Computational Modelling of Paracellular Diffusion and OCT3 Mediated Transport of Metformin in the Perfused Human Placenta.

Metformin is an antidiabetic drug, increasingly prescribed in pregnancy and has been shown to cross the human placenta. The mechanisms underlying placental metformin transfer remain unclear. This study investigated the roles of drug transporters and paracellular diffusion in the bidirectional transfer of metformin across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling.

3D visualization of trans-syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast.

The placental syncytiotrophoblast, a syncytium without cell-cell junctions, is the primary barrier between the mother and the fetus. Despite no apparent anatomical pathway for paracellular diffusion of solutes across the syncytiotrophoblast, size-dependent paracellular diffusion is observed. Here we report data demonstrating that the syncytiotrophoblast is punctuated by -syncytial nanopores (TSNs).

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D by endocytosis, placental metabolism of 25(OH)D into 24,25-dihydroxyvitamin D and active 1,25-dihydroxyvitamin D [1,25(OH)D], with subsequent release of these metabolites into both the maternal and fetal circulations.

Folding of the syncytiotrophoblast basal plasma membrane increases the surface area available for exchange in human placenta.

Introduction: The placental syncytiotrophoblast is the primary barrier between the mother and the fetus. To cross the placenta, nutrients and wastes must be transported across the apical microvillous and basal plasma membranes. While the syncytiotrophoblast basal plasma membrane is typically represented as relatively smooth, it has been shown to have invaginations that may increase its surface area.

N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta.

Introduction: Placental oxidative stress features in pregnancy pathologies but in clinical trials antioxidant supplementation has not improved outcomes. N-acetylcysteine (NAC) stimulates glutathione production and is proposed as a therapeutic agent in pregnancy. However, key elements of N-acetylcysteine biology, including its cellular uptake mechanism, remains unclear.

Pericytes on placental capillaries in terminal villi preferentially cover endothelial junctions in regions furthest away from the trophoblast.

Introduction: Pericytes are a common feature in the placental microvasculature but their roles are not well understood. Pericytes may provide physical or endocrine support for endothelium and in some tissues mediate vasoconstriction.

Methods: This study uses serial block-face scanning electron microscopy (SBFSEM) to generate three-dimensional (3D) reconstructions of placental pericytes of the terminal villi and transmission electron microscopy (TEM) to study pericyte endothelial cell interactions.

Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity.

The placenta mediates the transfer of maternal nutrients into the fetal circulation while removing fetal waste products, drugs and environmental toxins that may otherwise be detrimental to fetal development. This study investigated the role of drug transporters and protein binding in the transfer of the antidiabetic drug glibenclamide across the human placental syncytiotrophoblast using placental perfusion experiments and computational modeling. In the absence of albumin, placental glibenclamide uptake from the fetal circulation was not affected by competitive inhibition with bromosulphothalein (BSP), indicating that OATP2B1 does not mediate placental glibenclamide uptake from the fetus.

Serial block-face scanning electron microscopy reveals novel intercellular connections in human term placental microvasculature.

The placental microvasculature is a conduit for fetal blood allowing solute exchange between the mother and the fetus. Serial block-face scanning electron microscopy (SBF SEM) allows ultrastructure to be viewed in three dimensions and provides a new perspective on placental anatomy. This study used SBF SEM to study endothelial cells within the human placental microvasculature from uncomplicated pregnancies.

Human placental villi contain stromal macrovesicles associated with networks of stellate cells.

Placental function is essential for fetal development and establishing the foundations for lifelong health. The placental villous stroma is a connective tissue layer that supports the fetal capillaries and villous trophoblast. All the nutrients that cross the placenta must also cross the stroma, and yet little is known about this region.

Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Intrahepatic cholestasis of pregnancy (ICP) causes increased transfer of maternal bile acids to the fetus and an increased incidence of sudden fetal death. Treatment includes ursodeoxycholic acid (UDCA), but it is not clear if UDCA protects the fetus. This study explores the placental transport of the bile acid taurocholate (TC) by the organic anion-transporting polypeptide, (OATP)4A1, its effects on the placental proteome and vascular function, and how these are modified by UDCA.

Estrone sulphate uptake by the microvillous membrane of placental syncytiotrophoblast is coupled to glutamate efflux.

Organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs) are transport proteins that mediate exchange of metabolites, hormones and waste products. Directional transport by these transporters can occur when exchange is coupled to the gradients of other substrates. This study investigates whether the activity of OATP4A1 and OATP2A1 on the maternal facing microvillus membrane of the placental syncytiotrophoblast is coupled to the glutamate gradient.

A systems perspective on placental amino acid transport.

Placental amino acid transfer is a complex process that is essential for fetal development. Impaired amino acid transfer causes fetal growth restriction, which may have lifelong health consequences. Transepithelial transfer of amino acids across the placental syncytiotrophoblast requires accumulative, exchange and facilitated transporters on the apical and basal membranes to work in concert.

Serial block-face scanning electron microscopy of erythrocytes protruding through the human placental syncytiotrophoblast.

