Search

Objectives: Pre-eclampsia (PE) is associated with both postpartum structural asymptomatic heart disease (i.e. heart failure Stage B (HF-B)) and conventional cardiovascular (CV) risk factors. We aimed to evaluate the extent to which PE, adjusted for conventional CV risk factors, is associated independently with asymptomatic cardiac abnormalities postpartum.Methods: In this cross-sectional cohort study, 107 formerly pre-eclamptic women and 41 women with uneventful previous pregnancy (controls) were invited for CV risk assessment 4-10 years postpartum. This included cardiac ultrasound, blood pressure (BP) measurement and evaluation of metabolic syndrome determinants. Asymptomatic structural and functional cardiac abnormalities were classified as HF-B, according to the American Heart Association guidelines. Prehypertension was defined as systolic BP of 120-139 mmHg and/or diastolic BP of 80-89 mmHg. Univariate and multivariate regression analyses were performed to calculate associations of PE and conventional risk factors with HF-B.Results: The prevalence of asymptomatic HF-B was approximately 3.5-fold higher in the PE group compared with controls (25% vs 7%, P < 0.01); 67% of this group had concentric remodeling and 22% had mildly impaired ejection fraction. After adjustment for postpartum interval, hypertension and high-density lipoprotein, PE was significantly associated with HF-B (adjusted odds ratio, 4.4 (95% CI, 1.0-19.1)). Moreover, in the formerly pre-eclamptic group, prehypertension was associated significantly with HF-B (odds ratio, 4.3 (95% CI, 1.4-12.7)), while metabolic syndrome determinants were not.Conclusion: PE is associated with a four-fold increased female-specific risk of asymptomatic cardiac abnormalities. Prehypertension apparently increases this risk significantly, while metabolic syndrome determinants do not. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Solid-state NMR (ssNMR) spectroscopy facilitates the non-destructive characterization of structurally heterogeneous biomolecules in their native setting, for example, comprising proteins, lipids and polysaccharides. Here we demonstrate the utility of high and ultra-high field 1 H-detected fast MAS ssNMR spectroscopy, which exhibits increased sensitivity and spectral resolution, to further elucidate the atomic-level composition and structural arrangement of the cell wall of Schizophyllum commune, a mushroom-forming fungus from the Basidiomycota phylum. These advancements allowed us to reveal that Cu(II) ions and the antifungal peptide Cathelicidin-2 mainly bind to cell wall proteins at low concentrations while glucans are targeted at high metal ion concentrations. In addition, our data suggest the presence of polysaccharides containing N-acetyl galactosamine (GalNAc) and proteins, including the hydrophobin proteins SC3, shedding more light on the molecular make-up of cells wall as well as the positioning of the polypeptide layer. Obtaining such information may be of critical relevance for future research into fungi in material science and biomedical contexts., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus , SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections.

Germination of conidia is an essential process within the Aspergillus life cycle and plays a major role during the infection of hosts. Conidia are able to avoid detection by the majority of leukocytes when dormant. Germination can cause severe health problems, specifically in immunocompromised people. Aspergillosis is most often caused by Aspergillus fumigatus ( A. fumigatus ) and affects neutropenic patients, as well as people with cystic fibrosis (CF). These patients are often unable to effectively detect and clear the conidia or hyphae and can develop chronic non-invasive and/or invasive infections or allergic inflammatory responses. Current treatments with (tri)azoles can be very effective to combat a variety of fungal infections. However, resistance against current azoles has emerged and has been increasing since 1998. As a consequence, patients infected with resistant A. fumigatus have a reported mortality rate of 88% to 100%. Especially with the growing number of patients that harbor azole-resistant Aspergilli, novel antifungals could provide an alternative. Aspergilloses differ in defining characteristics, but germination of conidia is one of the few common denominators. By specifically targeting conidial germination with novel antifungals, early intervention might be possible. In this review, we propose several morphotypes to disrupt conidial germination, as well as potential targets. Hopefully, new antifungals against such targets could contribute to disturbing the ability of Aspergilli to germinate and grow, resulting in a decreased fungal burden on patients.

