The Musculoskeletal System in Pompe Disease: Pathology, consequences and treatment options

__Abstract__ Pompe disease, also known as glycogen storage disorder type II and acid maltase deficiency, is a rare metabolic myopathy. It is caused by a deficiency of lysosomal acid α-glucosidase which results in the accumulation of glycogen in cells, especially muscle cells. The disease presents as a broad clinical spectrum with progressive muscle weakness as prominent symptom and can hence be categorized as a lysosomal storage disorder, a glycogen storage disorder and also as a neuromuscular disorder. The broad term “neuromuscular disorders” encompasses many different syndromes and diseases that either directly or indirectly impair the function of the skeletal muscles, the muscles that enables to move the limbs and trunk. Myopathies, diseases of the muscle itself, are a subgroup of neuromuscular disorders and include muscular dystrophies, inflammatory disorders of the muscle and metabolic diseases of the muscle. Pompe disease was the first myopathy for which treatment became available. Enzyme replacement therapy (ERT) is the registered treatment for Pompe disease. It was shown to elicit positive effects first in babies with the most severe form of the disease1-5 and later also in children and adults with more slowly progressive forms of the disease.6-16 Despite improvements in skeletal muscle strength, walking distance, respiratory function and survival, not all patients respond equally well to treatment and not all muscle damage and functional impairment is resolved.14,17,18 Long-term clinical programs should therefore also focus on comorbidities and additional strategies to improve patients’ functioning. This thesis explores the muscle pathology in Pompe disease across the clinical spectrum, the interplay between skeletal muscle dysfunction and bone structure and the effect of enzyme therapy on it, as well as the use of exercise training to improve patients’ functioning. This introductory chapter gives an overview of the history, pathophysiology, clinical characteristics, diagnosis and treatment of Pompe disease and reviews the use of exercise training programs in myopathies

Co-receptor CD8-mediated modulation of T-cell receptor functional sensitivity and epitope recognition degeneracy

The interaction between T-cell receptors (TCRs) and peptide epitopes is highly degenerate: a TCR is capable of interacting productively with a wide range of different peptide ligands, involving not only cross-reactivity proper (similar epitopes elicit strong responses), but also polyspecificity (ligands with distinct physicochemical properties are capable of interacting with the TCR). Degeneracy does not gainsay the fact that TCR recognition is fundamentally specific: for the vast majority of ligands, the functional sensitivity of a given TCR is virtually null whereas this TCR has an appreciable functional sensitivity only for a minute fraction of all possible ligands. Degeneracy can be described mathematically as the probability that the functional sensitivity, of a given TCR to a randomly selected ligand, exceeds a set value. Variation of this value generates a statistical distribution that characterizes TCR degeneracy. This distribution can be modeled on the basis of a Gaussian distribution for the TCR/ligand dissociation energy. The kinetics of the TCR and the MHCI molecule can be used to transform this underlying Gaussian distribution into the observed distribution of functional sensitivity values. In the present paper, the model is extended by accounting explicitly for the kinetics of the interaction between the co-receptor and the MHCI molecule. We show that T-cells can modulate the level of degeneracy by varying the density of co-receptors on the cell surface. This could allow for an analog of avidity maturation during incipient T-cell responses

