Friedreich Ataxia: An (Almost) 30-Year History After Gene Discovery.

In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9.

Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study.

Background: Friedreich ataxia is a rare neurodegenerative disorder caused by frataxin deficiency. Both underweight and overweight occur in mitochondrial disorders, each with adverse health outcomes. We investigated the longitudinal evolution of anthropometric abnormalities in Friedreich ataxia and the hypothesis that both weight loss and weight gain are associated with faster disease progression.

T cell trafficking in human chronic inflammatory diseases.

Circulating T cells, which migrate from the periphery to sites of tissue inflammation, play a crucial role in the development of various chronic inflammatory conditions. Recent research has highlighted subsets of tissue-resident T cells that acquire migratory capabilities and re-enter circulation, referred to here as "recirculating T cells." In this review, we examine recent advancements in understanding the biology of T cell trafficking in diseases where T cell infiltration is pivotal, such as multiple sclerosis and inflammatory bowel diseases, as well as in metabolic disorders where the role of T cell migration is less understood.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study.

Background: Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death.

Objectives: To investigate predictors of survival in FA.

Methods: Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset.

Background: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA).

Methods: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models.

Effect of radiation therapy on fracture resistance of simulated immature teeth submitted to root reinforcement.

Background: The literature is scanty regarding the effect of radiation therapy (RT) on the mechanical properties of immature permanent teeth.

Aim: To evaluate the effect of RT on the fracture resistance of simulated immature teeth submitted to different types of root reinforcement.

Design: Sixty-four human teeth simulating the Cvek stage 3 of root development were distributed into eight groups (n = 8), according to exposure or not to RT (70 Gy) and the root reinforcement method: Group NR (control)-no reinforcement/no RT; Group NR + RT (control)-no reinforcement/RT; Group PO-tricalcium silicate-based cement (TS) apical plug/canal obturation/no RT; Group PO + RT-TS apical plug/canal obturation/RT; Group TS-canal filling with TS/no RT; Group TS + RT-canal filling with TS/RT; Group FP-TS apical plug/fibreglass post/no RT; and Group FP + RT-TS apical plug/fibreglass post/RT.

Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties.

Friedreich ataxia is an autosomal recessive multisystem disorder with prominent neurological manifestations and cardiac involvement. The disease is caused by large GAA expansions in the first intron of the gene, encoding the mitochondrial protein frataxin, resulting in downregulation of gene expression and reduced synthesis of frataxin. The selective loss of proprioceptive neurons is a hallmark of Friedreich ataxia, but the cause of the specific vulnerability of these cells is still unknown.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).

Background And Objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

Introduction: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA.

Clinical management guidelines for Friedreich ataxia: best practice in rare diseases.

Background: Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases.

Prediction of the disease course in Friedreich ataxia.

We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors.

MetaPhage: an Automated Pipeline for Analyzing, Annotating, and Classifying Bacteriophages in Metagenomics Sequencing Data.

Phages are the most abundant biological entities on the planet, and they play an important role in controlling density, diversity, and network interactions among bacterial communities through predation and gene transfer. To date, a variety of bacteriophage identification tools have been developed that differ in the phage mining strategies used, input files requested, and results produced. However, new users attempting bacteriophage analysis can struggle to select the best methods and interpret the variety of results produced.

Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation.

Clinical trials in rare diseases as Friedreich ataxia (FRDA) offer special challenges, particularly when multiple treatments become ready for clinical testing. Regulatory health authorities have developed specific pathways for "orphan" drugs allowing the use of a validated biomarker for initial approval. This study aimed to identify changes in cerebrospinal fluid (CSF) proteins occurring in FRDA patients that may be potential biomarkers in therapeutic trials.

Salivary microbiota composition may discriminate between patients with eosinophilic oesophagitis (EoE) and non-EoE subjects.

Background: Data on the role of the microbiome in adult patients with eosinophilic oesophagitis (EoE) are limited.

Aims: To prospectively collect and characterise the salivary, oesophageal and gastric microbiome in patients with EoE, further correlating the findings with disease activity.

Methods: Adult patients with symptoms of oesophageal dysfunction undergoing upper endoscopy were consecutively enrolled.

Shaping Ability of Reciprocating and Rotary Systems After Root Canal Retreatment: a CBCT Study.

The purpose of this in vitro study was to evaluate the shaping ability of reciprocating and continuous rotary systems after root canal retreatment. After preparation and root canal filling, mesial canals of 54 mandibular molars were distributed into 3 groups (n=18), according to the filling material removal and re-instrumentation protocols: WOG group - WaveOne Gold system; PTN group - ProTaper Next system; and PTU group - ProTaper Universal system. Cone-beam computed tomographic (CBCT) images acquisition of the mesial root canals was performed at different moments: (1) before instrumentation (unprepared root canals), (2) after preparation and filling, (3) after filling material removal and (4) re-instrumentation.

Recessive cerebellar and afferent ataxias - clinical challenges and future directions.

Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement.

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model.

Effect of root perforation repair with mineral aggregate-based cements on the retention of customized fiberglass posts.

The purpose of this study was to investigate whether the root perforation repair with mineral aggregate-based cements affects the retention of customized fiberglass posts to bovine intraradicular dentin. Sixty-four bovine mandibular incisors had their root canals endodontically treated and prepared for fiberglass posts luting. Teeth were randomly distributed into four groups (n = 16), according to the cement used for the perforations repair (MTA HP; calcium aluminate cement-CAC; and CAC + calcium carbonate nanoparticles-nano-CaCO) and control group (no perforation).

Fracture Resistance of Simulated Immature Teeth Reinforced with Different Mineral Aggregate-Based Materials.

This study assessed the fracture resistance of simulated immature teeth reinforced with calcium aluminate cement (CAC) or mineral trioxide aggregate (MTA) containing calcium carbonate nanoparticles (nano-CaCO3). The microstructural arrangement of the cements and their chemical constitution were also evaluated. Forty-eight canines simulating immature teeth were distributed into 6 groups (n=8): Negative control - no apical plug or root canal filling; CAC - apical plug with CAC; CAC/nano-CaCO3 - apical plug with CAC+5% nano-CaCO3; MTA - apical plug with MTA; MTA/nano-CaCO3 - apical plug with MTA+5% nano-CaCO3; and Positive control - root canal filling with MTA.

Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia.

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub-second dynamics of resting-state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA-related changes in resting-state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting-state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12-51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM).

Mediterranean diet, walking outdoors and polypharmacy in older patients with type II diabetes.

Background: Polypharmacy and its adverse health effects is an emerging public health issue, with increasing prevalence among patients with multiple chronic conditions, such as older adults with diabetes. A healthy lifestyle has been shown to improve both diabetes and polypharmacy incidence. We conducted a cross-sectional study to investigate the association of a healthy lifestyle with polypharmacy and comorbidities in older people with diabetes.