A study of the healthcare resource use for the management of postpartum haemorrhage in France, Italy, the Netherlands, and the UK.

OBJECTIVE: Postpartum haemorrhage (PPH) complicates approximately 5% of births worldwide and is a leading direct cause of maternal death. Rates of PPH are increasing in many developed countries, particularly PPH related to uterine atony. There is a lack of published up-to-date information about healthcare resource use associated with management of PPH following vaginal birth. The objective of this study was to describe healthcare resource use for the management of minor PPH (blood loss 500-1,000 ml) and major PPH (blood loss > 1,000 ml) compared to uncomplicated birth (no PPH) following hospital vaginal birth in France, Italy, the Netherlands, and the UK. STUDY DESIGN: In-depth interviews with two midwives from each participating country were conducted to establish differences in resource use for the management of minor PPH, major PPH, and uncomplicated birth. A web-survey was then developed and one obstetrician per participating country reviewed the survey. In total, 100 midwives (25 per country) completed the survey. Results were discussed at a multi-professional consensus meeting of midwives and obstetricians/gynaecologists (n = 6). RESULTS AND CONCLUSIONS: Midwives participating in the survey estimated that 80% of women receive Active Management of the Third Stage of Labour (AMTSL) and 93% of participants specified that uterotonics would routinely be used during AMTSL. Most participants (84%) reported that blood loss is routinely measured in their hospital, using a combination of methods. PPH is associated with increased healthcare resource use, including administration of additional uterotonics and use of additional medical interventions, such as urinary catheter, intravenous fluids, and possible requirement for surgery. The number of nurses, obstetricians/gynaecologists, and anaesthetists involved in the management of PPH increases with the occurrence and severity of PPH, as well as the proportion of healthcare personnel providing continuous care. Women may spend an additional 24 h in hospital following major PPH compared to uncomplicated birth. The results of this study highlight the burden of PPH management on healthcare resources. To reduce costs associated with PPH, prevention is the most effective strategy and can be enhanced with the use of an effective uterotonic as part of the active management of the third stage of labour.

Distinct roles of NFATc1 and NFATc4 in human primary myoblast differentiation and in the maintenance of reserve cells.

Ca2+ signaling plays a key role during human myoblast differentiation. Among Ca2+-sensitive pathways, calcineurin is essential for myoblast differentiation and muscle regeneration. Nuclear factor of activated T-cell (NFAT) transcription factors are the major calcineurin targets. We investigated the expression and the role of each NFAT gene during human primary myoblast differentiation. We found that three NFAT isoforms are present, NFATc1, NFATc3 and NFATc4. Importantly, while their mRNA expression increases during differentiation, NFATc1 is more highly expressed in myotubes, whilst NFATc4 is specifically maintained in reserve cells. NFATc3 is present in both cell types, although no specific role during myoblast differentiation was observed. Knockdown of either NFATc1 or NFATc4 affects the differentiation process similarly, by decreasing the expression of late differentiation markers, but impairs myotube formation differently. Whereas NFATc1 knockdown strongly reduced the number and the surface area of myotubes, NFATc4 knockdown increased the surface area of myotubes and reduced the pool of reserve cells. We conclude that NFAT genes have specific roles in myotube formation and in the maintenance of the reserve cell pool during human postnatal myogenesis.

Epidermal growth factor receptor down-regulation triggers human myoblast differentiation.

Initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are regulated by a tyrosine phosphorylation. Using human primary myoblast culture, we investigated a possible role of various receptor tyrosine kinases in the induction of the differentiation process. We found that Epidermal Growth Factor Receptor (EGFR) is a key regulator of myoblast differentiation. EGFR activity is down-regulated during early human myoblast differentiation, and this event is required for normal differentiation to take place. Furthermore, EGFR silencing in proliferation conditions was able to trigger the differentiation program. This occurs through an increase of Kir2.1 channel activity that, via a rise of store-operated Ca(2+) entry, leads to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, Myocyte Enhancer Factor 2 (MEF2), Myosin Heavy Chain (MyHC)). Finally, blocking myoblast cell cycle in proliferation conditions using a cdk4 inhibitor greatly decreased myoblast proliferation but was not able, on its own, to promote myoblast differentiation. Taken together, these results show that EGFR down-regulation is an early event that is required for the induction of myoblast differentiation.

Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.

Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.