Sex differences in cardiovascular morbidity associated with familial hypercholesterolaemia: A retrospective cohort study of the UK Simon Broome register linked to national hospital records

Background and aims: The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES).Methods: Of 3553 FH individuals in the SB register (aged 20-79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions).Results: At registration, men had significantly (p50 years, SMbR was 33% higher in women than men (6.11 [5.57-6.70] vs 4.59 [4.08-5.15]).Conclusions: Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30-50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH

Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial

Background: Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism. Objective: We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677C→T genotype. Design: A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid–fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 μg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 μg/d). Results: Plasma folate was higher (P ≤ 0.001) and plasma tHcy lower (P ≤ 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 μmol/L, P ≤ 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P ≤ 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097). Conclusions: A folate-rich diet including folic acid–fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention

Structural and biological control of the Cenozoic epithermal uranium concentrations from the Sierra Pena Blanca, Mexico

Epithermal uranium deposits of the Sierra Peña Blanca are classic examples of volcanic-hosted deposits and have been used as natural analogs for radionuclide migration in volcanic settings. We present a new genetic model that incorporates both geochemical and tectonic features of these deposits, including one of the few documented cases of a geochemical signature of biogenic reducing conditions favoring uranium mineralization in an epithermal deposit. Four tectono-magmatic faulting events affected the volcanic pile. Uranium occurrences are associated with breccia zones at the intersection of fault systems. Periodic reactivation of these structures associated with Basin and Range and Rio Grande tectonic events resulted in the mobilization of U and other elements by meteoric fluids heated by geothermal activity. Focused along breccia zones, these fluids precipitated under reducing conditions several generations of pyrite and uraninite together with kaolinite. Oxygen isotopic data indicate a low formation temperature of uraninite, 45-55°C for the uraninite from the ore body and ~20°C for late uraninite hosted by the underlying conglomerate. There is geochemical evidence for biological activity being at the origin of these reducing conditions, as shown by low δ 34S values (~-24. 5‰) in pyrites and the presence of low δ 13C (~-24‰) values in microbial patches intimately associated with uraninite. These data show that tectonic activity coupled with microbial activity can play a major role in the formation of epithermal uranium deposits in unusual near-surface environments