•Polymer-derived SiOC ceramics are studied as anode in Li-ion batteries.•Li insertion capacity and cycling stability are correlated to the structure of SiOC.•First insertion capacity of SiCxO2(1-x) ...network goes up to 1300 mAhg−1.•The specific capacity of the C-poor SiOC degrades faster than the C-rich SiOC.
Polymer derived silicon oxycarbide (SiOC) materials are prepared by the pyrolysis of preceramic polymers obtained from polyhydridomethylsiloxane using 1,3,5,7-tetramethyl1,3,5,7-tetravinyl cyclotetrasiloxane or divinyl benzene as a cross-linking agent. The pyrolysis is carried out in an inert atmosphere at 1000 and 1300°C. The carbon content of SiOC is varied by changing the amount of starting precursors maintaining the same O/Si atomic ratio of about 1. Electrochemical measurements are performed in order to evaluate the materials in terms of their application as anodes in Li-ion batteries. Detailed structural characterization study is performed using complementary techniques with the aim of correlating the electrochemical behavior with the structure of the SiOC anodes. Results suggest that SiOC anodes behave as a composite material consisting of a disordered silicon oxycarbide phase having a very high first insertion capacity of ca 1300 mAh g−1 and a free C phase. However, the charge irreversible trapped into the amorphous silicon oxycarbide network is also high and therefore the maximum reversible lithium storage capacity of 650mAh g−1 is measured on high-C content SiOCs for which the balance between the two phases, namely the amorphous silicon oxycarbide and the free C phase, is optimal. The high carbon content SiOC show also an excellent cycling stability and performance at high charging/discharging rate: the reversible capacity at 2C rate being around 200 mAh g−1. Increasing the pyrolysis temperature has an opposite effect on the low-C and high-C materials: for the latter one the reversible capacity decreases following a known trend while the former shows an increase of the reversible capacity which has never been observed before for similar materials.
Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, ...suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
The workshop held in the Netherlands from October 20–22, 2023, united 27 scientists from academia, healthcare, and industry representing 11 countries, alongside four patient and charity ...representatives. Focused on Kennedy's Disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), the workshop aimed to consolidate knowledge, align on clinical trial designs, and promote participative medicine for effective treatments. Discussions emphasized KD's molecular mechanisms, highlighting its status as a neuromuscular disorder with motor neuron degeneration. Strategies for therapeutic intervention, including AR activity modulation and targeting post-translational modifications, were proposed. The need for diagnostic, prognostic, and target engagement biomarkers was stressed. Challenges in patient stratification and clinical trial recruitment were acknowledged, with the International KD/SBMA Registry praised for its role. The workshop concluded with a patient-focused session, underscoring challenges in KD diagnosis and the vital support provided by patient associations.
Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also ...dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients.
A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes.
The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A→C p.T282P, c.941A→T p.Q314L, c.1670A→C p.K557T), one nonsense (c.67G→T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A→G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs.
In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease.
A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and ...efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group TG, vs 0.2-0.4 mEq/L, subtherapeutic group STG).
The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15).
As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009.
Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS.
The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.
Polymer derived carbon-rich SiOC ceramics are prepared from polysiloxane precursors through a pyrolysis process at 1000°C using pure argon and argon/hydrogen mixture as pyrolysis atmosphere. The ...precursor is synthesized from a linear (Si–H)-containing polysiloxane cross-linked with divinylbenzene using hydrosilylation reaction in the presence of a platinum catalyst. Pyrolysis in Ar/H2 mixtures, compared to the treatment under pure Ar, results into a decrease of the concentration of C dangling bonds as revealed by electron spin resonance (ESR) measurements. The amount of free carbon phase is 10wt.% lower in the sample pyrolysed in a Ar/H2 mixture, while the ratio of hydrogen to free carbon remains constant for both, in Ar and in Ar/H2 pyrolysed samples. The sample prepared under Ar/H2 mixture shows an excellent cycling stability with an increase in the specific capacity of about 150mAhg−1 compared to its analogues pyrolysed in pure argon atmosphere.
•Polymer derived carbon-rich SiOC ceramics•Sample prepared under Ar/H2 gas mixture shows an excellent cycling stability•Pyrolysis in H2-rich atmosphere leads to a reduction of the defect concentration in the final SiOC ceramic•Modification of the silicon oxycarbide network leading to a corresponding increase of Li storage capacity
Abstract Background and Purpose The aim was to investigate whether neurofilament light chain (NfL) and profilin‐1 (PFN‐1) might qualify as surrogate disease and treatment‐response biomarkers by ...correlating their concentrations dynamic with clinical status in a cohort of 30 adult spinal muscular atrophy type 3 patients during nusinersen therapy up to 34 months. Methods Neurofilament light chain was measured in cerebrospinal fluid at each drug administration with a commercial enzyme‐linked immunosorbent assay (ELISA); PFN‐1 concentrations were tested in serum sampled at the same time points with commercial ELISA assays. Functional motor scores were evaluated at baseline, at the end of the loading phase and at each maintenance dose and correlated to biomarker levels. The concurrent effect of age and clinical phenotype was studied. Results Neurofilament light chain levels were included in the reference ranges at baseline; a significant increase was measured during loading phase until 1 month. PFN‐1 was higher at baseline than in controls and then decreased during therapy until reaching control levels. Age had an effect on NfL but not on PFN‐1. NfL was partially correlated to functional scores at baseline and at last time point, whilst no correlation was found for PFN‐1. Conclusion Cerebrospinal fluid NfL levels did not qualify as an optimal surrogate treatment biomarker in adult spinal muscular atrophy patients with a long disease duration, whilst PFN‐1 might to a greater extent represent lower motor neuron pathological processes. The observed biomarker level variation during the first 2 months of nusinersen treatment might suggest a limited effect on axonal remodeling or rearrangement.
