Diagnosis and Clinical Development of Sporadic Inclusion Body Myositis and Polymyositis With Mitochondrial Pathology: A Single-Center Retrospective Analysis

To review our diagnostic and treatment approaches concerning sporadic inclusion body myositis (sIBM) and polymyositis with mitochondrial pathology (PM-Mito), we conducted a retrospective analysis of clinical and histological data of 32 patients diagnosed as sIBM and 7 patients diagnosed as PM-Mito by muscle biopsy. Of 32 patients identified histologically as sIBM, 19 fulfilled the 2011 European Neuromuscular Center (ENMC) diagnostic criteria for “clinico-pathologically defined sIBM” at the time of biopsy. Among these, 2 patients developed sIBM after years of immunosuppressive treatment for organ transplantation. Of 11 patients fulfilling the histological but not the clinical criteria, including 3 cases with duration <12 months, 8 later fulfilled the criteria for clinico-pathologically defined sIBM. Of 7 PM-Mito patients, 4 received immunosuppression with clinical improvement in 3. One of these later developed clinico-pathologically defined sIBM; 1 untreated patient progressed to clinically defined sIBM. Thus, muscle histology remains important for this differential diagnosis to identify sIBM patients not matching the ENMC criteria and the PM-Mito group. In the latter, we report at least 50% positive, if occasionally transient, response to immunosuppressive treatments and progression to sIBM in a minority. The mitochondrial abnormalities defining PM-Mito do not seem to define the threshold to immunosuppression unresponsiveness.

Influence of IGF-I serum concentration on muscular regeneration capacity in patients with sarcopenia

Background Previous research has described a neuroprotective effect of IGF-I, supporting neuronal survival, axon growth and proliferation of muscle cells. Therefore, the association between IGF-I concentration, muscle histology and electrophysiological markers in a cohort of patients with sarcopenia dares investigation. Methods Measurement of serum concentrations of IGF-I and binding partners, electromyographic measurements with the MUNIX (Motor Unit Number Index) method and muscle biopsies were performed in 31 patients with acute hip fracture older age 60 years. Molecular markers for denervation (neural cell adhesion molecule NCAM) and proliferation markers (Ki67) were assessed by immunofluorescence staining of muscle biopsy tissue. Skeletal muscle mass by bioelectrical impedance analysis and hand-grip strength were measured to assess sarcopenia status according to EWGSOP2 criteria. Results Thirty-one patients (20 women) with a mean age of 80.6 ± 7.4 years were included. Concentrations of IGF-I and its binding partners were significantly associated with sarcopenia (ß = − 0.360; p = 0.047) and MUNIX (ß = 0.512; p = 0.005). Further, expression of NCAM (ß = 0.380; p = 0.039) and Ki67 (ß = 0.424; p = 0.022) showed significant associations to IGF-I concentrations. Conclusions The findings suggest a pathogenetic role of IGF-I in sarcopenia based on muscle denervation.

Rectus Abdominis Flap Replantation after 18 h Hypothermic Extracorporeal Perfusion—A Porcine Model

Cold storage remains the clinical standard for composite tissue preservation but is time-limited. A long ischemia time during surgery will adversely affect postoperative outcomes due to ischemia-reperfusion injury. Extracorporeal perfusion (ECP) seems to be a promising alternative for prolonged preservation, but more evidence is needed to support its use and to identify optimal perfusion fluids. This article assessed musculocutaneous flap vitality after prolonged ECP and compared outcomes after replantation to short static cold storage (SCS). Unilateral musculocutaneous rectus abdominis flaps were raised from 15 pigs and preserved by 4 h SCS (n = 5), 18 h mid-thermic ECP with Histidine–Tryptophan–Ketoglutarate (HTK, n = 5) or University of Wisconsin solution (UW, n = 5). Flaps were replanted and observed for 12 h. Skeletal muscle histology was assessed (score 0–12; high scores equal more damage), blood and perfusate samples were collected and weight was recorded as a marker for oedema. Mean histological scores were 4.0 after HTK preservation, 5.6 after UW perfusion and 5.0 after SCS (p = 0.366). Creatinine kinase (CK) was higher after ECP compared to SCS (p < 0.001). No weight increase was observed during UW perfusion, but increased 56% during HTK perfusion. Following 12 h reperfusion, mean weight gain reduced 39% in the HTK group and increased 24% in the UW group and 17% in the SCS group. To conclude, skeletal muscle seemed well preserved after 18 h ECP with HTK or UW perfusion, with comparable histological results to 4 h SCS upon short reperfusion. The high oedema rate during HTK perfusion remains a challenge that needs to be further addressed.

Effects Of Doxycycline On Mice Neuromuscular Junction, In Situ

Background: The antibacterial mechanism of doxycycline is known, but on the nerve-muscle apparatus is yet unclear. Objective: To combine molecular targets of the neuromuscular machinery using the neuronal blocker effect doxycycline, a semisynthetic second-generation tetracycline derivative, on mice neuromuscular preparations, in situ. Methods: Doxycycline was assessed at the neurotransmission; presynaptic; synaptic cleft; and postsynaptic, including the muscle fiber, using the traditional myographic technique. Preliminarily, doxycycline showed an "all or nothing" effect, being "all" obtained with 4 µM and "nothing", with 1-3 µM. The rationale of this study was to apply known pharmacological tools against the blocker effect of 4 µM doxycycline such as F55-6 (Casearia sylvestris), CaCl2 (or Ca2+), atropine, neostigmine, polyethylene glycol (PEG 400), and d-Tubocurarine. The evaluation of cholinesterase enzyme activity, the diaphragm muscle histology, and protocols on the neuromuscular preparation submitted to indirect or direct stimuli were complementary. Results: Doxycycline does not affect cholinesterase activity nor cause damage to skeletal muscle diaphragm; acts on ryanodine receptor, sarcolemmal membrane, and on neuronal sodium channel with a postjunctional consequence due to the decreased availability of muscle nicotinic acetylcholine receptors. Conclusions: In conclusion, using the blocker effect we showed that doxycycline acts on multiple targets, among them, is antagonized by F55-6, a neuronal Na+-channel agonist and Ca2+, but not by neostigmine.

Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum

Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519) is an autosomal recessive disease caused by homozygous or compound heterozygous variants in SPTBN4 coding for type 4 βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Variants in SPTBN4 disrupt the cytoskeletal machinery that controls proper localization of ion channels and the function of axonal domains, thereby generating severe neurological dysfunction. We set out to analyze the genetic causes and describe the clinical spectrum of suspected cases of NEDHND. Variant screening was done by whole exome sequencing; clinical phenotypes were described according to the human phenotype ontology, and histochemical analysis was performed with disease-specific antibodies. We report four families with five patients harboring novel homozygous and compound heterozygous SPTBN4 variants, amongst them a multi-exon deletion of SPTBN4. All patients presented with the key features of NEDHND; severe muscular hypotonia, dysphagia, absent speech, gross motor, and mental retardation. Additional symptoms comprised horizontal nystagmus, epileptiform discharges in EEG without manifest seizures, and choreoathetosis. Muscle histology revealed both characteristics of myopathy and of neuropathy. This report expands the SPTBN4 variant spectrum, highlights the spectrum of morphological phenotypes of NEDHND-patients, and reveals clinical similarities between the NEDHND, non-5q SMA, and congenital myopathies.