Does the beneficial effect of HRT on endothelial function depend on lipid changes

OBJECTIVES: To determine whether improvement in endothelial function of the brachial artery observed in women treated with hormone replacement therapy (HRT) may be explained by changes in lipid profile or blood pressure, information was used obtained in a single-centre, randomised, double blind, placebo-controlled trial. METHODS: Hundred-and-five healthy postmenopausal women, aged 50-65 years, were treated with 0.625 mg conjugated equine estrogens (CEE) combined with 2.5 mg medroxyprogesterone acetate (MPA) (CEE+MPA), 2.5 mg tibolone or placebo for 3 months. At baseline and after 3 months, endothelial function was assessed using flow-mediated dilatation (FMD) and nitro glycerine-mediated dilatation (NMD). Furthermore, lipids were measured. Multivariate linear regression analysis was applied to address the research question. RESULTS: Treatment with CEE+MPA resulted in an improvement in FMD of 2.0% (95% CI: -0.1; 4.1). CEE/MPA reduced total cholesterol with 13% (95% CI: -18%; -7%), LDL-cholesterol with 23% (95% CI: -30%; -15%) and lipoprotein(a) (Lp(a)) with 14% (95% CI: -26%; -2%). The magnitude of the relation of CEE/MPA with endothelial function was attenuated to from 2.0 to 1.6% when change in Lp(a) was taken into account. Adjustments for other lipids or blood pressure did not attenuate the association. CONCLUSIONS: The improvement in endothelial function in postmenopausal women treated with CEE+MPA appears to be partially mediated by change in Lp(a), and apparently not by changes in other lipids.     

The role of hand dominance and sensorimotor congruence in voluntary movement

The present study evaluated the neural changes due to effector use (unimanual left, unimanual right, and bimanual) and visuomotor conflict induced by mirror-reversed vision during drawing behavior. EEG phase synchronization, expressing interregional communication, showed that visuomotor incongruence perturbed information processing in both hemispheres. Furthermore, it was observed that the left hemisphere became temporally dominant when movements were executed with visuomotor conflict, independent of the performing hand(s). This observation emphasizes the superiority of the left hemisphere to control complex movements. In addition, the functional interactions between the hemispheres were also perturbed due to visuomotor discordance, indicating the crucial role of interhemispheric communication for movement control. These results highlight that functional connectivity patterns provide higher-order coding mechanisms of information processing. The data further underline the significance of the left hemisphere for intricate visuomotor skills.     

Severe Maternal Morbidity in Canada: Temporal Trends and Regional Variations, 2003-2016

ObjectiveThis study sought to quantify temporal trends and provincial and territorial variations in severe maternal morbidity (SMM) in Canada.MethodsThe study used data on all hospital deliveries in Canada (excluding Québec) from 2003 to 2016 to examine temporal trends and from 2012 to 2016 to study regional variations. SMM was identified using diagnosis and intervention codes. Contrasts among periods and regions were quantified using rate ratios (RRs) and 95% confidence intervals (CIs). Temporal changes were also assessed using chi-square tests for trend (Canadian Task Force Classification II-1).ResultsThe study population included 3 882 790 deliveries between 2003 and 2016 and 1 418 545 deliveries between 2012 and 2016. Severe hemorrhage rates increased from 44.8 in 2003 to 62.4 per 10 000 deliveries in 2012 (P for trend <0.0001) and then declined to 41.8 per 10 000 deliveries in 2016 (P for trend <0.0001). Maternal intensive care unit admission and sepsis rates decreased between 2003 and 2016, whereas rates of stroke, severe uterine rupture, hysterectomy, obstetric embolism, shock, and assisted ventilation increased. Rates of composite SMM in 2012-2016 were higher in Newfoundland and Labrador (RR 1.15; 95% CI 1.04–1.26), Nova Scotia (RR 1.11; 95% CI 1.03–1.19), New Brunswick (RR1.22; 95% CI 1.13–1.32), Manitoba (RR 1.09; 95% CI 1.03–1.15), Saskatchewan (RR 1.15; 95% CI 1.09–1.22), the Yukon (RR 1.74; 95% CI 1.35–2.25), and Nunavut (RR 1.76; 95% CI 1.46–2.11) compared with the rest of Canada, whereas rates were lower in Alberta and British Columbia.ConclusionThis surveillance report helps inform clinical practice and public health policy for improving maternal health in Canada.     

Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle

Deconditioning is a risk factor for cardiovascular disease. Exercise reduces this risk, possibly by improving the vascular endothelial nitric oxide (NO) pathway. The effect of deconditioning on the NO pathway is largely unknown. This study was designed to assess baseline NO availability in the leg vascular bed after extreme, long-term deconditioning (spinal cord-injured individuals, SCI) as well as after moderate, short-term deconditioning (4 weeks of unilateral lower limb suspension, ULLS). For this purpose, seven SCI were compared with seven matched controls. Additionally, seven healthy subjects were studied pre- and post-ULLS. Leg blood flow was measured by venous occlusion plethysmography at baseline and during infusion of 5 incremental dosages of N ^G-monomethyl- l -arginine ( l -NMMA) into the femoral artery. Sodium nitroprusside (SNP) was infused to test vascular responsiveness to NO. Baseline leg vascular resistance tended to be higher in SCI compared with controls (37 ± 4 versus 31 ± 2 arbitrary units (AU), P = 0.06). Deconditioning altered neither the vasoconstrictor response to l -NMMA (increase in resistance in SCI versus controls: 102 ± 33% versus 69 ± 9%; pre- versus post-ULLS: 95 ± 18% versus 119 ± 15%), nor the vascular responsiveness to NO. In conclusion, two human in vivo models of deconditioning show a preserved baseline NO availability in the leg skeletal muscle vascular bed.     

Tissue-resident mucosal-associated invariant T (MAIT) cells in the human kidney represent a functionally distinct subset

Mucosal-associated invariant T (MAIT) cells are innate-like T-cells that recognize bacterial riboflavin metabolites. They are present in human blood but are abundant at barrier sites, including the liver, lungs, and kidneys, where they possess a CD69⁺/CD103^+/− tissue-resident phenotype. In renal tissue, MAIT cells likely defend against the ascending uropathogens responsible for urinary tract infections (UTIs), which are common, especially among renal transplant recipients (RTRs). Nevertheless, the functional role for MAIT cells in renal tissue and the influence of renal transplantation on MAIT cells remains unclear. Using multiparameter flow cytometry and the MR1-tetramer, we characterized MAIT cell phenotype and function in healthy renal tissue (n = 6), renal transplants explanted after allograft failure (n = 14) and in blood from healthy controls (n = 20) and RTRs before and 1-year after transplantation (n = 21). MAIT cells in renal tissue constitute a distinct CD69⁺CD103^+/− population that displays typical phenotypic features of tissue-resident T-cells and is skewed toward IL-2, GM-CSF, and IL-17A production upon stimulation. The circulating MAIT cell population was not decreased in number in RTRs pre- or post-transplantation. Tissue-resident MAIT cells in the kidney represent a functionally distinct population. This shows how MAIT cells in the kidney may be involved in the protection against microorganisms.     

Functional defects in the fanconi anemia pathway in pancreatic cancer cells

Biallelic BRCA2-mutations can cause Fanconi anemia and are found in approximately 7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconi-defective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G(2)/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.     

The effect of bed rest and an exercise countermeasure on leg venous function

This study was performed to assess the effect of resistive vibration exercise during bed rest deconditioning on venous vascular dimension and function, as measured with ultrasound in the popliteal vein. Sixteen men were assigned to bed rest (BR-Ctrl) or bed rest with resistive vibration exercise (BR-RVE). Before and at 25 and 52 days of bed rest, popliteal vein diameter was measured at increasing cuff pressures. Venous capacitance and compliance were calculated from the pressure–volume curve. After 52 days of bed rest, BR-Ctrl showed no change in baseline popliteal vein diameter or compliance, while venous capacitance decreased. Resistive vibration exercise had no effect on the response in venous diameter, capacitance or compliance to 52 days of bed rest. The decline in venous capacitance due to long-term bed rest is not effectively counteracted by resistive vibration exercise, indicating that an alternative factor during bed rest deconditioning is responsible for venous changes.     

Database Autopsy: An Efficient and Effective Confidential Enquiry into Maternal Deaths in Canada

BackgroundMaternal death surveillance in Canada relies on hospitalization data, which lacks information on the underlying cause of death. We developed a method for identifying underlying causes of maternal death, and quantified the frequency of maternal death by cause.MethodsWe used data from the Discharge Abstract Database for fiscal years 2013 to 2017 to identify women who died in Canadian hospitals (excluding Quebec) while pregnant or within 1 year of the end of pregnancy. A sequential narrative based on hospital admission(s) during and after pregnancy was constituted and reviewed to assign the underlying cause of death (based on the World Health Organization's framework). Maternal deaths (i.e., while pregnant or within 42 days after the end of pregnancy) and late maternal deaths (i.e., more than 42 days to a year after the end of pregnancy) were examined separately.ResultsWe identified 85 maternal deaths. Direct obstetric causes included 8 deaths (9%) related to complications of spontaneous or induced abortion; 9 (11%), to hypertensive disorders of pregnancy; 15 (18%), to obstetric hemorrhage; 11 (13%), to pregnancy-related infection; 16 (19%), to other obstetric complications; and <5 (<6%), to complications of management. There were 21 (25%) maternal deaths with indirect obstetric causes, and <5 (<6%) with undetermined causes. Of 120 late maternal deaths, 16 (13%) had direct obstetric causes, among them, 9 deaths by suicide (56%). One hundred late maternal deaths (83%) had indirect obstetric causes; and <5 (<4%) had undetermined causes.ConclusionsThe majority of maternal deaths in Canada have direct obstetric causes, whereas most late maternal deaths have indirect obstetric causes. Suicide is an important direct cause of late maternal death.