyzed by correlation with the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). Compared with the gait control of healthy subjects and concerning correlation with severity and disease specificity, our results suggest that the average amplitude of medial-lateral (upper back) of straight gait is a physiological biomarker for cerebellar ataxia. Our results suggest that gait analysis is a quantitative and concise evaluation scale for the severity of cerebellar ataxia.

Keywords
Cerebellar ataxia; Quantitative evaluation; Accelerometer; Biomarker; The Scale for the Assessment and Rating of Ataxia (SARA); Gait analysis
 
 



http://journals.lww.com/jcnmd/Abstract/2015/09000/
Atypical_Presentation_for_Friedreich_Ataxia_in_a.3.aspx
Atypical Presentation for Friedreich Ataxia in a Child
 
Caron, Elena MD*; Burns, Dennis MD†; Castro, Diana MD†; Iannaccone, Susan T. MD†


Abstract
Abstract: The classic phenotype of Friedreich ataxia is characterized by dysarthria, progressive limb and trunk ataxia, loss of reflexes, and gait disturbance with the onset of disease before the second decade. Homozygous trinucleotide repeat expansion of GAA in the FXN gene is found in 98% of patients. Two-5% of all patients have a repeat expansion on one allele and a point mutation on the other allele. Atypical phenotype is found in 25% of patients. A 10-year-old boy presented with congenital biliary atresia and progressive gait abnormality. His examination was significant for spastic gait, hyperreflexia, and sensory neuropathy. Genetic testing revealed a compound heterozygous mutation in the FXN gene. The absence of dysarthria and ataxia, retention of reflexes, absence of diabetes, and variable development of cardiomyopathy support a slow progression of disease with compound heterozygous mutation at G130V. Missense mutations are rare causes of Friedreich ataxia that can only be detected by sequencing of the FXN gene. Sequencing of the FXN gene is essential to make an early diagnosis when there is an atypical phenotype.
 
 



http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(15)00201-X/abstract
Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial
Figures
Figure 1


Trial profile
55 participants (28 in the riluzole group and 27 in the placebo group) were included in primary (intention-to-treat) and safety analyses. SCA=patient with spinocerebellar ataxia. FA=patient with Friedreich's ataxia.
Figure 2
Changes in SARA scores after 3 and 12 months
Data are mean SARA score changes (positive values show deterioration of cerebellar ataxia, negative values show improvement, and zero values show no change), after treatment (3 and 12 months), for 28 patients in the riluzole group and 27 in the placebo group.
Summary


Background
Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial.
Methods
Patients with spinocerebellar ataxia or Friedreich's ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov, number NCT01104649.


Findings
Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreich's ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreich's ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95–32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported.


Interpretation
Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice.
Funding
Agenzia Italiana del Farmaco.
 



 
http://www.future-science.com/doi/abs/10.4155/bio.15.118
Stable isotopes and LC–MS for monitoring metabolic disturbances in Friedreich's ataxia platelets
Andrew J Worth​‌1,2,3, Sankha S Basu​‌1,3, Eric C Deutsch​‌3,4, Wei-Ting Hwang​‌2,5, Nathaniel W Snyder​‌1,6, David R Lynch​‌4 & Ian A Blair​‌*,1,2,3 *Author for correspondence: ianblair@mail.med.upenn.edu  


Background: Friedreich's ataxia (FRDA) is an autosomal recessive disease with metabolic abnormalities that have been proposed to play an important role in the resulting neurodegeneration and cardiomyopathy. The inability to access the highly affected neuronal and cardiac tissues has hampered metabolic evaluation and biomarker development. Methods: Employment of a LC–MS-based method to determine whether platelets isolated from patients with FRDA exhibit differentiable metabolism compared with healthy controls. Results: Isotopologue analysis showed a marked decrease in glucose incorporation with a concomitant increase in palmitate-derived acyl-CoA thioesters in FRDA platelets compared with controls. Conclusion: Our findings demonstrate that platelets can be used as a surrogate tissue for in vivo biomarker studies to monitor new therapeutic approaches for the treatment of FRDA.
 



http://www.ojrd.com/content/10/1/108
Friedreich ataxia in Norway – an epidemiological, molecular and clinical study
Iselin Marie Wedding13*, Mette Kroken2, Sandra Pilar Henriksen1, Kaja Kristine Selmer23, Torunn Fiskerstrand45, Per Morten Knappskog45, Tone Berge1 and Chantal ME Tallaksen13
* Corresponding author: Iselin M Wedding i.m.wedding@medisin.uio.no


Abstract
Background
Friedreich ataxia is an autosomal recessive hereditary spinocerebellar disorder, characterized by progressive limb and gait ataxia due to proprioceptive loss, often complicated by cardiomyopathy, diabetes and skeletal deformities. Friedreich ataxia is the most common hereditary ataxia, with a reported prevalence of 1:20 000 – 1:50 000 in Central Europe. Previous reports from south Norway have found a prevalence varying from 1:100 000 – 1:1 350 000; no studies are previously done in the rest of the country.