The syncytiotrophoblast forms a continuous barrier between the maternal and fetal circulations. Here we present a serial block-face scanning electron microscopy (SBFSEM) study, based on a single image stack, showing pooling of fetal blood underneath a region of stretched syncytiotrophoblast that has become detached from the basement membrane. Erythrocytes are protruding from discrete holes in the syncytiotrophoblast suggesting that, under specific circumstances, the syncytiotrophoblast may be permeable to fetal cells.

Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation.

Membrane transporters are considered essential for placental amino acid transfer, but the contribution of other factors, such as blood flow and metabolism, is poorly defined. In this study we combine experimental and modeling approaches to understand the determinants of [(14)C]phenylalanine transfer across the isolated perfused human placenta. Transfer of [(14)C]phenylalanine across the isolated perfused human placenta was determined at different maternal and fetal flow rates.

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast.

The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter-ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation.

Partitioning of glutamine synthesised by the isolated perfused human placenta between the maternal and fetal circulations.

Introduction: Placental glutamine synthesis has been demonstrated in animals and is thought to increase the availability of this metabolically important amino acid to the fetus. Glutamine is of fundamental importance for cellular replication, cellular function and inter-organ nitrogen transfer. The objective of this study was to investigate the role of glutamate/glutamine metabolism by the isolated perfused human placenta in the provision of glutamine to the fetus.

Systems-based approaches to probing metabolic variation within the Mycobacterium tuberculosis complex.

The Mycobacterium tuberculosis complex includes bovine and human strains of the tuberculosis bacillus, including Mycobacterium tuberculosis, Mycobacterium bovis and the Mycobacterium bovis BCG vaccine strain. M. bovis has evolved from a M.

What factors determine placental glucose transfer kinetics?

Introduction: Transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations even when these are well above the physiological range. This study investigates the relationship between maternal and fetal glucose concentrations and transfer across the placenta.

Methods: Transfer of d-glucose, (3)H-3-o-methyl-d-glucose ((3)H-3MG) and (14)C-l-glucose across the isolated perfused human placental cotyledon was determined for maternal and fetal arterial d-glucose concentrations between 0 and 20 mmol/l.

A patient with bacteraemia and possible endocarditis caused by a recently-discovered genomospecies of Capnocytophaga: Capnocytophaga genomospecies AHN8471: a case report.

Introduction: Capnocytophaga are a genus of bacteria that have been found to be the causative organisms in a range of infections, including serious conditions such as bacteraemia, endocarditis and meningitis. This has been especially true amongst those with serious comorbidities and the immunocompromised populations. Although several species are known to cause human disease, historically, laboratories have often not identified isolates to species level due to the unreliable, laborious techniques needed.

Inherited thrombophilia in ischemic stroke and its pathogenic subtypes.

Background And Purpose: One or more of the inherited thrombophilias may be causal risk factor for a proportion of ischemic strokes, but few studies have addressed this association or the association between thrombophilia and pathogenic subtypes of stroke.

Methods: We conducted a case-control study of 219 hospital cases with a first-ever ischemic stroke and 205 randomly selected community control subjects stratified by age, sex, and postal code. With the use of established criteria, cases of stroke were classified by pathogenic subtype in a blinded fashion.

Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke.

Platelets are pivotal to the process of arterial thrombosis resulting in ischemic stroke. Occlusive thrombosis is initiated by the interaction of von Willebrand factor (vWf) and platelet glycoprotein (GP) Ibalpha. Three polymorphisms have been described in GP Ibalpha (Kozak T/C polymorphism, variable number of tandem repeats [VNTR], and the human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at position 145), each of which may enhance the vWf and GP Ibalpha interaction.

Detection of protein S deficiency: a new functional assay compared to an antigenic technique.

Congenital protein S (PS) deficiency is associated with increased risk of venous thrombosis. To investigate the possibility of automating PS testing with decreased turnaround time, a clotting-based functional protein S assay was evaluated and compared to an antigenic method. Samples were collected from 126 patients within 5 days of their first acute cerebral infarction, from 62 controls and from 47 consecutive samples for thrombophilia investigation.

Selective down-regulation of the G(q)alpha/G11alpha G-protein family in tumour necrosis factor-alpha induced cell death.

Investigations into the regulation of heterotrimeric GTP-binding protein alpha-subunits in models of tumour necrosis factor-alpha (TNF)-induced cell death, revealed the selective down-regulation of the G(q)alpha/G11alpha family of G-proteins. The human HeLa and murine L929 cells treated with recombinant human TNF for up to 24 h displayed down-regulated G(q)alpha/G11alpha family protein levels, but not G(s)alpha, G(i)alpha and G(o)alpha protein levels as determined by Western analyses. This effect of TNF was observed in a concentration--and time-dependent manner, consistent with the profiles of TNF-induced cell death observed.

Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke.

Background And Purpose: Elevated plasma homocyst(e)ine may be a causal and modifiable risk factor for ischemic stroke, but the results of previous studies have been conflicting. One possible explanation is that homocyst(e)ine may only be associated with certain pathophysiological subtypes of ischemic stroke.

Methods: We conducted a case-control study of 219 hospital cases with a first-ever ischemic stroke and 205 randomly selected community control subjects stratified by age, sex, and postal code.