Mortality risk and long-term exposure to ultrafine particles and primary fine particle components in a national U.S. Cohort.

The objective of this study was to estimate all-cause, cardiopulmonary, and cancer mortality associations for long-term exposure to ultrafine particles (UFP) and primary PM2.5 components. We utilized high-resolution, national-scale exposure estimates for UFP (measured as particle number concentration; PNC) and three primary PM2.5 components, namely black carbon (BC), traffic-emitted organic PM2.5 (hereafter, hydrocarbon-like organic aerosols; HOA), and cooking-emitted organic PM2.5 (cooking organic aerosols; COA). Two analytic cohorts were constructed from a nationally representative U.S. health survey. The larger cohort consisted of 617,997 adults with information on a broad set of individual-level risk factors; the smaller cohort was further restricted to those with information on physical activity (n = 396,470). In single-pollutant models, PNC was significantly associated with all-cause (larger cohort HR = 1.03, 95% CI [1.02, 1.04]; smaller cohort HR = 1.02, 95% CI [1.00, 1.04]) and cancer mortality (larger cohort HR = 1.05, 95% CI [1.02, 1.08]; smaller cohort HR = 1.06, 95% CI [1.02, 1.10]). In two-pollutant models, mortality associations varied based on co-pollutant adjustment; PNC mortality associations were generally robust to controlling for PM10-2.5 and SO2, but not PM2.5. In contrast, we found some evidence that the HOA and COA mortality associations are independent of total PM2.5 mass exposure. Nevertheless, PM2.5 mass was the most robust predictor of air pollution related mortality, providing some support for current regulatory policies.

Mortality risk associated with greenness, air pollution, and physical activity in a representative U.S. cohort.

Several cohort studies suggest greenness is associated with decreased mortality risk. Potential confounding by or interactions between physical activity and air pollution remains unclear. This study evaluates associations of greenness, air pollution, and physical activity with mortality risk and investigates confounding and effect modification across these key risk factors. National Health Interview Survey (NHIS) data covering 1997-2014 were linked to the National Death Index to generate a cohort of 403,748 individuals with 39,528 deaths. Greenness, represented by census-tract Normalized Difference Vegetation Index (NDVI) for the seasonal period of May-October, was averaged over the years 2003-2016. Air pollution was estimated by census-tract level PM2.5 concentrations from 1999 to 2015. Cox Proportional Hazard Models were used to estimate hazard ratios (HR) for differences in greenness, air pollution, and physical activity. Alternative models that evaluated potential confounding and stratified models that evaluated effect modification were examined. Mortality risks were associated with PM2.5 (HR = 1.14, 95% CI: 1.09-1.19 per 10 µg/m3) and physical inactivity (1.49, 1.44-1.54 relative to sufficiently active), but not with greenness (1.01, 0.99-1.03 per IQR). The PM2.5-mortality association was mitigated at high levels of greenness (1.05, 0.91-1.22). There was no strong evidence of confounding between air pollution, physical activity, and greenness. However, stratified analysis suggested effect modification for PM2.5 and NDVI by physical activity. A significant protective greenness-mortality association was observed for only highly active individuals (0.91, 0.86-0.96). Also, relatively high PM2.5-mortality HRs were observed for more physically active individuals (1.25, 1.12-1.40). PM2.5 air pollution and physical inactivity are robustly associated with mortality risk. Greenness may be most beneficial and air pollution relatively harmful to highly active individuals. This analysis provides evidence that, in addition to not smoking, being physically active and living in a clean, green environment contributes to improved health and reduced risk of mortality.

Cardiopulmonary Mortality and Fine Particulate Air Pollution by Species and Source in a National U.S. Cohort.

