Central and cerebrovascular effects of leg crossing in humans with sympathetic failure

General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. A B S T R A C T Leg crossing increases arterial pressure and combats symptomatic orthostatic hypotension in patients with sympathetic failure. This study compared the central and cerebrovascular effects of leg crossing in patients with sympathetic failure and healthy controls. We addressed the relationship between MCA V mean (middle cerebral artery blood velocity; using transcranial Doppler ultrasound), frontal lobe oxygenation [O 2 Hb (oxyhaemoglobin)] and MAP (mean arterial pressure), CO (cardiac output) and TPR (total peripheral resistance) in six patients (aged 37-67 years; three women) and age-and gender-matched controls during leg crossing. In the patients, leg crossing increased MAP from 58 (42-79) In the control subjects, CO increased 11 % (P < 0.05) with no change in TPR. By contrast, in the patients, CO increased 9 % (P < 0.05), but also TPR increased by 13 % (P < 0.05). In conclusion, leg crossing improves cerebral perfusion and oxygenation both in patients with sympathetic failure and in healthy subjects. However, in healthy subjects, cerebral perfusion and oxygenation were improved by a rise in CO without significant changes in TPR or MAP, whereas in patients with sympathetic failure, cerebral perfusion and oxygenation were improved through a rise in MAP due to increments in both CO and TPR

Homeomorphic Embedding for Online Termination of Symbolic Methods

Well-quasi orders in general, and homeomorphic embedding in particular, have gained popularity to ensure the termination of techniques for program analysis, specialisation, transformation, and verification. In this paper we survey and discuss this use of homeomorphic embedding and clarify the advantages of such an approach over one using well-founded orders. We also discuss various extensions of the homeomorphic embedding relation. We conclude with a study of homeomorphic embedding in the context of metaprogramming, presenting some new (positive and negative) results and open problems

Central and cerebrovascular effects of leg crossing in humans with sympathetic failure

A B S T R A C T Leg crossing increases arterial pressure and combats symptomatic orthostatic hypotension in patients with sympathetic failure. This study compared the central and cerebrovascular effects of leg crossing in patients with sympathetic failure and healthy controls. We addressed the relationship between MCA V mean (middle cerebral artery blood velocity; using transcranial Doppler ultrasound), frontal lobe oxygenation [O 2 Hb (oxyhaemoglobin)] and MAP (mean arterial pressure), CO (cardiac output) and TPR (total peripheral resistance) in six patients (aged 37-67 years; three women) and age-and gender-matched controls during leg crossing. In the patients, leg crossing increased MAP from 58 (42-79) to 72 (52-89) compared with 84 (70-95) to 90 (74-94) mmHg in the controls. MCA V mean increased from 55 (38-77) to 63 (45-80) and from 56 (46-77) to 64 (46-80) cm/s respectively (P < 0.05), with a larger rise in O 2 Hb [1.12 (0.52-3.27)] in the patients compared with the controls [0.83 (− 0.11 to 2.04) μmol/l]. In the control subjects, CO increased 11 % (P < 0.05) with no change in TPR. By contrast, in the patients, CO increased 9 % (P < 0.05), but also TPR increased by 13 % (P < 0.05). In conclusion, leg crossing improves cerebral perfusion and oxygenation both in patients with sympathetic failure and in healthy subjects. However, in healthy subjects, cerebral perfusion and oxygenation were improved by a rise in CO without significant changes in TPR or MAP, whereas in patients with sympathetic failure, cerebral perfusion and oxygenation were improved through a rise in MAP due to increments in both CO and TPR

Translating HbA1c measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA1c measurements are applicable to pregnant women with diabetes. Methods CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA1c measure. In total, 688 average glucose–HbA1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA1c. Results There was a strong association between HbA1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. Conclusions/interpretation The HbA1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention