Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015

GBD 2015 Healthcare Access and Quality Collaborators (Ryan M Barber, Nancy Fullman, Reed J D Sorensen, Thomas Bollyky, Martin McKee, Ellen Nolte, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Cristiana Abbafati, Kaja M Abbas et al); The Lancet, Volume null, Issue null, DOI:10.1016/S0140-6736(17)30818-8

Funding: Bill & Melinda Gates Foundation.

Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.

National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.

Regulators of frataxin PATENT WO 2017037567 A1

Pfizer Inc., 9 Mar 2017. This invention relates to a method of treating a condition or a disease associated with decreased levels or activity of frataxin, including Friedreich's ataxia, comprising administering to a subject in needthereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof. Related methods, pharmaceutical uses and pharmaceutical compositions are disclosed herein.

Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.

Nrf2, cellular redox regulation, and neurologic implications

Eduardo E. Benarroch, MD; Neurology May 16, 2017, 88:20 1942-1950; published ahead of print April 19, 2017, 1526-632X  doi: 10.​1212/​WNL.​0000000000003946

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.

Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration

Wilkins HM, Weidling IW, Ji Y and Swerdlow RH (2017). Front. Immunol. 8:508. doi: 10.3389/fimmu.2017.00508


Friedreich’s ataxia is caused by autosomal recessive inheritance of a mutant Frataxin gene. The product of the Frataxin gene is responsible for iron homeostasis within mitochondria, and loss of this gene in Schwann cells leads to reduced mitochondrial respiration, inflammation, increased mitochondrial iron concentrations, and cell death. COX2 expression is elevated in both animal models and Friedreich’s ataxia patient lymphocytes, an indicator of increased inflammation.

Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review

Hakala, A. K., Fergusson, D. and Kimmelman, J., Ann Neurol.. Accepted Author Manuscript. doi:10.1002/ana.24952

Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.

Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Cai K, Tonelli M, Frederick RO, Markley JL. Biochemistry. 2017;56(3):487-499. doi:10.1021/acs.biochem.6b00447.

Physical Therapy for Cerebellar Ataxia

Akiyoshi Matsugi (2017). Physical Therapy for Cerebellar Ataxia, Neurological Physical Therapy, Prof. Toshiaki Suzuki (Ed.), InTech, ISBN 978-953-51-3114-4, Print ISBN 978-953-51-3113-7, Published: May 10, 2017 under CC BY 3.0 license.

Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.

Inducible And Reversible Phenotypes In A Novel Mouse Model Of Friedreich's Ataxia

Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C. Jordan, Daniel H. Geschwind; bioRxiv 137265 This article is a preprint and has not been peer-reviewed doi:10.1101/137265

We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction.

Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed.

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

James L. Miller, Myriam Rai, Normand L. Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R. Spencer; Neuropharmacology, Available online 11 May 2017, ISSN 0028-3908, doi:10.1016/j.neuropharm.2017.05.011.

STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human neuronal cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FRDA patient-derived PBMC by 20%–40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo.

STS-E412 (2-[2-(4-chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine),nonpeptidyl compound selective activator of the tissue-protective EPOR/CD131 receptor.

Building the patient community

F Raffai and O Timmis; Gene Therapy (3 May 2017) doi:10.1038/gt.2017.

There are many challenges in conducting rare disease research. The conditions are often poorly understood, small patient populations are dispersed around the world, and there are limited funding opportunities. Patient groups can serve as a key partner in overcoming these challenges, as they understand the impact of rare conditions on patients’ lives. This gives patient groups valuable scientific insights into the disease. This can be used to create research strategies, address research bottlenecks and directly fund research that appropriately addresses patient needs. Patient groups can also play a critical role in recruiting and retaining patients for clinical trials, which reduces time and resource waste. By partnering with patient groups, research teams can improve efficiency of research and best meet the needs of patients. Researchers can also play an important role in building and supporting patient groups to unlock these benefits.