Wicks Paul, Richards Tessa, Denegri Simon, Godlee Fiona. Patients’ roles and rights in research BMJ 2018; 362 :k3193 doi:10.1136/bmj.k3193
Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.
Tuesday, October 30, 2018
Patients’ roles and rights in research- Patients in research: one step in a long path
Wicks P, Richards T, Denegri S, Godlee F. BMJ 2018;362:k3193. 10.1136/bmj.k3193 30045909
We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.
We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.
Unraveling the Role of Heme in Neurodegeneration
Chiabrando Deborah, Fiorito Veronica, Petrillo Sara, Tolosano Emanuela. Frontiers in Neuroscience 12 (2018) 712 DOI=10.3389/fnins.2018.00712
Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.
Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.
Monday, October 29, 2018
The impact of histone post-translational modifications in neurodegenerative diseases
Samantha N. Cobos, Seth A. Bennett, Mariana P. Torrente, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.10.019.
Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.
Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.
Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia
Schirinzi, T., Romano, A., Favetta, M., Sancesario, A., Burattini, R., Summa, S., Della Bella, G., Castelli, E., Bertini, E., Petrarca, M., … Vasco, G. (2018). Frontiers in neurology, 9, 849. doi:10.3389/fneur.2018.00849
Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.
Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.
A case series of hereditary cerebellar ataxias in a highly consanguineous population from Northeast Brazil
Deborah Moreira Rangel, Paulo Ribeiro Nóbrega, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim, Pedro Braga-Neto, Parkinsonism & Related Disorders, 2018, ISSN 1353-8020, doi:10.1016/j.parkreldis.2018.10.027.
A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.
A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.
Saturday, October 27, 2018
Intraepidermal Nerve Fiber Density in Friedreich’s Ataxia
Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Dagmar Rudzki, Julia Wanschitz, Sylvia Boesch; Journal of Neuropathology & Experimental Neurology, , nly100, doi:10.1093/jnen/nly100
In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.
In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.
Wednesday, October 24, 2018
Investigating the landscape of US orphan product approvals
Kathleen L. Miller and Michael Lanthier, Orphanet Journal of Rare Diseases 2018 13:183, doi:10.1186/s13023-018-0930-3
The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations.
The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations.
The deoxyribose phosphate lyase of DNA polymerase β suppresses a processive DNA synthesis to prevent trinucleotide repeat instability
Yanhao Lai, Yossi Weizmann, Yuan Liu. Nucleic Acids Research, Volume 46, Issue 17, 28 September 2018, Pages 8940–8952, Doi:10.1093/nar/gky700
The results indicate that pol β dRP lyase activity restrained the pol β-dRP interaction to suppress a pol β processive DNA synthesis, thereby preventing TNR deletion. This further implicates a potential of pol β dRP lyase inhibition as a novel treatment of TNR-expansion diseases.
The results indicate that pol β dRP lyase activity restrained the pol β-dRP interaction to suppress a pol β processive DNA synthesis, thereby preventing TNR deletion. This further implicates a potential of pol β dRP lyase inhibition as a novel treatment of TNR-expansion diseases.
Ion Mobility-Mass Spectrometry Reveals Details of Formation and Structure for GAA·TCC DNA and RNA Triplexes
Jiawei Li, Alexander Begbie, Belinda J. Boehm, Alexander Button, Charles Whidborne, Yannii Pouferis, David M. Huang, Tara L. Pukala. J. Am. Soc. Mass Spectrom. (2018). https://doi.org/10.1007/s13361-018-2077-9
DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia. We demonstrate that, contrary to other examples, parallel triplex structures are favored for these sequences and that stability is enhanced by increasing oligonucleotide length and decreasing pH. We also provide evidence for the self-association of these triplexes, consistent with a proposed model of higher order DNA structures formed in Friedreich’s ataxia. By comparing triplex assembly using DNA- and RNA-based triplex-forming oligonucleotides, we demonstrate more favorable formation of RNA triplexes, suggesting a role for their formation in vivo.
DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia. We demonstrate that, contrary to other examples, parallel triplex structures are favored for these sequences and that stability is enhanced by increasing oligonucleotide length and decreasing pH. We also provide evidence for the self-association of these triplexes, consistent with a proposed model of higher order DNA structures formed in Friedreich’s ataxia. By comparing triplex assembly using DNA- and RNA-based triplex-forming oligonucleotides, we demonstrate more favorable formation of RNA triplexes, suggesting a role for their formation in vivo.
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