Identification of genes which modify cancer risk in a sex-specific manner

Cancer, one of the leading causes of death world wide, frequently exhibits a marked sex preference with respect of incidence, course of disease and survival time. The development of malignant tumors is determined by exogenic factors as well as risk modifying gene variants. The specific causes of cancers and of their sex preference are mostly unknown. The identification of tumor risk modifying gene variants is an essential prerequisite for the development of efficient prevention measures and curative therapies on the long run. Importantly, in contrast to tumor suppressor genes cancer risk modifying gene variants are not necessarily expressed in the tissue the tumor arises from, but also can act systemically. Inbred rodent models are particularly suitable for the analysis of the genetic basis of tumor susceptibility and resistance, respectively, since these animals are genetically identical and can be maintained under standardized living conditions. After application of ethylnitrosourea (ENU) on postnatal day 1, BDIX rats develop malignant tumors of the peripheral nervous system with an incidence of > 85 %, arising from Neu/Erbb2 mutated premalignant Schwann cells in the trigeminal nerves. In MPNST resistant BDIV rats, the premalignant cells are eliminated under the participation of the immune system, thereby preventing tumor development. Genome wide association analyses using ENU-treated segregating crosses of BDIX and BDIV rats identified seven autosomal loci controlling tumor risk in an allele- and sex-specific manner. Homozygous BDIV alleles at the locus Mss4 on chromosome 6 mediated tumor resistance in female (BDIV x BDIX) F2 rats. The effect of the locus was confirmed by ENU application to congenic BDIX.BDIV-Mss4a rats. This strain carries BDIV alleles exclusively in the telomeric 60 % of the tumor resistance haplotype, which was previously identified in the F2 generation. This dissertation included fine mapping of the Mss4 locus originally spanning 20 Mb to approximately 1.1 Mb by exposing three additional congenic and subcongenic rat strains, carrying BDIV alleles in different segments of the tumor resistance haplotype, to ENU and subsequently analyzing their tumor incidences and survival times. The fine mapped Mss4 interval comprised 15 positional candidate genes. Comparative sequencing of protein coding and regulatory portions of the candidate genes in BDIX and BDIV rats, transcriptional analyses in the trigeminal nerves and functional information were used to prioritize candidate genes with respect to their potential relevance for the sex-specific tumor risk. Gpx2, encoding glutathione peroxidase 2, has been associated with resistance towards tumor initiation repeatedly, and therefore represented a particularly interesting candidate gene. However the trigeminal nerves of the parental as well as of the (sub)congenic rat strains did not unequivocally express Gpx2 protein. However, an invasion of Gpx2 expressing mast cells in the trigeminal nerves of ENU-exposed BDIX and BDIV rats could be noticed. Notably peritoneal BDIV mast cells expressed Gpx2 to a higher extent than BDIX mast cells. The Esr2 gene encodes the estrogen receptor beta. While in congenic strains each BDIV insert mediated tumor resistance to a similar degree, only the Mss4a fragment mediated a sex-specific effect. In contrast to the Mss4c and Mss4d fragments, it covers the telomeric third of the tumor resistance haplotype which might contain the BDIV variant of a cofactor of Esr2. The Med6 gene constitutes an interesting functional and positional candidate, the BDIV allele of which might interact with Esr2 to mediate the sex preference of MPNST development by inducing a sex biased regulation of gene expression in trigeminal nerves

Stress imaging in patients with a Fontan circulation:A systematic review

Introduction: The aims of this study were to provide an overview of the cardiac stress response in Fontan patients and of the use, safety and clinical value of stress imaging in Fontan patients. Methods: Studies evaluating cardiac function using stress imaging in Fontan patients published up until 12 December 2021 were included in this review. Results: From 1603 potential studies, 32 studies met the inclusion criteria. In total, stress imaging tests of 728 Fontan patients were included. Cardiac function was most often measured using physical stress (61%), all other studies used dobutamine-induced stress. Stroke volume (SV) increased in most studies (71%), mean SV at rest ranged from 27 mL/m2 to 60 mL/m2 versus 27 mL/m2 to 101 mL/m2 during stress, and increased with an average of 4%. Ejection fraction increased in almost all studies, whereas both end-systolic volume and end-diastolic volume decreased during stress. Higher heart rates were obtained with physical stress (82–180) compared to dobutamine induced stress (73–128). Compared to controls, increases in heartrate and SV were lower and end-diastolic volume decreased abnormally in 75% of reporting studies. No major adverse events were reported. Poorer cardiac stress response was related to decreased exercise capacity and higher risk for long-term (adverse) outcomes in Fontan patients. Discussion: Cardiac stress response in Fontan patients differs from healthy subjects, reflected by lower increases in heart rate, diminished preload and decreased cardiac output, especially during higher levels of exercise. Stress imaging is safe, however the added clinical value needs to be investigated in more detail.</p

Environmental psychology:History, scope and methods

This book aims to give an introduction in environmental psychology. We defi ne environmental psychology as the discipline that studies the interplay between individuals and their built and natural environment. This means that environmental psychology examines the infl uence of the environment on human experiences, behaviour and well - being, as well as the infl uence of individuals on the environment, that is, factors infl uencing environmental behaviour, and ways to encourage pro - environmental behaviour. This book will give an overview of theories and research on each of these topics. In this introductory chapter we fi rst give a brief overview of the history of the fi eld of environmental psychology, followed by a discussion of characteristics of the fi eld and a description of the main methods used in research. The chapter ends with an outline and rationale of the book

Environmental psychology:History, scope and methods

This book aims to give an introduction in environmental psychology. We defi ne environmental psychology as the discipline that studies the interplay between individuals and their built and natural environment. This means that environmental psychology examines the infl uence of the environment on human experiences, behaviour and well - being, as well as the infl uence of individuals on the environment, that is, factors infl uencing environmental behaviour, and ways to encourage pro - environmental behaviour. This book will give an overview of theories and research on each of these topics. In this introductory chapter we fi rst give a brief overview of the history of the fi eld of environmental psychology, followed by a discussion of characteristics of the fi eld and a description of the main methods used in research. The chapter ends with an outline and rationale of the book

Health-related quality of life and mental health problems after a disaster: Are chronically ill survivors more vulnerable to health problems?

Studies have shown that the chronically ill are at higher risk for reduced health-related quality of life (HRQL) and for mental health problems. A combination with traumatic events might increase this risk. This longitudinal study among 1216 survivors of a disaster examines whether chronically ill survivors had a different course of HRQL and mental health problems compared to survivors without chronic diseases. HRQL and mental health problems were measured 3 weeks, 18 months and 4 years post-disaster. Data on pre-disaster chronic diseases was obtained from the electronic medical records of general practitioners. Random coefficient analyses showed significant interaction effects for social functioning, bodily pain and emotional role limitations at T2 only. Chronically ill survivors did not consistently have a different course of general health, physical role limitations, and mental health problems. In conclusion, chronic diseases were not an important risk factor for impaired HRQL and mental health problems among survivors

The comparison of the interpersonal action component of woman-centred care reported by healthy pregnant women in different sized practices in the Netherlands: A cross-sectional study

Background: The number of interventions is lower, and the level of satisfaction is higher among women who receive midwife-led primary care from one or two midwives, compared to more midwives. This suggests that midwives in small-sized practices practice more women-centred. This has yet to be explored.Objective: To examine pregnant women’s perceptions, of the interpersonal action component of woman-centred care by primary care midwives, working in different sized practices.Methods: A cross-sectional study using the Client Centred Care Questionnaire (CCCQ), administered during the third trimester of pregnancy among Dutch women receiving midwife-led primary care from midwives organised in small-sized practices (1-2 midwives), medium-sized (3-4 midwives) and large-sized practices (≥5 midwives). A Welch ANOVA with post hoc Bonferroni correction was performed to examine the differences.Results: 553 completed questionnaires were received from 91 small-sized practices/104 women, 98 medium-sized practices/258 women and 65 large-sized practices/191 women. The overall sum scores varied between 57–72 on a minimum/maximum scoring range of 15-75. Women reported significantly higher woman-centred care scores of midwives in small-sized practices (score 70.7) compared with midwives in medium-sized practices (score 63.6) (p<.001) and large-sized practices (score 57.9) (p<.001), showing a large effect (d .88; d 1.56). Women reported statistically significant higher woman-centred care scores of midwives in medium-sized practices compared with large-sized practices (p<.001), showing a medium effect (d .69).Conclusion: There is a significant variance in woman-centred care based on women’s perceptions of woman-midwife interactions in primary care midwifery, with highest scores reported by womenreceiving care from a maximum of two midwives. Although the CCCQ scores of all practices are relatively high, the significant differences in favour of small-sized practices may contribute to moving woman centred care practice from ‘good’ to ‘excellent’ practice