Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

OBJECTIVE To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions

Linkages Over Time Between Adolescents' Relationships with Parents and Friends

This 5-wave longitudinal study examines linkages over time between adolescents’ perceptions of relationships with parents and friends with respect to support, negative interaction, and power. A total of 575 early adolescents (54.1% boys) and 337 middle adolescents (43.3% boys) participated. Path analyses mainly showed bidirectional associations between adolescents’ perceptions of parent–adolescent relationships and friendships with a predominantly stronger influence from parent–adolescent relationships to friendships than vice versa in early to middle adolescence and an equal mutual influence in middle to late adolescence. The findings support the theoretical ideas that perceptions of relationships with parents generalize to perceptions of relationships with friends and that relationship skills and principles of adolescent friendships generalize to relationships with parents. Furthermore, the results indicate that the influence of parents decreases, whereas the influence of friends increases, and that both social worlds become equally important and overlapping towards late adolescence

Beyond the merchant and the clergyman: assessing moral claims about development cooperation

This article proposes to move beyond the categories of altruism and self-interest in the analyses of the motives for development cooperation. This opposition ignores the inherently moral nature of development policy. The article illustrates the shortcomings of such a perspective by tracing the metaphor of the merchant and the clergyman as archetypical figures shaping Dutch development policy. Through these images the suggestion of an opposition between moral and amoral motives in the history of development has gained a strong foothold within the interplay of scholars, policy makers and public opinion. We go on to assess claims about economy, security, solidarity, prestige and guilt, and ecology, which have been brought forward to legitimise Dutch foreign aid. This analysis calls for research on the dynamics of the transnational exchanges of ideas, interests and expectations, especially during episodes when the moral validity of policy has been explicitly contested

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Transforming Power Relations: Mid-term Synthesis Report for the Right to be Heard Outcome Area of the Oxfam Strategic Plan 2013-2019

This report consists of a systematic review of 26 evaluation reports from programs in 24 countries (in Asia and the Pacific, Africa and Latin America as well as domestic programs in the US and Australia), where five Oxfam affiliates engaged in the field of "Transforming power relations." Changes in three generic outcome areas of power relations were examined.

Spatiotemporal Dynamics of Single and Paired Pulse TMS-EEG Responses

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spatiotemporal dynamics and stability of single and paired pulse TMS-EEG responses, and assess long intracortical inhibition (LICI) at the cortical level. Twenty-five healthy subjects were studied twice, approximately one week apart. Manual coil positioning was applied in sixteen subjects and robot-guided positioning in nine. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at each of the five interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. To assess stability and LICI, the intraclass correlation coefficient and cluster-based permutation analysis were used. We found great resemblance in the topographical distribution of the characteristic TMS-EEG components for single and paired pulse TMS. Stimulation of the dominant and non-dominant hemisphere resulted in a mirrored spatiotemporal dynamics. No significant effect on the TMS-EEG responses was found for either stimulated hemisphere, time or coil positioning method, indicating the stability of both single and paired pulse TMS-EEG responses. For all ISIs, LICI was characterized by significant suppression of the late N100 and P180 components in the central areas, without affecting the early P30, N45 and P60 components. These observations in healthy subjects can serve as reference values for future neuropsychiatric and pharmacological studies