The Association of Episiotomy with Obstetric Anal Sphincter Injury–A Population Based Matched Cohort Study

Objectives

To estimate the independent association of episiotomy with obstetric anal sphincter injuries (OASIS) using first a cross-sectional and then a matched pair analysis.

Design

A matched cohort.

Setting

Data was gathered from the Finnish Medical Birth Register from 2004–2011.

Population

All singleton vaginal births (n = 303,758).

Methods

Women resulting matched pairs (n = 63,925) were matched based on baseline risk of OASIS defined based on parity (first or second/subsequent vaginal births), age, birth weight, mode of delivery, prior caesarean section, and length of active second stage of birth.

Results

In cross-sectional analysis episiotomy was associated with a 12% lower incidence of OASIS (adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.80 to 0.98) in first vaginal births and with a 132% increased incidence of OASIS in second or subsequent vaginal births (aOR 2.32, 95% CI 1.77 to 3.03). In matched pair analysis episiotomy was associated with a 23% (aOR 0.77, 95% CI 0.69 to 0.86) lower incidence of OASIS in first vaginal births and a 61% (aOR 1.61, 95% CI 1.14 to 2.29) increased incidence of OASIS in second or subsequent vaginal births compared to women who gave birth without an episiotomy. The matched pair analysis showed a 12.5% and a 31.6% reduction in aORs of OASIS associated with episiotomy, respectively.

Conclusions

A matched pair analysis showed a substantial reduction in the aORs of OASIS with episiotomy, due to confounding by indication. This indicates that results of observational studies evaluating an association between episiotomy and OASIS should be interpreted with caution.     

Open tundra persist,but arctic features decline—Vegetation changes in the warming Fennoscandian tundra

In the forest‐tundra ecotone of the North Fennoscandian inland, summer and winter temperatures have increased by two to three centigrades since 1965, which is expected to result in major vegetation changes. To document the expected expansion of woodlands and scrublands and its impact on the arctic vegetation, we repeated a vegetation transect study conducted in 1976 in the Darju, spanning from woodland to a summit, 200 m above the tree line. Contrary to our expectations, tree line movement was not detected, and there was no increase in willows or shrubby mountain birches, either. Nevertheless, the stability of tundra was apparent. Small‐sized, poorly competing arctic species had declined, lichen cover had decreased, and vascular plants, especially evergreen ericoid dwarf shrubs, had gained ground. The novel climate seems to favour competitive clonal species and species thriving in closed vegetation, creating a community hostile for seedling establishment, but equally hostile for many arctic species, too. Preventing trees and shrubs from invading the tundra is thus not sufficient for conserving arctic biota in the changing climate. The only dependable cure is to stop the global warming.     

Immunochemical analysis of the electronegative LDL subfraction shows that abnormal N-terminal apolipoprotein B conformation is involved in increased binding to proteoglycans

Electronegative LDL (LDL(-)) is a minor subfraction of modified LDL present in plasma. Among its atherogenic characteristics, low affinity to the LDL receptor and high binding to arterial proteoglycans (PGs) could be related to abnormalities in the conformation of its main protein, apolipoprotein B-100 (apoB-100). In the current study, we have performed an immunochemical analysis using monoclonal antibody (mAb) probes to analyze the conformation of apoB-100 in LDL(-). The study, performed with 28 anti-apoB-100 mAbs, showed that major differences of apoB-100 immunoreactivity between native LDL and LDL(-) concentrate in both terminal extremes. The mAbs Bsol 10, Bsol 14 (which recognize the amino-terminal region), Bsol 2, and Bsol 7 (carboxyl-terminal region) showed increased immunoreactivity in LDL(-), suggesting that both terminal extremes are more accessible in LDL(-) than in native LDL. The analysis of in vitro-modified LDLs, including LDL lipolyzed with sphingomyelinase (SMase-LDL) or phospholipase A(2) (PLA(2)-LDL) and oxidized LDL (oxLDL), suggested that increased amino-terminal immunoreactivity was related to altered conformation due to aggregation. This was confirmed when the aggregated subfractions of LDL(-) (agLDL(-)) and oxLDL (ag-oxLDL) were isolated and analyzed. Thus, Bsol 10 and Bsol 14 immunoreactivity was high in SMase-LDL, ag-oxLDL, and agLDL(-). The altered amino-terminal apoB-100 conformation was involved in the increased PG binding affinity of agLDL(-) because Bsol 10 and Bsol 14 blocked its high PG-binding. These observations suggest that an abnormal conformation of the amino-terminal region of apoB-100 is responsible for the increased PG binding affinity of agLDL(-).     

Growth and genotype × environment interactions in Betula pendula: can tree genetic variation be maintained by small-scale forest ground heterogeneity?