Background and purpose
Literature data on spinal and bulbar muscular atrophy (SBMA) epidemiology are limited and restricted to specific populations. The aim of our study was to accurately collect ...information about SBMA patients living in the Veneto region in Italy to compute reliable epidemiological data. Androgen receptor (AR) lineages were genotyped to evaluate the presence of a founder effect.
Methods
A prevalence survey considering all SBMA patients diagnosed in the Italian Veneto region on 31 January 2018 was carried out. The presence of different haplotypes obtained genotyping 15 polymorphic markers (single nucleotide polymorphisms and short tandem repeats) around the AR gene was evaluated.
Results
Based on 68 patients, the punctual prevalence of the disease on 31 January 2018 was 2.58/100 000 (95% confidence interval 1.65–3.35) in the male population. Five different haplotypes were identified, confirming the existence of multiple founder effects. It was also observed that, within the same haplotype, patients had a similar CAG repeat number (P‐value < 0.001).
Conclusions
A reliable estimation of SBMA prevalence in the Italian Veneto region was calculated which does not seem to be affected by a strong founder effect. Moreover, our data suggest that the length of the CAG expansion could be preserved in patients harbouring the same haplotype.
The polymer-to-ceramic transformation of a polysilazane/divinylbenzene aerogel leading to SiCN aerogel was studied. The pre-ceramic samples were obtained by crosslinking a commercially available ...polysilazane with divinylbenzene in a highly diluted solution. Wet gels were supercritically dried using CO2 to get the pre-ceramic aerogel. The weight change during pyrolysis in flowing argon was studied by thermogravimetric analysis (in-situ measurements) and by measuring the weight change on samples pyrolyzed in a tubular furnace after cooling down to room temperature (ex-situ measurements). The structural transformation was followed by infrared spectroscopy while the microstructural changes were studied by nitrogen adsorption analysis. Results point out that samples pyrolyzed at intermediate temperature, i.e., around 600–800°C, react with the laboratory atmosphere forming SiO bonds and SiOH moieties. This out-of-furnace oxidation leads to an uncontrolled increase of the oxygen content of the pyrolyzed ceramics and eventually reduces the microporosity of the samples and its stability.
The objective of this study was to determine the degree of brain involvement in a cohort of myotonic dystrophy type 1 and type 2 (DM1, DM2) patients by brain studies and functional tests and to ...compare the results of the two groups. DM1, DM2 are multisystemic disorders due to polynucleotide expansions. Previous studies on brain involvement by neuroimaging and functional methods have led to contradictory results. Fifty molecularly defined DM1 patients and 14 DM2 patients, were recruited for the study. Age at recruitment, age at disease onset, disease duration and educational level were recorded. Neuromuscular assessment was done by MIRS. An extensive neuropsychological battery was performed in 48/50 DM1 and in a control group of 44 healthy matched subjects. Forty six of 50 DM1 and 12/14 DM2 underwent brain MRI; 21/50 DM1 and 9/14 DM2 underwent brain perfusion SPECT, with semiquantitative analysis of the results. MRI images were classified by ARWMC (age-related white matter changes) score, in order to quantify recurrence, localization and patterns of distribution of white matter hyperintense lesions (WMHLs) in our two cohorts. MRI results were matched to SPECT and to neuropsychological results. Thirty-seven of 46 DM1 and 10/12 DM2 had abnormal MRI imaging, showing scattered supratentorial, bilateral, symmetrical focal or diffuse WMHLs. A typical temporo-insular diffuse subcortical pattern was seen in DM1 subjects only, with no correlation with cognitive involvement. Major cognitive involvement was seen in the case of diffuse frontal lesions. A relationship with CTG expansion size was documented for DM1 subjects. SPECT showed minimal hypoperfusion in the posterior cortex planes in DM1 and, to a lesser extent, in DM2. Very mild degrees of involvement in the DM2 cohort were seen. Neuroimaging and functional investigations confirmed a more severe involvement of the brain in DM1 compared to DM2. A temporo-insular diffuse lesional pattern, specific for DM1, was found on MRI. This confirms greater expansion size as a risk factor for more extensive brain involvement in DM1.
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