The apple allergy in Northern Europe is a cross-reaction to the birch pollen allergy. No correlation between the allergenicity of an apple variety and the content of the major apple allergen Mal d 1, ...a homologue to the Bet v 1 allergen in birch, could be found using ELISA, so far. Therefore, an impact of polyphenols and/or differences in the isoallergen profile are discussed. To allow a more detailed analysis of the Mal d 1 content and the isoallergen profile, a mass spectrometric method was applied to investigate differences in the flesh and peel of 10 traditional varieties and 10 commercial breeds. The data revealed often, but not always, lower Mal d 1 contents in traditional varieties grown in orchard meadows, which was more obvious in the flesh. Differences among the peels were less pronounced. A closer look at the individual isoallergens 1.01, 1.02, 1.03, and 1.06 reveals an increased impact of the minor isoallergens 1.03 and 1.06 on the allergenic potential, since commercial breeds like Braeburn, Santana, and Holstein Cox, which are considered to have reduced allergenic potentials, were characterized by low levels of these isoallergens.
Patients who suffer from birch pollinosis often develop adverse reactions to the consumption of fresh apples due to the structural similarity of the allergens Bet v 1 and Mal d 1 from birch and ...apples, respectively. A different allergenic potential for Mal d 1 isoallergens is postulated, but approaches to quantify the Mal d 1 isoallergen-specific are missing. Therefore, a bottom-up proteomics approach was developed to quantify Mal d 1 by stable isotope dilution and microHPLC-QTOF analyses. Marker peptides for individual isoallergens (Mal d 1.01–Mal d 1.03 and Mal d 1.06), combinations thereof (Mal d 1.01 + 1.02, Mal d 1.02 + 1.06, and Mal d 1.04 + 1.05), and two global marker peptides, comprising Mal d 1.01 + 1.02 + 1.04 + 1.05 and Mal d 1.03 + 1.06 + 1.07 + 1.08 + 1.09, were identified. By the use of an extraction standard (r-Mal d 1_mut), an optimized protocol for extraction and tryptic digestion of apple proteins was developed, and the variety-specific extraction efficiency was monitored for the flesh and peel of apples. The Mal d 1 contents in flesh and peel of five commercial apple breeds and four apple varieties from orchard meadows were quantified isoallergen-specific.
•Miscarriage and interventional delivery more common in neuromuscular disease.•Non-ambulant report more miscarriage and intervention than ambulant patients.•Gestational hypertension common in LGMD2A ...and myotonic dystrophy.•Falls during pregnancy common and risk should be addressed.•Specialist peri‑natal input should be considered for all.
Pregnancy and birth in women with neuromuscular conditions has been associated with more rapid disease progression and obstetric complications. This study assessed the impact of functional status and specific diagnosis on patient reported pregnancy and birth outcomes in 26 genetic neuromuscular diseases. Pregnancy and birth outcomes were collected through electronic patient questionnaires and analysed by mobility group and diagnosis. Free text responses were grouped into themes. 721 pregnancies were reported by 305 women. Miscarriage (21% of pregnancies), caesarean delivery (38% of births) and instrumental vaginal delivery (19% of births) were all more frequent in respondents than in the general population (p<0.05), and were more common in those who were non-ambulant at conception than other mobility levels (p <0.05). Falls occurred during 42% of pregnancies and a deterioration in muscle strength during 43%. There was not an increased incidence of maternal complications, apart from maternal hypertension which was more common in limb girdle muscular dystrophy 2A/R1 (35%) and myotonic dystrophy (24%). Patients offered specific practical advice to prospective mothers. Women with neuromuscular conditions have a more complex antenatal and perinatal course than unaffected women. Prenatal counselling, specialist obstetric review and additional occupational therapy support should be considered.
Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a group of heterogeneous muscle diseases that share several common denominators. Beside the same mode of inheritance, patients develop ...progressive weakness and wasting of their shoulder and pelvic girdle muscles whilst muscle biopsies generally show dystrophic histological features. Coming to a specific diagnosis in a patient with LGMD2 can be quite challenging. Diagnostic clues for the clinician can be the age of onset, the ethnic background, the involvement of respiratory muscles, the heart or other organ systems, the selective pattern of muscle pathology and immunoanalysis of the muscle biopsy. Next generation sequencing strategies, especially gene panel and exome sequencing approaches, are gradually replacing the often cumbersome gene by gene mutation analysis and should help to provide all patients with LGMD2 with a precise diagnosis over the next few years. The identification of the underlying genetic defect in almost 20 different forms of LGMD2 so far has helped to generate animal models and to study disease pathogenesis. Nevertheless there is currently no licensed drug for LGMD2 and treatment strategies focus on the improvement of symptoms. One of the biggest challenges is the low number of identified LGMD2 patients. Whereas in some forms of LGMD2 several hundred patients have been diagnosed, in other forms only very few families have been characterized. Over the coming years it will be important to develop a successful translational research pathway in LGMD2 by creating patient registries, developing standards of care and establishing validated outcome measures and disease biomarkers. These objectives can only be achieved through a close partnership between scientists, healthcare professionals, patient organizations, the pharmaceutical industry and regulators. The presentation will focus on the current stage of translational research approaches in LGMD2 and on future perspectives.
