Background and purpose
HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3‐hydroxyisobutyryl‐coenzyme A (CoA) hydrolase (HIBCH) and short‐chainenoyl‐CoA ...hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.
Methods
We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.
Results
The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh‐like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.
Conclusions
Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.
Flow chart.
The skin is the organ that is most susceptible to the impact of the exposome. Located at the interface with the external environment, it protects internal organs through the barrier function of the ...epidermis. It must adapt to the consequences of the harmful effects of solar radiation, the various chemical constituents of atmospheric pollution, and wounds associated with mechanical damage: oxidation, cytotoxicity, inflammation, and so forth. In this biological context, a capacity to adapt to the various stresses caused by the exposome is essential; otherwise, more or less serious conditions may develop accelerated aging, pigmentation disorders, atopy, psoriasis, and skin cancers. Nrf2‐controlled pathways play a key role at this level. Nrf2 is a transcription factor that controls genes involved in oxidative stress protection and detoxification of chemicals. Its involvement in UV protection, reduction of inflammation in processes associated with healing, epidermal differentiation for barrier function, and hair regrowth, has been demonstrated. The modulation of Nrf2 in the skin may therefore constitute a skin protection or care strategy for certain dermatological stresses and disorders initiated or aggravated by the exposome. Nrf2 inducers can act through different modes of action. Keap1‐dependent mechanisms include modification of the cysteine residues of Keap1 by (pro)electrophiles or prooxidants, and disruption of the Keap1–Nrf2 complex. Indirect mechanisms are suggested for numerous phytochemicals, acting on upstream pathways, or via hormesis. While developing novel and safe Nrf2 modulators for skin care may be challenging, new avenues can arise from natural compounds‐based molecular modeling and emerging concepts such as epigenetic regulation.
Viral primary infections and reactivations are common complications in patients after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) and are associated with high ...morbidity and mortality. Among these patients, viral infections are frequently associated with viremia. Beyond the usual well-known viruses that are part of the routine clinical management of transplant recipients, numerous other viral signatures or genomes can be identified in the blood of these patients. The identification of novel viral species and variants by metagenomic next-generation sequencing has opened up a new field of investigation and new paradigms. Thus, there is a need to thoroughly describe the state of knowledge in this field with a review of all viral infections that should be scrutinized in high-risk populations. Here, we review the eukaryotic DNA and RNA viruses identified in blood, plasma, or serum samples of pediatric and adult SOT/HSCT recipients and the prevalence of their detection, with a particular focus on recently identified viruses and those for which their potential association with disease remains to be investigated, such as members of the
,
,
, and
families. Current knowledge of the clinical significance of these viral infections with associated viremia among transplant recipients is also discussed. To ensure a comprehensive description in these two populations, individuals described as healthy (mostly blood donors) are considered for comparative purposes. The list of viruses that should be on the clinicians' radar is certainly incomplete and will expand, but the challenge is to identify those of possible clinical significance.
Mitochondria as a target in treatment Frantz, Marie-Céline; Wipf, Peter
Environmental and molecular mutagenesis,
June 2010, Letnik:
51, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Mitochondria are key organelles that perform essential cellular functions and play pivotal roles in cell death and survival signaling. Hence, they represent an attractive target for drugs to treat ...metabolic, degenerative, and hyperproliferative diseases. Targeting mitochondria with organelle-specific agents or prodrugs has proven to be an effective therapeutic strategy. More specifically, controlling the cellular ROS balance via selective delivery of an antioxidant "payload" into mitochondria is an elegant emerging therapeutic concept. Herein, we review the recent medicinal chemistry and clinical data of these exploratory strategies, which should point the way for future generations of therapeutics. Environ. Mol. Mutagen. 2010.
Following the first proof of concept of using small nucleic acids to modulate gene expression, a long period of maturation led, at the end of the last century, to the first marketing authorization of ...an oligonucleotide-based therapy. Since then, 12 more compounds have hit the market and many more are in late clinical development. Many companies were founded to exploit their therapeutic potential and Big Pharma was quickly convinced that oligonucleotides could represent credible alternatives to protein-targeting products. Many technologies have been developed to improve oligonucleotide pharmacokinetics and pharmacodynamics. Initially targeting rare diseases and niche markets, oligonucleotides are now able to benefit large patient populations. However, there is still room for oligonucleotide improvement and further breakthroughs are likely to emerge in the coming years. In this review we provide an overview of therapeutic oligonucleotides. We present in particular the different types of oligonucleotides and their modes of action, the tissues they target and the routes by which they are administered to patients, and the therapeutic areas in which they are used. In addition, we present the different ways of patenting oligonucleotides. We finally discuss future challenges and opportunities for this drug-discovery platform.
