Objective
To investigate the safety and efficacy of
N
-acetyl-
l
-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) ...patients.
Methods
In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Results
33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75,
p
= 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred.
Conclusions
NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC.
Clinicaltrials.gov identifier
NCT03759639.
Mutations in the voltage-gated sodium channel Na
1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on ...patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant Na
1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients' treatment, and finally indicate misdiagnosis of SCN1A related epilepsies.
•CDD clinical features have different onset and severity between genders.•CDKL5 screening should be considered in patients diagnosed with West syndrome.•CDD onset in mosaic form can be after six ...months of age.
CDKL5 deficiency disorder (CDD) is an independent clinical entity associated with early-onset encephalopathy, which is often considered the type of epileptic encephalopathy with CDKL5 mutation also found in children diagnosed with early-onset seizure (Hanefeld) type of Rett syndrome, epileptic spasms, West syndrome, Lennox-Gastaut syndrome, or autism. Since early seizure onset is a prominent feature, in this study, a cohort of 54 unrelated patients consisting of 26 males and 28 females was selected for CDKL5 screening, with seizures presented before 12 months of age being the only clinical criterion. Five patients were found to have pathogenic or likely pathogenic variants in CDKL5 while 1 was found to have a variant of uncertain significance (p.L522V). Although CDKL5 variants are more frequently identified in female patients, we identified three male and three female patients (11.1 %, 6/54) in this study. Missense variant with unknown inheritance (p.L522V), de novo missense variant (p.E60 K), two de novo splicing (IVS15 + 1G > A, IVS16 + 2 T > A), and one de novo nonsense variant p.W125* were identified using Sanger sequencing. Whole exome analysis approach revealed de novo frameshift variant c.1247_1248delAG in a mosaic form in one of the males. Patient clinical features are reviewed and compared to those previously described in related literature. Variable clinical features were presented in CDKL5 positive patients characterised in this study. In addition to more common features, such as early epileptic seizures, severe intellectual disability, and gross motor impairment, inappropriate laughing/screaming spells and hypotonia appeared at the age of 1 year in all patients, regardless of the type of CDKL5 mutation or sex. All three CDKL5 positive males from our cohort were initially diagnosed with West syndrome, which suggests that the CDKL5 gene mutations are a significant cause of West syndrome phenotype, and also indicate the overlapping characteristics of these two clinical entities.
In Niemann–Pick disease type C, a rare lysosomal storage disorder, treatment with
N
-acetyl-
l
-leucine, which may ameliorate lysosomal and metabolic dysfunction, resulted in better neurologic status ...than placebo.
Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the
PSAP
gene. Only ten pathogenic variants were described in the ...PSAP gene in MLD patients to date. We report on two novel variants in the
PSAP
gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A–D) or whole prosaposin. The patient’s phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with
PSAP
mutations.
Millions of individuals worldwide suffer from a motor disability, impeding their ability to perform daily tasks independently. Thanks to modern technologies, such as electrooculography (EOG), it is ...possible to provide them with a tool enhancing their quality of life. EOG, an electrophysiological method, detects DC potentials influenced by eye movements, making it particularly advantageous for individuals with motor impairments who retain ocular mobility. The article describes pilot experiments that includes the basic design of electrodes configuration for peripheral solutions, their optimization and the addition of sensors to measure other vital physiological parameters such as photoplethysmography (PPG) and electrocardiography (ECG) on demand. We tested all the EOG methodologies and connections that our device should contain with the help of Mindmedia Nexus-10 MKII, PPG signals with the Analog Devices MAXM86146 optical biosensor module and ECG with the Texas Instruments ADS1299 biopotential circuit. The evaluation and filtering of the collected data was carried out in the MATLAB environment. In the final, we present a hardware concept based on a new approach that, unlike the standard EOG, incorporates 3 large-area conductive fabric electrodes in a headband for practical and comfort long-term non-manual human-machine interface (HMI). Our measurements are crucial for monitoring the patient's health status, mood variations, and can help prevent complications or speed up treatment. The primary goal of this research was present our innovative concept and confirm its feasibility, bringing us closer to the realization of a fully developed and functional device.
Collagen-based scaffolds provide a promising option for the treatment of bone defects. One of the key parameters of such scaffolds consists of porosity, including pore size. However, to date, no ...agreement has been found with respect to the methodology for pore size evaluation. Since the determination of the exact pore size value is not possible, the comparison of the various methods applied is complicated. Hence, this study focuses on the comparison of two widely-used methods for the characterization of porosity-scanning electron microscopy (SEM) and micro-computed tomography (micro-CT).
7 types of collagen-based composite scaffold models were prepared by means of lyophilization and collagen cross-linking. Micro-CT analysis was performed in 3D and in 2D (pore size parameters were: major diameter, mean thickness, biggest inner circle diameter and area-equivalent circle diameter). Afterwards, pore sizes were analyzed in the same specimens by an image analysis of SEM microphotographs. The results were statistically evaluated. The comparison of the various approaches to the evaluation of pore size was based on coefficients of variance and the semi-quantitative assessment of selected qualities (e.g. the potential for direct 3D analysis, whole specimen analysis, non-destructivity).
The pore size values differed significantly with respect to the parameters applied. Median values of pore size values were ranging from 20 to 490 µm. The SEM values were approximately 3 times higher than micro-CT 3D values for each specimen. The Mean thickness was the most advantageous micro-CT 2D approach. Coefficient of variance revealed no differences among pore size parameters (except major diameter). The semi-quantitative comparison approach presented pore size parameters in descending order with regard to the advantages thereof as follows: (1) micro-CT 3D, (2) mean thickness and SEM, (3) biggest inner circle diameter, major diameter and area equivalent circle diameter.
The results indicated that micro-CT 3D evaluation provides the most beneficial overall approach. Micro-CT 2D analysis (mean thickness) is advantageous in terms of its time efficacy. SEM is still considered as gold standard for its widespread use and high resolution. However, exact comparison of pore size analysis in scaffold materials remains a challenge.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective This study aimed (1) to determine whether scanner arm rotation causes significant movement of the head restraint and (2) to measure patient movement and its variation during the scan. Study ...Design The iCAT scanner and a high-speed camera were used. The 40 patients were divided into 2 groups: the open-eyed group and the blindfolded group. Results The mean level of head restraint movement was 0.130 mm, with a significantly higher level at the beginning, probably owing to the accelerating arm. Mean movement of patients was 1.135 mm and 1.119 mm in the open-eyed and blindfolded groups, respectively. Patient movement was also significantly higher at the beginning of the scan, when noise and vibrations are likely to surprise the patient. Conclusions Patient instruction and a dry-run scan should be done by clinicians. Manufacturers should consider separating the seat and head restraint from the rest of the scanner to avoid vibration transfer.
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