The purpose of this study was to estimate cardiopulmonary mortality associations for long-term exposure to PM2.5 species and sources (i.e., components) within the U.S. National Health Interview Survey cohort. Exposures were estimated through a chemical transport model for six species (i.e., elemental carbon (EC), primary organic aerosols (POA), secondary organic aerosols (SOA), sulfate (SO4), ammonium (NH4), nitrate (NO3)) and five sources of PM2.5 (i.e., vehicles, electricity-generating units (EGU), non-EGU industrial sources, biogenic sources (bio), "other" sources). In single-pollutant models, we found positive, significant (p < 0.05) mortality associations for all components, except POA. After adjusting for remaining PM2.5 (total PM2.5 minus component), we found significant mortality associations for EC (hazard ratio (HR) = 1.36; 95% CI [1.12, 1.64]), SOA (HR = 1.11; 95% CI [1.05, 1.17]), and vehicle sources (HR = 1.06; 95% CI [1.03, 1.10]). HRs for EC, SOA, and vehicle sources were significantly larger in comparison to those for remaining PM2.5 (per unit µg/m3). Our findings suggest that cardiopulmonary mortality associations vary by species and source, with evidence that EC, SOA, and vehicle sources are important contributors to the PM2.5 mortality relationship. With further validation, these findings could facilitate targeted pollution regulations that more efficiently reduce air pollution mortality.

Shape of BMI-Mortality Risk Associations: Reverse Causality and Heterogeneity in a Representative Cohort of US Adults.

OBJECTIVE: This study examines BMI-mortality associations and evaluates strategies intended to limit reverse causality. Heterogeneity in BMI-mortality risk associations across subgroups and causes of death is explored. METHODS: A cohort of 654,382 adults from the US National Health Interview Survey was constructed. Associations between unit BMI levels and mortality were estimated using Cox proportional hazards models, including and excluding the first 5 years of follow-up, with and without controls for smoking or preexisting conditions, and including and excluding ever-smokers and individuals with preexisting conditions. Stratified analyses by individual characteristics were performed. RESULTS: Addressing reverse causality led to reduced risk of mortality among those with low BMI levels (<18 kg/m2 ). Excluding ever-smokers and individuals with preexisting conditions further led to increased risk among those with high BMI levels (between 33 kg/m2 and >40 kg/m2 ) and lowered the estimated nadir risk from 27 kg/m2 to 23 kg/m2 . After excluding ever-smokers and individuals with preexisting conditions, limiting the analysis to >5 years of follow-up produced no substantive changes. Heterogeneous results were observed across individual characteristics, particularly age and causes of death. CONCLUSIONS: The exclusion of smokers and individuals with preexisting conditions alters the BMI-mortality risk association and results in a somewhat lower range of BMI with minimum mortality risk.

Fine particulate air pollution and human mortality: 25+ years of cohort studies.

Much of the key epidemiological evidence that long-term exposure to fine particulate matter air pollution (PM2.5) contributes to increased risk of mortality comes from survival studies of cohorts of individuals. Although the first two of these studies, published in the mid-1990s, were highly controversial, much has changed in the last 25 + years. The objectives of this paper are to succinctly compile and summarize the findings of these cohort studies using meta-analytic tools and to address several of the key controversies. Independent reanalysis and substantial extended analysis of the original cohort studies have been conducted and many additional studies using a wide variety of cohorts, including cohorts constructed from public data and leveraging natural experiments have been published. Meta-analytic estimates of the mean of the distribution of effects from cohort studies that are currently available, provide substantial evidence of adverse air pollution associations with all-cause, cardiopulmonary, and lung cancer mortality.

Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a ß-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

Adipocyte factors, high-sensitive C-reactive protein levels and lipoxidative stress products in overweight postmenopausal women with normal and impaired OGTT.

