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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,

To investigate the impact of continuous glucose monitoring (CGM) on health-related quality of life (HRQOL), treatment satisfaction (TS) medical resource use, and indirect costs in the SWITCH study. SWITCH was a multicentre, randomized, crossover study. Patients with type 1 diabetes (n = 153) using continuous subcutaneous insulin infusion (CSII) were randomized to a 12 month sensor-On/Off or sensor-Off/On sequence (6 months each treatment), with a 4-month washout between periods. HRQOL in children and TS in adults were measured using validated questionnaires. Medical resource utilization data were collected. In adults, TS was significantly higher in the sensor-On arm, and there were significant improvements in ratings for treatment convenience and flexibility. There were no clinically significant differences in children’s HRQOL or parents’ proxy ratings. The incidence of severe hypoglycaemia, unscheduled visits, or diabetes-related hospitalizations did not differ significantly between the two arms. Adult patients made fewer telephone consultations during the sensor-On arm; children’s caregivers made similar numbers of telephone consultations during both arms, and calls were on average only 3 min longer during the sensor-On arm. Regarding indirect costs, children with >70 % sensor usage missed fewer school days, compared with the sensor-Off arm (P = 0.0046) but there was no significant difference in the adults days of work off. The addition of CGM to CSII resulted in better metabolic control without imposing an additional burden on the patient or increased medical resource use, and offered the potential for cost offsets.

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.

Hypoxia increases the release of neurotransmitters from chemoreceptor cells of the carotid body (CB) and the activity in the carotid sinus nerve (CSN) sensory fibers, elevating ventilatory drive. According to previous reports, perinatal hyperoxia causes CSN hypotrophy and varied diminishment of CB function and the hypoxic ventilatory response. The present study aimed to characterize the presumptive hyperoxic damage. Hyperoxic rats were born and reared for 28 days in 55%-60% O 2 ; subsequent growth (to 3.5-4.5 months) was in a normal atmosphere. The parenchyma of the carotid body (CB) is formed by chemoreceptor and sustentacular cells organized in clusters surrounded by a dense network of capillaries. Sensory nerve terminals of the carotid sinus nerve (CSN) penetrate the clusters to synapse with chemoreceptor cells (Verna, 1997). Functionally, chemoreceptor cells are activated by hypoxia and hypercapnia, and they respond with an increased release of neurotransmitters that activate the sensory nerve endings of the CSN and produce an increase in the action potential frequency in the CSN. Central projections of the CSN produce a ventilatory response, which facilitates homeostasis of blood O 2 and CO 2 levels. Catecholamines (CA) are the most abundant neurotransmitters present in chemoreceptor cells. Many groups have demonstrated that CA metabolism, including rate of synthesis and release, parallel the level of CB stimulation and action potential frequency in the CSN (Gonzalez et al. , 1994 and references therein). In adult mammals the CB is responsible for the entire hyperventilation evoked by hypoxia and for about 30-50% of the hyperventilation triggered by hypercapnia and acidosis (Cherniack & Altose 1997;Gonzalez et al. 2002a). In the intact animal a decrease in arterial P O 2 from 100 to about 75 mmHg produces only minor changes in the basal level of CSN activity or ventilation. At P O 2 below the apparent threshold of 75 mmHg there is an almost exponential increase in either response. CSN activity and ventilation double at about 50-55 mmHg, and increase by a factor of four near 40 mmHg. In the case of CO 2 the activity in the CSN and the ventilation mediated by the CB increase linearly with the P CO 2 , doubling every 15-20 mmHg (Gonzalez et al. 1994). In neonatal animals, the apparent threshold for the hypoxic response is set at a much lower P O 2 , in the range of 20-25 mmHg, i.e. at P O 2 comparable to that found in utero. At lower P O 2 , the hypoxic response increases with a lower slope than in adults. In response to elevated CO 2 there is a comparable hyposensitivity in newborn animals (Hanson & Kumar 1994;Donnelly, 1997). Functional maturation of the CB during postnatal life occurs in the first few weeks after birth, with some differences among species. In the rat, at four weeks of age the responses are fully developed (Eden & Hanson 1987a;Donnelly & Doyle 1994;Rigual et al. 2000;Donnelly, 1997). Maturation of CB function is greatly affected by the ambient P O 2 in the perinatal period. Thus, if animals ...

Aim To investigate real‐world glycaemic outcomes and goals achieved by users of the MiniMed 780G advanced hybrid closed loop (AHCL) system aged younger and older than 15 years with type 1 diabetes (T1D). Materials and Methods Data uploaded by MiniMed 780G system users from 27 August 2020 to 22 July 2021 were aggregated and retrospectively analysed based on self‐reported age (≤15 years and >15 years) for three cohorts: (a) post‐AHCL initiation, (b) 6‐month longitudinal post‐AHCL initiation and (c) pre‐ versus post‐AHCL initiation. Analyses included mean percentage of time spent in AHCL and at sensor glucose ranges, insulin delivered and the proportion of users achieving recommended glucose management indicator (GMI < 7.0%) and time in target range (TIR 70‐180 mg/dl > 70%) goals. Results Users aged 15 years or younger (N = 3211) achieved a GMI of 6.8% ± 0.3% and TIR of 73.9% ± 8.7%, while spending 92.7% of time in AHCL. Users aged older than 15 years (N = 8874) achieved a GMI of 6.8% ± 0.4% and TIR of 76.5% ± 9.4% with 92.3% of time in AHCL. Time spent at less than 70 mg/dl was within the recommended target of less than 4% (3.2% and 2.3%, respectively). Similar outcomes were observed for each group (N = 790 and N = 1642, respectively) in the first month following AHCL initiation, and were sustained over the 6‐month observation period. Conclusions This real‐world analysis shows that more than 75% of users with T1D aged 15 years or younger using the MiniMed 780G system achieved international consensus‐recommended glycaemic control, mirroring the achievements of the population aged older than 15 years.