Methods
In this cross-sectional study, Friedreich ataxia patients were identified through colleagues in neurological, pediatric and genetic departments, hospital archives searches, patients’ associations, and National Centre for Rare Disorders. All included patients, carriers and controls were investigated clinically and molecularly with genotype characterization including size determination of GAA repeat expansions and frataxin measurements. 1376 healthy blood donors were tested for GAA repeat expansion for carrier frequency analysis.


Results
Twenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752–1:112]) was found. Homozygous GAA repeat expansions in the FXN gene were found in 27/29, while two patients were compound heterozygous with c.467 T < C, L157P and the deletion (g.120032_122808del) including exon 5a. Two additional patients were heterozygous for GAA repeat expansions only. Significant differences in the level of frataxin were found between the included patients (N = 27), carriers (N = 37) and controls (N = 27).


Conclusions
In this first thorough study of a complete national cohort of Friedreich ataxia patients, and first nation-wide study of Friedreich ataxia in Norway, the prevalence of Friedreich ataxia in Norway is lower than in Central Europe, but higher than in the last Norwegian report, and as expected from migration studies. A south–north prevalence gradient is present. Based on Hardy Weinberg’s equilibrium, the carrier frequency of 1:196 is consistent with the observed prevalence. All genotypes, and typical and atypical phenotypes were present in the Norwegian population. The patients were phenotypically similar to European cohorts. Frataxin was useful in the diagnostic work-up of heterozygous symptomatic cases.


Friedreich ataxia; FRDA; Frataxin; Ataxia; Autosomal recessive; Norway
 



http://www.sciencedirect.com/science/article/pii/
S1567724915300209
Investigation of mitochondrial DNA variations among Indian Friedreich's ataxia (FRDA) patients
Inder Singha,
Mohammed Faruq
b,
Madakasira Vasantha Padma
a,
Vinay Goyal
a,
Madhuri Behari
a,
Ashoo Grover
c,
Mitali Mukerji
b,
Achal K. Srivastava
a,


Abstract
Objective
The loss of function mutations (biallelic) in frataxin (FXN) has primarily been implicated in Friedreich's ataxia (FRDA), an autosomal recessive cerebellar ataxia. The protein product of FXN is a nuclear-encoded mitochondrial protein required for the biogenesis of iron– clusters (Fe–S). FRDA is characterized by neurological and non-neurological features which show variable expression in affected individuals. An inverse relationship has been demonstrated between GAA repeat size and age at onset and explains 50% variability of the age at onset. MtDNA variations and haplogroups could be one of the contributory factors to explain the remaining heterogeneity in FRDA, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of FRDA.


Methods
In our study, targeted resequencing of the D-loop and coding region of mitochondrial genes (ND1-6 and ATP) was conducted in 30 genetically confirmed FRDA patients and 62 ethnicity-matched unrelated healthy controls to identify the functionally important mtDNA variations and to trace the mitochondrial lineage of Indian FRDA patients. Cumulative mitochondrial SNP scores were computed for the identified variations in the functional region and haplogroups were determined by Haplogrep.


Results
A significantly higher load of overall mitochondrial variations (with a trend toward the coding region) per individual was noted among FRDA cases rather than controls (p-value < 0.03). A non-synonymous variation (p. L237M) in ND2 was over-represented among FRDA cases (p-value 0.04). This variation has a reported association with longevity and myocardial infarction. We also observed over-representation of H haplogroup (Caucasian mitochondrial haplogroup) among FRDA patients. We have not observed the influence of mitochondrial variations and haplogroup upon age at onset of FRDA.


Conclusions
Overall, our study identifies the functionally important variations and mitochondrial lineage of Indian FRDA cases and, that underscores the importance of studying the role of mitochondrial genome variations in FRDA.
 
Keywords
FRDA;
Friedreich's ataxia;
Haplogroup;
Mitochondria
 



http://www.sciencedirect.com/science/article/pii/
S002751071530035X
Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia
Daman Kumaria,
Bruce Hayward
a,
Asako J. Nakamura
b1,
William M. Bonner
b,
Karen Usdin
a,


Abstract
Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site.



http://www.sciencedirect.com/science/article/pii/
S0891422215001225 
An exploratory qualitative investigation of psychosocial determinants of parental decisions to support sport participation for youth with a mobility impairment
Celina H. Shirazipoura,
Amy E. Latimer-Cheung
a,
Kelly P. Arbour-Nicitopoulos
b
 
Abstract
Introduction
Parents of youth with a mobility impairment (MI) have an important influence on their children's sport participation. The current study consists of an exploratory qualitative investigation of the relevance of HAPA for understanding parental support behaviours for youth with MI's sport participation.