α‐methylacyl‐CoA racemase (AMACR) deficiency is a rare disorder, affecting peroxisomal metabolism of pristanic acid, with ten published adult cases. We describe an AMACR deficiency case with a ...clinical presentation dominated by episodic hyperCKaemia, suggesting that myopathic features of AMACR should be considered.
α‐methylacyl‐CoA racemase (AMACR) deficiency is a rare disorder, affecting peroxisomal metabolism of pristanic acid, with ten published adult cases. We describe an AMACR deficiency case with a clinical presentation dominated by episodic hyperCKaemia, suggesting that myopathic features of AMACR should be considered.
Abstract Introduction Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the ...introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. Method A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). Results Detailed information was available on 21 patients. Group one comprises 17 patients; mean age at death was 23.9 (14.4-39.5) years. Group two, comprises 4 patients; mean age at death was 14 (12.7-14.9) years. They died of acute pneumonia, cardio-respiratory arrest following trauma and exercise and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. Conclusions The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death.
Myogenic vasoconstriction results from pressure-induced vascular smooth muscle cell depolarization and Ca(2+) influx via voltage-dependent Ca(2+) channels, a process that is significantly attenuated ...by inhibition of protein kinase C (PKC). It was recently reported that the melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced smooth muscle depolarization and constriction in cerebral arteries. Interestingly, PKC activity enhances the activation of cloned TRPM4 channels expressed in cultured cells by increasing sensitivity of the channel to intracellular Ca(2+). Thus we postulated that PKC-dependent activation of TRPM4 might be a critical mediator of vascular myogenic tone. We report here that PKC inhibition attenuated pressure-induced constriction of cerebral vessels and that stimulation of PKC activity with phorbol 12-myristate 13-acetate (PMA) enhanced the development of myogenic tone. In freshly isolated cerebral artery myocytes, we identified a Ca(2+)-dependent, rapidly inactivating, outwardly rectifying, iberiotoxin-insensitive cation current with properties similar to those of expressed TRPM4 channels. Stimulation of PKC activity with PMA increased the intracellular Ca(2+) sensitivity of this current in vascular smooth muscle cells. To validate TRPM4 as a target of PKC regulation, antisense technology was used to suppress TRPM4 expression in isolated cerebral arteries. Under these conditions, the magnitude of TRPM4-like currents was diminished in cells from arteries treated with antisense oligonucleotides compared with controls, identifying TRPM4 as the molecular entity responsible for the PKC-activated current. Furthermore, the extent of PKC-induced smooth muscle cell depolarization and vasoconstriction was significantly decreased in arteries treated with TRPM4 antisense oligonucleotides compared with controls. We conclude that PKC-dependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone.
There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as ...an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation.
We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe).
In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years.
This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials.
•Testosterone therapy for pubertal induction was associated with improvements in QoL.•Physical changes during puberty played an important role.•Low self-esteem was also a prevailing ...theme.•Parent-reported QoL scores were lower than patient-reports, consistent with other literature.•Data from this study will provide a useful foundation for future work.
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood. It is associated with progressive muscle function decline and premature death. Long-term oral glucocorticoid use slows muscle weakness but is associated with several side effects including delayed puberty. This study assessed the impact of a 2-year incremental intramuscular testosterone regimen on quality of life (QoL) in a cohort of 15 adolescents with DMD. The Pediatric Quality of Life Inventory (PedsQL) Neuromuscular module was used to assess QoL and was completed by parent-child dyads. Semi-structured interviews were carried out to understand patient views on testosterone therapy. QoL scores increased in 10 of the 15 participants during treatment, with a mean total PedsQL score of 74.6 pre-treatment v 80.2 post treatment (p = 0.04). This was supported by comments in the semi-structured interviews. Parent-reported PedsQL scores were lower than their child's post treatment (p = 0.007). Testosterone therapy for pubertal induction was associated with an improvement in QoL and the observed physical changes during puberty played an important role. Low self-esteem was also a prevailing theme. This data supports the inclusion of testosterone therapy for pubertal induction as a Standard of Care.
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