Switching opioid-dependent patients in substitution treatment from racemic methadone, levomethadone and buprenorphine to slow-release oral morphine: Analysis of the switching process in routine care

Since 2015 slow-release oral morphine (SROM) is approved for opioid substitution treatment (OST) in Germany. The SROMOS study (efficacy and tolerability of slow-release oral morphine in opioid substitution treatment) evaluates the efficacy and safety of SROM in routine care. This article describes the switching process from racemic methadone, levomethadone and buprenorphine to SROM.Between July 2016 and November 2017 180 patients in 23 study centers in Germany were included in the prospective, non-interventional, naturalistic observational study. Patients were already in OST and switched from a previous medication to SROM. The switching process was analyzed during a period of fourteen days.Data were available for 169 participants. The switching process had a different progression depending on premedication and pre dosage. On the fourteenth day of SROM treatment patients switched from racemic methadone took an average dosage of 922.2 mg/day, from levomethadone 801.0 mg/day and from buprenorphine 626.7 mg/day. Average conversion ratio racemic methadone to SROM was 1:11.8, levomethadone to SROM 1:17.4 and buprenorphine to SROM 1:58.0.This study provides the first data on the switching process from buprenorphine to SROM. Average dose ratio racemic methadone to SROM on the fourteenth day of treatment was considerably higher than recommended in the prescribing information

Randomised controlled trial combining vitamin E-functionalised chocolate with physical exercise to reduce the risk of protein-energy malnutrition in predementia aged people: study protocol for Choko-Age

Objective: Protein-energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. Methods and analysis: In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the 'Joint Programming Initiative A healthy diet for a healthy life'. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9-1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. Ethics and dissemination: All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects' regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. Trial registration number: NCT05343611

The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K

International audienceBackground: Mutations in GDAP1 associate with both demyelinating (CMT4A) and axonal (CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the latter being characterized by milder phenotypes and later onset. The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with only 4 heterozygous mutations identified in AD-CMT2K. Methods: We screened GDAP1 gene in a series of 43 index patients, 39 with CMT2 and 4 with intermediate CMT, with both sporadic and familial occurrence of the disease. Results: Three novel mutations were identified in three families with dominant segregation of the disease: two missense changes, p.Arg226Ser and p.Ser34Cys, affecting the GST domain of the GDAP1 protein and a novel deletion (c.23delAG) leading to early truncation of the protein upstream the GST domain. Wide variability in clinical presentation is shared by all three families mostly in terms of age at onset and disease severity. A rare variant p.Gly269Arg, located within the GST domain, apparently acts as phenotype modulator in the family carrying the deletion. Conclusion: The results obtained reveal a GDAP1 mutation frequency of 27% in the dominant families analyzed, a figure still unreported for this gene, thus suggesting that GDAP1 involvement in dominant CMT2 might be higher than expected

Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant

Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible patho-genetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases. OBJECTIVE: To search for disease-causing mutations in a large series of Italian patients with HSP. DESIGN: Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13. SETTING: Molecular testing facility in Italy. PATIENTS: Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP. MAIN OUTCOME MEASURES: Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13. RESULTS: We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene. CONCLUSIONS: The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.Comparative StudyJournal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe