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AimsThe mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV.Methods and resultsCeramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response.ConclusionnSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.

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Background: The MiniMed™ 780G system includes an Advanced Hybrid Closed Loop (AHCL) algorithm which provides for both automated basal and correction bolus insulin delivery. The preliminary performance of the system in real-world settings was evaluated.Methods: Data uploaded from August 2020 to March 2021 by individuals living in Belgium,

Background: Sensor-augmented pump (SAP) therapy can improve glycemic control, compared with multiple daily insulin injections or with insulin pump therapy alone, without increasing the risk of hypoglycemia. Subjects and Methods: A 12-month observational study in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII), upon the introduction of continuous glucose monitoring (CGM), was conducted in 15 countries (in Europe and in Israel) to document the real-life use of SAP and assess which variables are associated with improvement in type 1 diabetes management. Results: Data from 263 patients (38% male; mean age, 28.0 -15.7 years [range, 1-69 years]; body mass index, 23.3 -4.9 kg/m 2 ; diabetes duration, 13.9 -10.7 years; CSII duration, 2.6 -3 years) were collected. Baseline mean glycated hemoglobin A1c (HbA 1c ) was 8.1 -1.4%; 82% had suboptimal HbA 1c ( ‡ 7%). The average sensor use for 12 months was 30% (range, 0-94%), and sensor use decreased with time (first 3 months, 37%; last 3 months, 27%). Factors associated with improvement in HbA 1c after 12 months in patients with baseline HbA 1c ‡ 7% were high baseline HbA 1c (P < 0.001), older age group (P < 0.001), and more frequent sensor use (P = 0.047). Significantly less hospitalization, increased treatment satisfaction, and reduced fear of hypoglycemia were reported after 12 months of SAP. Conclusions: This is the largest and longest multicenter prospective observational study providing real-life data on SAP. These results are consistent with those of controlled trials showing the effectiveness of CGM in pump users.