Fungi produce a wide diversity of secondary metabolites with interesting biological activities for the health, industrial, and agricultural sectors. While fungal genomes have revealed an unexpectedly high number of biosynthetic pathways that far exceeds the number of known molecules, accessing and characterizing this hidden diversity remain highly challenging. Here, we applied a combined phylogenetic dereplication and comparative genomics strategy to explore eight lichenizing fungi. The determination of the evolutionary relationships of aromatic polyketide pathways resulted in the identification of an uncharacterized biosynthetic pathway that is conserved in distant fungal lineages. The heterologous expression of the homologue from Aspergillus parvulus linked this pathway to naphthalenone compounds, which were detected in cultures when the pathway was expressed. Our unbiased and rational strategy generated evolutionary knowledge that ultimately linked biosynthetic genes to naphthalenone polyketides. Applied to many more genomes, this approach can unlock the full exploitation of the fungal kingdom for molecule discovery. IMPORTANCE Fungi have provided us with life-changing small bioactive molecules, with the best-known examples being the first broad-spectrum antibiotic penicillin, immunosuppressive cyclosporine, and cholesterol-lowering statins. Since the 1980s, exploration of chemical diversity in nature has been highly reduced. However, the genomic era has revealed that fungal genomes are concealing an unexpected and largely unexplored chemical diversity. So far, fungal genomes have been exploited to predict the production potential of bioactive compounds or to find genes that control the production of known molecules of interest. But accessing and characterizing the full fungal chemical diversity require rational and, thus, efficient strategies. Our approach is to first determine the evolutionary relationships of fungal biosynthetic pathways in order to identify those that are already characterized and those that show a different evolutionary origin. This knowledge allows prioritizing the choice of the pathway to functionally characterize in a second stage using synthetic-biology tools like heterologous expression. A particular strength of this strategy is that it is always successful: it generates knowledge about the evolution of bioactive-molecule biosynthesis in fungi, it either yields novel molecules or links the studied pathway to already known molecules, and it reveals the chemical diversity within a given pathway, all at once. The strategy is very powerful to avoid studying the same pathway again and can be used with any fungal genome. Functional characterization using heterologous expression is particularly suitable for fungi that are difficult to grow or not genetically tractable. Thanks to the decreasing cost of gene synthesis, ultimately, only the genome sequence is needed to identify novel pathways and characterize the molecules that they produce. Such an evolution-informed strategy allows the efficient exploitation of the chemical diversity hidden in fungal genomes and is very promising for molecule discovery.

Biofilm formation during infections with the opportunistic pathogen Aspergillus fumigatus can be very problematic in clinical settings, since it provides the fungal cells with a protective environment. Resistance against drug treatments, immune recognition as well as adaptation to the host environment allows fungal survival in the host. The exact molecular mechanisms behind most processes in the formation of biofilms are unclear. In general, the formation of biofilms can be categorized roughly in a few stages; adhesion, conidial germination and development of hyphae, biofilm maturation and cell dispersion. Fungi in biofilms can adapt to the in-host environment. These adaptations can occur on a level of phenotypic plasticity via gene regulation. However, also more substantial genetic changes of the genome can result in increased resistance and adaptation in the host, enhancing the survival chances of fungi in biofilms. Most research has focused on the development of biofilms. However, to tackle developing microbial resistance and adaptation in biofilms, more insight in mechanisms behind genetic adaptations is required to predict which defense mechanisms can be expected. This can be helpful in the development of novel and more targeted antifungal treatments to combat fungal infections.

Background During uncomplicated pregnancy, left ventricular remodeling occurs in an eccentric way. In contrast, during preeclamptic gestation, the left ventricle hypertrophies concentrically, concurrent with loss in circulatory volume and increased blood pressure. Concentric cardiac structure persists in a substantial proportion of women and may be associated with pressure and volume load after preeclampsia. We hypothesize that low volume load, as indicated by plasma volume (PV) after preeclampsia and increased pressure load, is associated with remote concentric remodeling. Methods and Results In this longitudinal cohort study, we included 100 formerly preeclamptic women. Two visits were performed: at 0.8 years postpartum and at 4.8 years postpartum. During visit 1, we measured blood pressure and PV (I 125 dilution technique, low PV ≤48 mL/kg lean body mass). During the second visit, we assessed cardiac geometry by cardiac ultrasound. Concentric remodeling was defined as relative wall thickness >0.42 and left ventricular mass index ≤95 g/m 2 . We adjusted multivariable analysis for primiparity, systolic blood pressure, PV mL/kg lean body mass, and antihypertensive medication at visit 1. Low PV is associated with remote concentric remodeling (odds ratio [OR], 4.37; 95% CI, 1.06-17.40; and adjusted OR, 4.67; 95% CI, 1.02-21.42). Arterial pressure load (systolic, diastolic, and mean arterial pressure) is also associated with development of concentric remodeling (OR, 1.15 [95% CI, 0.99-1.35]; OR, 1.24 [95% CI, 0.98-1.58]; and OR, 1.20 [95% CI, 0.98-1.47], respectively). Conclusions In former preeclamptic women, development toward left ventricular concentric remodeling is associated with low volume load and increased pressure load.

