Thursday, November 15, 2018

Neuromuscular diseases with hypertrophic cardiomyopathy

Cesar S.; Global Cardiology Science and Practice 2018:27 doi:10.21542/gcsp.2018.27

Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.

Wednesday, November 14, 2018

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Lynch, D. R., Farmer, J. , Hauser, L. , Blair, I. A., Wang, Q. Q., Mesaros, C. , Snyder, N. , Boesch, S. , Chin, M. , Delatycki, M. B., Giunti, P. , Goldsberry, A. , Hoyle, C. , McBride, M. G., Nachbauer, W. , O'Grady, M. , Perlman, S. , Subramony, S. H., Wilmot, G. R., Zesiewicz, T. and Meyer, C. (2018), Ann Clin Transl Neurol. . doi:10.1002/acn3.660

Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.

Wednesday, October 31, 2018

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093

We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease.

Kasai Shuya, Mimura Junsei, Ozaki Taku, Itoh Ken. Frontiers in Veterinary Science 5,242 2018 DOI=10.3389/fvets.2018.00242

In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.

Tuesday, October 30, 2018

Patients in research: still many roadblocks

Roos Eric C. BMJ 2018; 363 :k4387 doi:10.1136/bmj.k4387

Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.

Full partnership with patients is essential to any modern research enterprise

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.

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.

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.

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.

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.