Methods
Parents of youth athletes (Mage = 11.10; SD = 2.77) and non-athletes (Mage = 11.50; SD = 3.84) participated in semi-structured interviews with question development guided by the Health Action Process Approach (HAPA).


Results
Constructs from HAPA were expressed as relevant to parental decisions, with differing subthemes emerging based upon parental group (i.e. parents of non-athletes or parents of athletes). Other constructs that emerged included barriers, facilitators, and resources.


Discussion
Constructs from the motivational phase of HAPA were relevant for parents of athletes and non-athletes, while the volitional phase demonstrated utility for understanding the views of parents of athletes. Differences between the patterns of responses of both groups were apparent in how the constructs were expressed. Findings identify key areas for research, as well as practical applications. For example, future programs can target parental positions on specific HAPA constructs (e.g. risk perceptions) where differences were found between both groups of parents in order to promote parental decisions that support their children's sport participation.
 
Keywords
Health Action Process Approach;
Mobility impairment;
Parents;
Sport;
Youth
 



 
http://jbx.sagepub.com/content/early/2015/08/18/
1087057115600433.abstract
Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection

M. Grazia Cotticelli1,2
Fabio Acquaviva3
Shujuan Xia1
Avinash Kaur1,2
Yongping Wang1
Robert B. Wilson1,2

Abstract
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix and regulates the iron–sulfur cluster (ISC) assembly complex. ISCs are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain. Decreased expression of frataxin is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. In media with beta-hydroxybutyrate (BHB) as carbon source, primary FRDA fibroblasts grow poorly and/or lose viability over several days. We screened a random, short-hairpin-RNA (shRNA)-expressing library in primary FRDA fibroblasts and identified two shRNAs that reverse the growth/viability defect in BHB media. One of these two clones increases frataxin expression in primary FRDA fibroblasts, either as a vector-expressed shRNA or as a transfected short-interfering RNA (siRNA). 

 



http://bmjopen.bmj.com/content/5/6/e007199.full
Effectiveness, safety and costs of orphan drugs: an evidence-based review
Igho J Onakpoya1,
Elizabeth A Spencer
1,
Matthew J Thompson
2,
Carl J Heneghan
1


Abstract
Introduction Several orphan drugs have been approved by the European Medicines Agency (EMA) over the past two decades. However, the drugs are expensive, and in some instances, the evidence for effectiveness is not convincing at the time of regulatory approval. Our objective was to evaluate the clinical effectiveness of orphan drugs that have been granted marketing licenses in Europe, determine the annual costs of each drug, compare the costs of branded orphan drugs against their generic equivalents, and explore any relationships between orphan drug disease prevalence and annual costs.


Methods We searched the EMA database to identify orphan drugs granted marketing authorisation up to April 2014. Electronic searches were also conducted in PubMed, EMBASE and Google Scholar, to assess data on effectiveness, safety and annual costs. 2 reviewers independently evaluated the levels and quality of evidence, and extracted data.


Results We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of evidence. 85% showed significant clinical effects, but serious adverse events were reported in 86.5%. Their annual costs were between £726 and £378 000. There was a significant inverse relationship between disease prevalence and annual costs (p=0.01); this was largely due to the influence of the ultra-orphan diseases. We could not determine whether the balance between effectiveness and safety influenced annual costs. For 10 drugs where generic alternatives were available, the branded drugs were 1.4 to 82 000 times more expensive.


Conclusions The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases, far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative.
 
 



http://www.nature.com/ejhg/journal/v23/n9/full/
ejhg2014272a.html?WT.ec_id=EJHG-201509&spMailingID=49313076&spUserID=
NDQwOTM2MDQ1OQS2&spJobID
=742079872&spReportId=NzQyMDc5ODcyS0
 
The EuroBioBank Network: 10 years of hands-on experience of collaborative, transnational biobanking for rare diseases
EJHGOpen
Marina Mora1, Corrado Angelini2,3, Fabrizia Bignami4, Anne-Mary Bodin5, Marco Crimi6, Jeanne- Hélène Di Donato7, Alex Felice8, Cécile Jaeger9, Veronika Karcagi10, Yann LeCam5, Stephen Lynn11, Marija Meznaric12, Maurizio Moggio13, Lucia Monaco6, Luisa Politano14, Manuel Posada de la Paz15, Safaa Saker16, Peter Schneiderat17, Monica Ensini11, Barbara Garavaglia18, David Gurwitz19, Diana Johnson20, Francesco Muntoni20, Jack Puymirat21, Mojgan Reza11, Thomas Voit22, Chiara Baldo23, Franca Dagna Bricarelli24, Stefano Goldwurm25, Giuseppe Merla26, Elena Pegoraro3, Alessandra Renieri27, Kurt Zatloukal28, Mirella Filocamo29 and Hanns Lochmüller11


Abstract
The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003–2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and ‘omics’ data, thus challenging the fragmentation of international cooperation on the field.

 

 

 

Volver a la Portada