One strategy to promote the use of natural dyes consists of developing solvents capable of increasing their solubility. Herein, in silico predictions of activity coefficients based on the ...conductor-like screening model COSMO-SAC were used to screen the most promising ionic solventsionic liquids or eutectic mixturesfor the dissolution of three natural dyes, namely, indigo, alizarin, and curcumin. The predicted logarithmic activity coefficients at infinite dilution, lnγ∞, indicate that small ions having high charge density and capable of establishing strong hydrogen bonds appear to be the best candidates. Anions such as acetate, methanesulfonate, chloride, bromide, and methyl- or ethyl-sulfate combined with small tetraalkylammonium-based, pyrrolidinium-based, and imidazolium-based cations seem to be the best candidates for the interaction and thus possible dissolution of the natural dyes. The eutectic mixture of such small cation–anion combinations with primary amines, small carboxylic acids, and zwitterions such as betaine and carnitine can lead to ionic solvents that are liquids at room temperature. The chosen potential ionic solvents were prepared, and the experimental solubility of the three natural dyes was measured and compared with that in water.
The decision-making process around the (non-)use of assistive technologies is multifactorial. The goal of the present study was to identify which factors predict or correlate with the use of a ...head-mounted magnification device for low vision (LV) (eSight Eyewear), by applying this multifactorial paradigm in order to tailor LV rehabilitation interventions to reduce device abandonment.
Using a cross-sectional design, participants were recruited from 567 eSight Eyewear owners to complete a 45-min survey online including questions from standardized questionnaires classified into four families: personal, device-related, environmental, and interventional. Using current device use/nonuse as a binary outcome, logistic regression analyses were performed to identify the variables that predicted the highest percentage of variance in eSight use.
The 109 (19.2%) respondents with complete data had a mean age of 47.7 years (SD = 25.4, range: 9-96), 51% self-reported a central visual impairment. The final regression model alternatives accounted for 84.7%, 68.7%, 83.7%, and 64.7% (Nagelkerke's pseudo R
2
) of the variance in eSight use. The most consistently predictive variables of sustained device use across models were: higher scores on the Psychological Impact of Assistive Devices Scale (PIADS) and the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST) scale, and participants' lack of experiencing headaches while using the device.
None of the traditional clinical variables (demographics, ocular, or general health), or LV rehabilitation experience was predictive of sustained use of a head-mounted LV display. However, the administration of standardized device-impact questionnaires may be able to identify device users that could benefit from individualized attention during LV rehabilitation provision to reduce the probability of device abandonment.
Implications for rehabilitation
Investigating the factors predicting (non-)use of head-mounted magnification devices for low vision (LV) is important to identify patients with a higher risk of device nonuse and to provide evidence for interventions designed to improve use.
The optimal combinations of our statistical analysis models highlighted the importance of individualized attention focusing on the user during LV rehabilitation provision of, and training with, head-mounted devices.
Standardized device-related quality of life measures were robust predictors of device use and may be able to identify individuals that could benefit from individualized attention during LV rehabilitation.
The absence of headaches while using a head-mounted magnification device was a robust predictor of continued use.
User follow-up service satisfaction strongly predicted continued devices use, indicating that manufacturers and rehabilitation service organizations need to maintain a high level of service.
We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, ...failure to thrive. He progressively developed dystonia-parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2-WI hyperintensities and brain atrophy. Molecular analysis was performed post-mortem following the diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile-onset DRPLA.
Head-mounted low vision devices have become a viable alternative to enhance residual vision. This study supports the use of a head-mounted display to improve aspects of functional vision and quality ...of life. Much is still unknown regarding the required frequency, duration, or potential effectiveness of this telerehabilitation training protocol or what characteristics best identify optimal users.
A randomized study explored the effect of telerehabilitation on quality of life and functional vision in individuals with low vision using a head-mounted display.
We recruited 57 participants (age, 21 to 82 years; mean, 54.5 years) among new prospective eSight Eyewear users, randomized 1:1 into two parallel groups; the experimental group received the telerehabilitation training provided by a low vision therapist, whereas the control group received the self-training standard offered by the device manufacturer and without involvement of a low vision therapist. The primary outcome measures were the impact of telerehabilitation on validated measures of assistive technology-related quality of life: the Psychosocial Impact of Assistive Devices Scale and the Quebec User Evaluation of Satisfaction with Assistive Technology scale. Exploratory outcomes were the assessment of self-reported functional vision using the Veterans Affairs Low Vision Visual Functioning Questionnaire-48 and cybersickness associated with head-mounted display use with the Simulator Sickness Questionnaire.
Assistive technology-related quality of life was improved when measured by the satisfaction scale but not the psychosocial scale within the first 3 months, independently of training type. Overall, functional vision improvement was observed within the first 2 weeks of device use and maintained during the 6-month study, independently of group type. Cybersickness outcomes were similar between training groups and did not change significantly for 6 months.
eSight Eyewear, either with telerehabilitation or with the manufacturer self-training comparison, improved functional vision and increased users' quality of life within the initial 3 months of device training and practice.
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