Perceived Fatigue and Energy are Independent Unipolar States: Supporting Evidence

Bryan D. Loy, Michelle H. Cameron, Patrick J. O'Connor, Medical Hypotheses, Available online 19 February 2018, ISSN 0306-9877, doi:10.1016/j.mehy.2018.02.014.

Persistent fatigue is a common problem (∼20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as “a lack of energy”, thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes.
When mental and physical aspects of energy and fatigue were measured in individuals with Friedreich’s ataxia, low physical energy was found while no differences were observed for mental energy or mental or physical fatigue. This type of information appears logical and is potentially useful because Friedreich’s ataxia is a disease that targets pyramidal nerves, causing muscle incoordination and reduced physical activity that worsens over time yet largely preserves mental functioning.

Progress in the treatment of Friedreich ataxia

Geneieve Tai, Louise A. Corben, Eppie M. Yiu, Sarah C. Milne, Martin B. Delatycki, Neurologia i Neurochirurgia Polska, Available online 19 February 2018, ISSN 0028-3843, doi:10.1016/j.pjnns.2018.02.003.

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA.

Meet Our Scientists. Ernest Giralt: "There are many diseases caused by failures in the protein-protein interactions”

IRB Barcelona, Institutional news. 14 Feb 2018

The Meet Our Scientists series presents Ernest Giralt, doctor of chemical sciences, who is the head of the Peptides and Proteins laboratory at IRB Barcelona.

In the video "The power of medicinal chemistry", Giralt highlights his interest in deciphering the language used by proteins to interact with each other.

The chemist Ernest Giralt (Viladecans, 1948) is the head of the Peptides and Proteins Laboratory at IRB Barcelona, ​​composed of more than 20 people among researchers and PhD students. This group focuses its research on peptides, small proteins, and on the dynamic properties of proteins.
Giralt has always been interested in trying to decipher the language that different proteins use to interact with each other, not only to unravel the biology of these interactions but also for their biomedical applicability since "there are many illnesses that are caused by errors in these interactions ".
The peptides designed in their laboratory are destined to interrupt or favour the unwanted interaction between the proteins. Among other advances, they have discovered some that interrupt very effectively an interaction between proteins related to cancer, which could open a door to new therapies against this disease. Likewise, they develop shuttle peptides that cross the blood-brain barrier to be able to supply drugs to the brain and that can be used for the treatment of pediatric brain cancer and for Friedrich's ataxia, a hereditary neurodegenerative disease.

Rules for processing genetic data for research purposes in view of the new EU General Data Protection Regulation

Mahsa Shabani & Pascal Borry; European Journal of Human Geneticsvolume 26, pages149–156 (2018) doi:10.1038/s41431-017-0045-7

Genetic data contain sensitive health and non-health-related information about the individuals and their family members. Therefore, adopting adequate privacy safeguards is paramount when processing genetic data for research or clinical purposes. One of the major legal instruments for personal data protection in the EU is the new General Data Protection Regulation (GDPR), which has entered into force in May 2016 and repealed the Directive 95/46/EC, with an ultimate goal of enhancing effectiveness and harmonization of personal data protection in the EU.
The new Regulation has already fueled concerns among various stakeholders, owing to the challenges that may emerge when implementing the Regulation across the countries. Notably, the provided definition for pseudonymized data has been criticized because it leaves too much room for interpretations, and it might undermine the harmonization of the data protection across the countries.

Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy.

QingQing Wang, Lili Guo, Cassandra J. Strawser, Lauren A. Hauser, Wei-Ting Hwang, Nathaniel W. Snyder, David R. Lynch, Clementina Mesaros, Ian A. Blair. PLoS ONE 13(2): e0192779. doi:10.1371/journal.pone.0192779

Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.

Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Theresa A. Zesiewicz, George Wilmot, Sheng-Han Kuo, Susan Perlman, Patricia E. Greenstein, Sarah H. Ying, Tetsuo Ashizawa, S.H. Subramony, Jeremy D. Schmahmann, K.P. Figueroa, Hidehiro Mizusawa, Ludger Schöls, Jessica D. Shaw, Richard M. Dubinsky, Melissa J. Armstrong, Gary S. Gronseth and Kelly L. Sullivan. Neurology published online February 9, 2018 doi:10.1212/WNL.0000000000005055

Objective To systematically review evidence regarding ataxia treatment.

Methods A comprehensive systematic review was performed according to American Academy of Neurology methodology.

Conclusions For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis–associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly

Kai Cai. Volume 114, Issue 3, Supplement 1, 2 February 2018, Pages 571a, doi:10.1016/j.bpj.2017.11.3123

Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.

RNA–DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication

Alexander J Neil Miranda U Liang Alexandra N Khristich Kartik A Shah Sergei M Mirkin; Nucleic Acids Research, , gky099, doi:10.1093/nar/gky099

Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA–DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich’s ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA–DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA–DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA–DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.

Restless legs syndrome and periodic leg movements in patients with movement disorders: Specific considerations

Högl, B. and Stefani, A. (2017), Mov. Disord., 32: 669–681. doi: 10.1002/mds.26929

The diagnostic criteria for restless legs syndrome (RLS) have been continuously updated in recent years, considerably facilitating both an accurate diagnosis and appropriate management of RLS.
Periodic leg or limb movements during sleep (PLMS) are present in patients with and without RLS and can be seen as biomarkers of genetic susceptibility to RLS.
Restless legs syndrome, and eriodic leg movements during wakefulness (PLMW) were significantly higher in Friedrich’s ataxia patients with RLS than in those without. Interestingly, in most of them RLS onset was after Friedreich’s ataxia onset, and Friedreich’s ataxia patients with RLS had significantly lower ferritin levels than those without.
Substantia nigra echogenicity correlated inversely with disease severity of Friedrich’s ataxia and was significantly associated with RLS. In contrast, few Friedreich’s ataxia patients fulfilled RLS criteria.
Although the large variation of RLS frequencies reported in these patients could indicate diagnostic difficulties because of confounding symptoms, the apparent high frequency of RLS in Frie-
dreich’s ataxia and the association with disturbed brain iron metabolism is interesting and requires further study.

New Approaches to Exciting Exergame-Experiences for People with Motor Function Impairments

Eckert, M.; Gómez-Martinho, I.; Meneses, J.; Martínez, J.-F.; Sensors 2017, 17, 354. doi:10.3390/s17020354             
OPEN ACCESS

The work presented here suggests new ways to tackle exergames for physical rehabilitation and to improve the players’ immersion and involvement. The primary (but not exclusive) purpose is to increase the motivation of children and adolescents with severe physical impairments, for doing their required exercises while playing. The proposed gaming environment is based on the Kinect sensor and the Blender Game Engine. A middleware has been implemented that efficiently transmits the data from the sensor to the game. Inside the game, different newly proposed mechanisms have been developed to distinguish pure exercise-gestures from other movements used to control the game (e.g., opening a menu). The main contribution is the amplification of weak movements, which allows the physically impaired to have similar gaming experiences as the average population. To test the feasibility of the proposed methods, four mini-games were implemented and tested by a group of 11 volunteers with different disabilities, most of them bound to a wheelchair. Their performance has also been compared to that of a healthy control group. Results are generally positive and motivating, although there is much to do to improve the functionalities. There is a major demand for applications that help to include disabled people in society and to improve their life conditions. This work will contribute towards providing them with more fun during exercise.