Forest ground heterogeneity can affect interactions among tree species and control the assembly of local forest communities. Less is known of the effects of spatial heterogeneity on the maintenance of tree genetic variation through small-scale genotype × environment (G × E) interactions. We measured growth variation within and among 17 Betula pendula genotypes, planted in a clear-cut forest site through the summers 2009–2011. We assessed the spatial heterogeneity at two scales: among forest stands having history of the same or different tree species combinations (treated as replicate blocks), and along a gradient of within-block forest density, revealed by the stump density. To add a temporal perspective, we distinguished between old (cut 50 years earlier) and new stumps (cut one year earlier). The broad-sense heritabilities for growth were 0.093–0.055 and the coefficients of genotypic variation 0.37–0.21 in 2009–2011. The growth difference among the genotypes was 3.5–5.5 fold, significant in all years, and the rank of genotype means correlated positively between the years. The most favourable block had 106 % higher growth than the least favourable block and the amount of total variation explained by block increased from 0.4 % in 2009 to 6.9 % in 2011. Genotype × block interaction was marginally significant in 2009, but not later. Similarly, the response of growth to old stump density in sapling vicinity varied among the genotypes in 2009, but not later. In 2010 and 2011, the mean growth increased by 50–91 % along the old stump density gradient. Our results suggest that despite creating significant variation in sapling growth the small-scale forest ground heterogeneity, which reflects the recent forest history, may not significantly contribute to the maintenance of genetic variation in B. pendula populations.     

Three complementary techniques for the clarification of temperature effect on low-density lipoprotein–chondroitin-6-sulfate interaction

A rigorous processing of adsorption data from quartz crystal microbalance technology was successfully combined with the data obtained by partial filling affinity capillary electrophoresis and molecular dynamics for the clarification of the temperature effect on the interaction of a major glycosaminoglycan chain chondroitin-6-sulfate (C6S) of proteoglycans with low-density lipoprotein (LDL) and with a peptide fragment of apolipoprotein B-100 (residues 3359–3377 of LDL, PPBS). Two experimental techniques and computational atomistic methods demonstrated a nonlinear pattern of the affinity of C6S at temperatures above 38.0 °C to both LDL and PPBS. The temperature affects the interaction of C6S with LDL and PPBS by influencing the structural behavior of glycosaminoglycan C6S and/or that of LDL.     

Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

Background

Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1β and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1β has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.

Principal Findings

Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1β from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1β was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1β secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1β secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.

Conclusions

The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.     

Activated Human Mast Cells Induce LOX-1-Specific Scavenger Receptor Expression in Human Monocyte-Derived Macrophages

Objective

Activated mast cells in atherosclerotic lesions degranulate and release bioactive compounds capable of regulating atherogenesis. Here we examined the ability of activated human primary mast cells to regulate the expression of the major scavenger receptors in cultured human primary monocyte-derived macrophages (HMDMs).

Results

Components released by immunologically activated human primary mast cells induced a transient expression of lectin-like oxidized LDL receptor (LOX-1) mRNA in HMDMs, while the expression of two other scavenger receptors, MSR1 and CD36, remained unaffected. The LOX-1-inducing secretory components were identified as histamine, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta (TGF-β1), which exhibited a synergistic effect on LOX-1 mRNA expression. Histamine induced a transient expression of LOX-1 protein. Mast cell –induced increase in LOX-1 expression was not associated with increased uptake of oxidized LDL by the macrophages.

Conclusions

Mast cell-derived histamine, TNF-α, and TGF-β1 act in concert to induce a transient increase in LOX-1 expression in human primary monocyte-derived macrophages. The LOX-1-inducing activity potentially endows mast cells a hitherto unrecognized role in the regulation of innate immune reactions in atherogenesis.     

High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level

Electronegative LDL [LDL(-)] is an atherogenic subfraction of plasma LDL that has increased apolipoprotein E (apoE) and apoC-III content, high density, and increased susceptibility to aggregation. These characteristics suggest that LDL(-) could bind to proteoglycans (PGs); therefore, our aim was to evaluate its affinity to PGs. Binding of LDL(-) and native LDL [LDL(+)] to human aortic PGs was determined by precipitation of LDL-glycosaminoglycan complexes, LDL incubation in PG-coated microtiter wells, and affinity chromatography on PG column. All methods showed that LDL(-) had higher binding affinity to PGs than did LDL(+). PG capacity to bind LDL(-) was increased approximately 4-fold compared with LDL(+) in precipitation and microtiter assays. Chromatography on PG column showed LDL(-) to consist of two subpopulations, one with higher and one with lower PG binding affinity than LDL(+). Unexpectedly, the lower PG affinity subpopulation had increased apoE and apoC-III content. In contrast, the high PG affinity subpopulation presented phospholipase C (PLC)-like activity and increased aggregation. These results suggest that PLC-like activity could alter LDL lipid composition, thereby promoting particle aggregation and binding to PGs. This propensity of a subpopulation of LDL(-) to bind to PGs could facilitate its retention in the extracellular matrix of arterial intima and contribute to atherosclerosis progression.