OBJECTIVE: In obese postmenopausal women we assessed leptin and adiponectin, high-sensitive C-reactive protein (hsCRP), serum lipids and lipoxidative stress products: oxidized LDL (oxLDL) and malondialdehyde (MDA), in relation to impaired glucose tolerance (IGT). METHODS: Thirty-eight overweight/obese postmenopausal women were included in the study. Eighteen with normal glucose metabolism (NGT) and twenty with IGT, as it is diagnosed by OGTT. Serum leptin, adiponectin, hsCRP and MDA were measured at time 0 and 120 min of OGTT while total-cholesterol, LDL, HDL, triglycerides, oxLDL and anti-oxLDL autoantibodies at time 0. Insulin resistance (HOMA)/sensitivity (QUICKI) indexes were estimated. RESULTS: In subjects with NGT, hsCRP was positively correlated with fasting leptin and HOMA, while in subjects with IGT negatively with QUICKI. In both groups, hsCRP was positively correlated with fasting insulin, body mass index and waist circumference. Fasting adiponectin was positively associated with HDL in both groups and negatively with triglycerides in subjects with NGT as well as with serum glucose levels at time 120 min of OGTT in subjects with IGT. No association was observed between oxLDL and adipokines. A significant positive association was found between oxLDL and HOMA in subjects with IGT. During OGTT there was a significant increase of leptin and MDA levels in both groups. CONCLUSIONS: A relationship exists between obesity, insulin and sub-clinical inflammation. Leptin and lipid peroxidation are linked to hyperglycaemic state while oxLDL might be considered as a predictor of insulin resistance. Adiponectin could exert its antiatherogenic effect through HDL independently of the presence of IGT.

Elevation of serum N-terminal pro-brain natriuretic peptide after exercise is an index of myocardial damage or a cytoprotective reflection?

AIM: Recent investigations have suggested the occurrence of transient cardiac dysfunction and reversible myocardial injury in healthy individuals after heavy exercise. Our purpose was to examine if the release of N-terminal pro-brain natriuretic peptide (NT-proBNP) after intense exercise in obviously healthy participants may have cytoprotective and growth-regulating effects or may result from myocardial dysfunction/damage with changes in cTnT as a marker for myocardial cell necrosis during exercise. METHODS: In 43 highly-trained male athletes <35 years old, who were examined immediately after exercising as well as 2 days later, 21 age-matched male patients classified as stage-B according to ACC/AHA guidelines and 35 healthy age-matched males, we evaluated NT-proBNP and 3rd generation's cTnT by electrochemiluminescence immunoassay. All participants underwent a detailed cardiac protocol including echocardiography and electrocardiogram (ECG). RESULTS: In athletes, cTnT consistently remained <0.01 mg/L after exercising as well as after 2 days. NTproBNP immediately after exercising was 58.27+/-19.48 ng/L, without reaching pathological levels, decreasing 2 days later to 22.93+/-10.22 ng/L. Our patients maintained high levels of NTproBNP, as much as a six-fold increase with reference to the levels of our study's control group and with cTnT <0.01 mg/L. In the control group, cTnT and NTproBNP levels were statistically similar with those of the athletes 2 days after exercising. NT-proBNP as a biological marker can reliably discriminate pathological from physiological cardiac hypertrophy. CONCLUSION: A normal plasma concentration of NT-proBNP in consecutive routine check-up, before and after exercise, could minimize the possibility of cardiac dysfunction, whereas persistent elevated plasma concentrations warrant further cardiological evaluation.

Effects of hormone replacement therapy on the phospholipid composition of high density lipoproteins in postmenopausal women.

The beneficial effect of hormone replacement therapy (HRT) in reducing the risk of cardiovascular disease may be partly mediated by favourable changes in the phospholipid composition of high density lipoprotein (HDL) subclasses. In group A(oestrogen alone) HDL phosphatidylcholine increased (P<0.01), while 2 there was a decrease in HDL phosphaditylinositol (P<0.05) 2 and HDL phosphatidylethanolamine (P<0.01) compared with 2 controls (baseline). In the same group, HDL phosphatidylcholine 3 increased (P<0.01) and HDL phosphatidylethanolamine decreased (P<0.05). In group B (oestrogen plus progestogens), HDL phosphatidylcholine increased (P<0.001) while there were 2 decreases in HDL sphingomyelin (P<0.01), HDL 2 2 phosphatidylserine (P<0.05), HDL phosphatidylethanolamine 2 (P<0.01) and HDL diphosphatidylglycerol (P<0.05). In the 2 same group, an increase in HDL phosphatidylcholine (P<0.01) 3 and HDL phosphatidylserine (P<0.01) were observed, as well 3 as a decrease in HDL phosphatidylethanolamine (P<0.001). 3 The significance of these results is discussed.