Objectives: After pre-eclampsia (PE), the prevalence of structural heart disease without symptoms, i.e. heart failure Stage B (HF-B), may be as high as one in four women in the first year postpartum. We hypothesize that a significant number of formerly pre-eclamptic women with HF-B postpartum are still in their resolving period and will not have HF-B during follow-up., Methods: In this prospective longitudinal cohort study, we included 69 formerly pre-eclamptic women who underwent serial echocardiographic measurements at 1 and 4 years postpartum. HF-B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m 2 ), concentric remodeling (relative wall thickness > 0.42 and LVMi ≤ 95 g/m 2 ), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Women were subdivided and analyzed according to HF-B outcome: no HF-B at either visit; HF-B at first visit only; HF-B at second visit only; HF-B at both visits., Results: The prevalence of HF-B in formerly pre-eclamptic women was 23% in the first year postpartum and 23% after 4 years. At the second visit, HF-B had resolved in 62.5% of affected women but was newly developed in 19% of initially unaffected women. At the first visit, 56% of women diagnosed with HF-B had reduced systolic function whereas at the second visit 69% of women with HF-B had concentric remodeling with mostly normal ejection fraction, consistent with diastolic dysfunction., Conclusions: The prevalence of HF-B can be considered consistently high (1 in 4) amongst formerly pre-eclamptic women at follow-up. Nonetheless, at an individual level, more than 60% of women found initially to be affected by HF-B will recover, whilst about 20% of formerly pre-eclamptic women with normal echocardiography in the first year postpartum will develop HF-B over the following years. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To assess the effect on mode of delivery of the routine use of labour epidural analgesia (EA) compared with analgesia on request., Design: Randomised non-inferiority trial., Setting: One university and one non-university teaching hospital in The Netherlands., Population: Women with a singleton pregnancy in cephalic presentation beyond 36 + 0 weeks' gestation., Methods: Participants were randomly allocated to receive either routine EA or analgesia on request. Intention-to-treat (ITT) and per-protocol (PP) analyses were performed, with confidence intervals (CI) calculated for the differences in percentages or means., Main Outcome Measures: Rate of operative delivery (instrumental vaginal or caesarean), labour characteristics, and adverse labour and neonatal outcomes., Results: A total of 488 women were randomly allocated to the routine EA (n = 233) or analgesia on request group (n = 255). In the routine EA group, 89.3% (208/233) received EA. According to ITT analysis, 34.8% (81/233) women in the routine EA group had an operative delivery, compared with 26.7% (68/255) in the analgesia on request group (difference 8.1%, 95% CI -0.1 to 16.3). The difference in rate of operative deliveries according to the PP analysis was statistically significant (difference 8.9%, 95% CI 0.4 to 17.4). Inferiority of EA could not be rejected, as in both analyses the upper bound of the confidence interval exceeded the pre-specified inferiority criterion of +10%. Women in the routine EA group had more adverse effects, including hypotension (difference 9.5%, 95% CI 4.2 to 14.9), and motor blockade (difference 6.8%, 95% CI 1.1 to 12.5)., Conclusion: Non-inferiority of routine EA could not be demonstrated in this trial. Routine EA use is likely to lead to more operative deliveries and more maternal adverse effects. The results of our study do not justify routine use of EA., (© 2014 Royal College of Obstetricians and Gynaecologists.)

A 87-year-old woman presented with vaginal blood loss. A tumor protruded through the anterior vaginal wall. Biopsy revealed transitional epithelium without atypia. In 1975 the urethra was dilated because of ischuria after a midline cystocele repair resulted in trauma. A post-traumatic transvaginal diverticulum of the urethra was diagnosed and closed.