Synthesis of alternating polydepsipeptides by ring-opening polymerization of morpholine-2,5-dione derivatives

Polydepsipeptides with alternating -hydroxy acid and -amino acid residues were synthesized by ring-opening polymerization of morpholine-2,5-dione derivatives. The polymerizations were performed in the melt using stannous octoate as an initiator. Molecular weights of the polydepsipeptides obtained ranged from 0,9 · 104 to 7,4 · 104. Morpholine-2,5-dione derivatives unsubstituted at the 6-position gave polymers with the highest molecular weights. Poly((S)-alanine-alt-glycolic acid) was semi-crystalline, whereas all other polydepsipeptides synthesized were amorphous. Morpholine-2,5-dione derivatives were synthesized by N-acylation of glycine, (S)-alanine or (S)-valine with chloroacetyl chloride or (R,S)-2-bromopropionyl bromide, followed by ring-closure of N-(2-halogenacyl)-amino acid sodium salts in the melt in 4 to 83% yield. Low yields in the cyclization reaction of N-(2-halogenacyl)-(S)-valine were accompanied by the formation of the corresponding polydepsipeptides in 13 to 46% yield, with molecular weights ranging from 3,3 · 104 to 4,9 · 104

Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy

To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 ) ARVC patients and in 39 (15 ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 of R14del carriers. Compared with R14del DCM patients, R14del DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 vs. 10 , P 0.001), cardiac transplantation (18 vs. 2 , P 0.001), and a family history for sudden cardiac death (SCD) at 50 years (36 vs. 16 , P 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 ) R14del ARVC samples, but in only one of nine (11 ) R14del DCM samples (P 0.03). The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of oarrhythmogenic cardiomyopathy

Frequencies and clinical associations of myositis-related antibodies in The Netherlands: A one-year survey of all Dutch patients

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of connective tissue diseases, collectively known as myositis. Diagnosis of IIM is challenging while timely recognition of an IIM is of utter importance considering treatment options and otherwise irreversible (severe) long-term clinical complications. With the EULAR/ACR classification criteria (2017) considerable advancement has been made in the diagnostic workup of IIM. While these criteria take into account clinical parameters as well as presence of one autoantibody, anti-Jo-1, several autoantibodies are associated with IIM and are currently evaluated to be incorporated into classification criteria. As individual antibodies occur at low frequency, the development of line blots allowing multiplex antibody analysis has improved laboratory diagnostics for IIM. The Euroline myositis line-blot assay (Euroimmun) allows screening and semi-quantitative measurement for 15 autoantibodies, i.e. myositis specific antibodies (MSA) to SRP, EJ, OJ, Mi-2α, Mi-2β, TIF1-γ, MDA5, NXP2, SAE1, PL-12, PL-7, Jo-1 and myositis associated antibodies (MAA) to Ku, PM/Scl-75 and PM/Scl-100. To evaluate the clinical significance of detection and levels of these autoantibodies in the Netherlands, a retrospective analysis of all Dutch requests for extended myositis screening within a 1 year period was performed. A total of 187 IIM patients and 632 non-IIM patients were included. We conclude that frequencies of MSA and MAA observed in IIM patients in a routine diagnostic setting are comparable to cohort-based studies. Weak positive antibody levels show less diagnostic accuracy compared to positive antibody levels, except for anti-NXP2. Known associations between antibodies and skin involvement (anti-MDA5, anti-TIF1-γ), lung involvement (anti-Jo-1), and malignancy (anti-TIF1-γ) were confirmed in our IIM study population. The availability of multiplex antibody analyses will facilitate inclusion of additional autoantibodies in clinical myositis guidelines and help to accelerate diagnosing IMM with rare but specific antibodies