36 research outputs found

    Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

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    CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

    An updated view of hypothalamic-vascular-pituitary unit function and plasticity

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    The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment

    The risks of overlooking the diagnosis of secreting pituitary adenomas

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    Specific Design Features of Solid Propellant Rocket Motors for Shoulder-Launched Weapon Systems

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    Solid propellant rocket motors for Shoulder Launched Infantry Weapon Systems (SLWS) are characterized with a very short burning time, high-pressure combustion and a wide spectrum of design solutions for rocket motor structure. Interior ballistic behaviour of such rocket motors depends on many factors such as design structure, propellant grain shape, propellant grain joint to the rocket motor case, type and location of the igniter, spinning mode and nozzle design. Erosive burning also plays important role due to high combustion gases mass flow rate. Numerical simulation of the igniter combustion gases flow through the hollow of the propellant grain tubes with gas temperature distribution was carried out in this paper. Results confirmed assumptions that igniter interior gas flow affected duration of the pressure rise. A mathematical model approach for prediction of the curve p = f(t) which was included in a model of the corrected propellant grain burning surface for two types of short-time rocket motors has been presented. A good agreement with measured curves was achieved

    Datadriven testfallsdesign av automatiska testfall med Markovkedjor och en Markov chain Monte Carlo-metod

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    Large and complex software that is frequently changed leads to testing challenges. It is well established that the later a fault is detected in software development, the more it costs to fix. This thesis aims to research and develop a method of generating relevant and non-redundant test cases for a regression test suite, to catch bugs as early in the development process as possible. The research was executed at Axis Communications AB with their products and systems in mind. The approach utilizes user data to dynamically generate a Markov chain model and with a Markov chain Monte Carlo method, strengthen that model. The model generates test case proposals, detects test gaps, and identifies redundant test cases based on the user data and data from a test suite. The sampling in the Markov chain Monte Carlo method can be modified to bias the model for test coverage or relevancy. The model is generated generically and can therefore be implemented in other API-driven systems. The model was designed with scalability in mind and further implementations can be made to increase the complexity and further specialize the model for individual needs
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