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  • A Hulten, Maj, et al. (författare)
  • On the origin of the maternal age effect in trisomy 21 Down syndrome: the Oocyte Mosaicism Selection model
  • 2010
  • Ingår i: Reproduction. - 1470-1626 .- 1476-3990. ; 139:1, s. 1-9
  • Forskningsöversikt (refereegranskat)abstract
    • We have recently documented that trisomy 21 mosaicism is common in human foetal ovaries. On the basis of this observation we propose that the maternal age effect in Down syndrome (DS) is caused by the differential behaviour of trisomy 21 in relation to disomy 21 oocytes during development from foetal life until ovulation in adulthood. in particular, we suggest that trisomy 21 oocytes, lagging behind those that are disomic, may escape the timed pruning of the seven million in foetal life to the 300-400 finally selected for ovulation. The net effect of this preferential elimination will be an accumulation of trisomy 21 oocytes in the ovarian reserve of older women. We here highlight the implications of this Oocyte Mosaicism Selection (OMS) model with respect to the prevalent view that the maternal age effect is complex, dependent on many different biological and environmental factors. We examine conclusions drawn from recent large-scale studies in families, tracing DNA markers along the length of chromosome 21q between parents and DS children, in comparison to the OMS model. We conclude that these family linkage data are equally compatible with the maternal age effect originating from the accumulation of trisomy 21 oocytes with advancing maternal age. One relatively straightforward way to get to grips with what is actually going on in this regard would be to compare incidence of trisomy 21 oocytes (and their pairing configurations) in foetal ovaries with that in oocytes at the meiosis I stage from adult women.
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  • Aagaard, Philip (författare)
  • Cardiovascular assessment in middle-aged male long distance runners
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Endurance events such as long distance running races are increasing in popularity and convey multiple health benefits. However, such exercise forms also represent a major challenge to human cardiovascular physiology and are associated with a momentarily increased risk for adverse cardiac events. Using the world’s largest cross-country running race Lidingöloppet as a model of endurance events, this thesis aims to: 1) investigate male and female participation and performance trends 2) detail the cardiovascular findings of a comprehensive cardiovascular preparticipation evaluation in novice male race participants aged 45 years and older 3) study the impact of race participation on cardiac autonomic tone and 4) assess features of cardiovascular function and vectorcardiography (VCG), and their response to endurance exercise in individuals with early repolarisation (ER). Study I Participation and performance trends were investigated in >120,000 runners partaking in the Lidingöloppet between 1993 and 2007. In a subgroup of 249 middle-aged males, the association between the cardiac biomarker NT-proBNP and runtime was also studied. Participation increased over the study period, particularly in females and older males, while participants’ fitness deteriorated, as measured by an average increase in runtime of 21 ± 31 min. Longer runtimes were independently associated with higher levels of NT-proBNP. Study II A preparticipation cardiovascular exam was performed in 153 middle-aged male first-time Lidingöloppet race participants. Runners were assessed by medical history and physical exam, 12-lead ECG, echocardiography, and blood tests. 9 % of runners required further diagnostic work-up and 2 % were discouraged from race participation due to cardiac abnormalities that could increase their risk of exercise- related cardiac events. Study III Heart rate (HR) and heart rate variability (HRV) was continuously measured from 48 hours before until 96 hours after a Lidingöloppet 30km race. Compared to pre-race values, HR was elevated during the night after the race while HRV remained depressed for 64 [51 - 96] hours after the race. A reduced HR recovery and a greater fall in HRV post race were associated with higher levels of high-sensitivity troponin T (hsTnT). Study IV The prevalence and associated cardiac features of ER, characterized by ST-segment elevation (STE) and/or J-waves, was investigated in 153 middle-aged males registered for first-time participation in the Lidingöloppet 10, 15 or 30km race. ER was present in 40 % and generally associated with features of better cardiovascular fitness. The cardiovascular effects of participating in the 30km race (n= 94) were also assessed after the race; runners with J-waves, but not with STE alone, showed changes of repolarisation parameters usually considered unfavourable (e.g. prolonged T peak-to-end (Tpe) and QTc). Conclusion This thesis demonstrated that increased participation in a long distance running event (Lidingöloppet) was paralleled by deteriorating runtimes. In middle-aged men, longer runtimes were associated with higher levels of NT-proBNP. These findings may raise concern regarding the fitness and cardiovascular health of some of today’s race participants. A comprehensive preparticipation evaluation identified 9 % of first- time runners needing additional work-up and 2% who were ultimately discouraged from participating, suggesting that such a protocol is useful to identify individuals requiring further testing prior to vigorous exercise. After the race there was a prolonged depression of HRV. The magnitude and duration of HRV depression correlated with higher levels of hsTnT, suggesting that the degree of troponin (Tn) increase after strenuous exercise may reflect the level of exercise-induced cardiovascular stress. ER was generally associated with a benign cardiovascular profile, although subjects with J-waves showed post-race changes in some parameters of ventricular repolarisation that are usually associated with increased arrhythmia propensity. More research into the mechanisms and potential preventive measures of adverse exercise related effects on cardiac function is warranted.
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