Placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a specific histiocytic intervillositis. Placental fibrin depositions can decrease the maternal-fetal interface causing fetal distress. Coronavirus disease 2019-related placental inflammation can lead to SARS-CoV-2-associated pediatric inflammatory multisystem syndrome.
We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log
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increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.
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Heart failure (HF) and chronic kidney disease (CKD) co-exist, and it is estimated that about 50% of HF patients suffer from CKD. Although studies have been performed on the association between CKD and HF with reduced ejection fraction (HFrEF), less is known about the link between CKD and heart failure with preserved ejection fraction (HFpEF). Approximately, 50% of all patients with HF suffer from HFpEF, and this percentage is projected to rise in the coming years. Therapies for HFrEF are long established and considered quite successful. In contrast, clinical trials for treatment of HFpEF have all shown negative or disputable results. This is likely due to the multifactorial character and the lack of pathophysiological knowledge of HFpEF. The typical co-existence of HFpEF and CKD is partially due to common underlying comorbidities, such as hypertension, dyslipidemia and diabetes. Macrovascular changes accompanying CKD, such as hypertension and arterial stiffening, have been described to contribute to HFpEF development. Furthermore, several renal factors have a direct impact on the heart and/or coronary microvasculature and may underlie the association between CKD and HFpEF. These factors include: (1) activation of the renin-angiotensin-aldosterone system, (2) anemia, (3) hypercalcemia, hyperphosphatemia and increased levels of FGF-23, and (4) uremic toxins. This review critically discusses the above factors, focusing on their potential contribution to coronary dysfunction, left ventricular stiffening, and delayed left ventricular relaxation. We further summarize the directions of novel treatment options for HFpEF based on the contribution of these renal drivers.
Background
The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity.
Methods
Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified.
Findings
Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE.
Interpretation
The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial.
Fund
This study was funded by an mRACE Erasmus MC grant.
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