Diazepam treatment in rats induces changes in the concentrations of different phospholipid classes in liver and liver mitochondria.

Liver phospholipid concentrations were determined in rats after the administration of diazepam (5 mg/Kg/day), for a period of two months. Increased concentrations of total phospholipids (P < 0.05), phosphatidylcholine (P < 0.05) and phosphatidylinositol (P < 0.05) were found in the rats taking diazepam. In contrast, a decreased concentration of phosphatidylserine (P < 0.01) was observed in the same group of animals. In addition, changes in the concentration of rat liver mitochondrial phospholipids after the administration of diazepam during the same period of time were determined. Increased concentrations of total phospholipids (P < 0.01), phosphatidylcholine (P < 0.001) and diphosphatidylglycerol (P < 0.001) were found in the rats treated with diazepam. In contrast, decreased phosphatidylserine (P < 0.001) and phosphatidylinositol (P < 0.01) concentrations were observed in the same group of animals. The considerable changes observed in liver phospholipids and individual classes of liver mitochondrial phospholipids induced by long-term administration of diazepam, possibly suggest a stimulation of liver phospholipid biosynthesis. This effect may be related to enzymatic systems which are involved in phospholipid pathways, and are linked to benzodiazepinergic binding sites.

Serum sex hormone binding globulin in prepubertal girls and adult women.

Serum SHBG concentration depends on the hormonal status. Androgens decrease while estrogens increase SHBG biosynthesis in the liver. In the present study an attempt was made to investigate whether the changes that occur in the ratio of estrogen to androgen concentration between prepubertal girls and women could have influenced plasma SHBG levels. For this reason serum concentrations of SHBG, E2, T and DHEA-S were measured in 31 girls, aged 4.5-9 years, at Tanner stage I of pubertal development, and in 24 normal women. The girls were divided into 2 groups of different ages. The concentrations of non-SHBG-bound E2 and T and free E2 and T were calculated. The results showed a negative correlation between SHBG serum levels and the age of prepubertal girls while the ratio of E2/T did not change. Although the ratio of E2/T was found increased by 10 times between older prepubertal girls and women in the luteal phase of menstrual cycle, serum SHBG levels only slightly decrease in the group of women. The non-SHBG-bound E2 and free E2 levels were significantly higher in women than those in prepubertal girls indicating an increase of estrogen milieu in target tissues. It seems that apart from the changes that occur in the ratio of E2/T the serum SHBG levels may be also under the control of other factors.

Prostaglandins: PGF2 alpha, PGE2, 6-keto-PGF1 alpha and TXB2 serum levels in dysmenorrheic adolescents before, during and after treatment with oral contraceptives.

Ten adolescents with primary dysmenorrhea (PD) were treated with the oral contraceptive (OC) Lyndiol 2.5 mg (R) for one cycle. The levels of PGF2 alpha, PGE2 and the metabolites of PGI2 and TXA2: 6-keto-PGF1 alpha and TXB2 were tested by a radioimmunoassay method during the 1st and 23rd day of the pre-treatment cycle (PrTC), the 23rd day of treatment (TC) and the 1st day of the post-treatment cycle (PoTC). The ratios PGF2 alpha/PGE2 and TXB2/6-keto-PGF1 alpha were also tested and compared during the above-mentioned days. Analytical comparison was made, for each Prostaglandin (PG) separately, between the 1st day of the PrTC and PoTC as well as the 23rd day of the PrTC and TC, respectively. All PG levels during TC and PoTC were found significantly lower, compared to those of the PrTC respectively. With regard to the ratios mentioned above, no statistically significant differences were found on the same days and cycles as previously stated. The reduction of the PG levels in PD patients after treatment with oral contraceptives, together with an improvement of the clinical findings of the disease, support the theory that oral contraceptives can be used for the treatment of PD cases, especially for those adolescents who also desire a contraceptive method.