Cation distribution in manganese cobaltite spinels Co3−xMnxO4 (0 ≤ x ≤ 1) determined by thermal analysis

Thermogravimetric analysis was used in order to study the reduction in air of submicronic powders of Co3−x Mn x O4 spinels, with 0 ≤ x ≤ 1. For x = 0 (i.e. Co3O4), cation reduction occurred in a single step. It involved the CoIII ions at the octahedral sites, which were reduced to Co2+ on producing CoO. For 0 < x ≤ 1, the reduction occurred in two stages at increasing temperature with increasing amounts of manganese. The first step corresponded to the reduction of octahedral CoIII ions and the second was attributed to the reduction of octahedral Mn4+ ions to Mn3+. From the individual weight losses and the electrical neutrality of the lattice, the CoIII and Mn4+ ion concentrations were calculated. The distribution of cobalt and manganese ions present on each crystallographic site of the spinel was determined. In contrast to most previous studies that took into account either CoIII and Mn3+ or Co2+, CoIII and Mn4+ only, our thermal analysis study showed that Co2+/CoIII and Mn3+/Mn4+ pairs occupy the octahedral sites. These results were used to explain the resistivity measurements carried out on dense ceramics prepared from our powders sintered at low temperature (700–750 °C) in a Spark Plasma Sintering apparatus

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807)

A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers

Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population

Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from −0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to −0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier

Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update

© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.info:eu-repo/semantics/publishedVersio

Inotersen treatment for patients with hereditary transthyretin amyloidosis

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .)

Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis.

INTRODUCTION: Paraneoplastic neurological syndromes (PNS) consist of a heterogeneous group of neurological disorders triggered by cancer. The aim of this systematic review is to estimate the reported prevalence of pain in patients with paraneoplastic peripheral neuropathy (PPN). METHODS: A systematic computer-based literature search was conducted on PubMed database. RESULTS: Our search strategy resulted in the identification of 126 articles. After the eligibility assessment, 45 papers met the inclusion criteria. Full clinical and neurophysiological data were further extracted and involved 92 patients with PPN (54.5% males, mean age 60.0 ± 12.2 years). The commonest first manifestation of PPN is sensory loss (67.4%), followed by pain (41.3%), weakness (22.8%), and sensory ataxia (20.7%). In 13.0% of the cases, pain was the sole first manifestation of the PPN. During the course of the PPN, 57.6% of the patients may experience pain secondary to the neuropathy. CONCLUSIONS: Pain is very prevalent within PPN. Pain specialists should be aware of this. Detailed history-taking, full clinical examination, and requesting nerve conduction studies might lead to an earlier diagnosis of an underlying malignancy

Genetic spectrum of hereditary neuropathies with onset in the first year of life

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset