Pro-opiomelanocortin and ACTH–cortisol dissociation during pediatric cardiac surgery

In critically ill adults, high plasma cortisol in the face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0–36 months), plasma was obtained pre-operatively, intraoperatively, and on post-operative days 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (P &lt; 0.0001) but no longer thereafter (P &gt; 0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (P &lt; 0.0001), glucocorticoid-treated patients had already suppressed ACTH intraoperatively (P ≤ 0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally activated HPA axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH. Significance statement Glucocorticoids are often administered during pediatric cardiac surgery. In critically ill children, endogenous systemic glucocorticoid availability is elevated already upon ICU admission while ACTH levels are normal. This hormonal constellation suggests the presence of active feedback inhibition of ACTH. In this study, we have documented that intraoperative administration of glucocorticoids accelerates the suppression of ACTH, resulting in low plasma ACTH already upon ICU admission. Pre-operative plasma POMC, the ACTH precursor, but not ACTH, was increased. This is compatible with a centrally activated HPA axis prior to surgery in young children but reduced processing of POMC into ACTH within the pituitary. These findings suggest that glucocorticoid treatment in the context of pediatric cardiac surgery may amplify pre-existing impaired pituitary processing of the prohormone POMC.</p

Pro-opiomelanocortin and ACTH–cortisol dissociation during pediatric cardiac surgery

In critically ill adults, high plasma cortisol in the face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0–36 months), plasma was obtained pre-operatively, intraoperatively, and on post-operative days 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (P &lt; 0.0001) but no longer thereafter (P &gt; 0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (P &lt; 0.0001), glucocorticoid-treated patients had already suppressed ACTH intraoperatively (P ≤ 0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally activated HPA axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH. Significance statement Glucocorticoids are often administered during pediatric cardiac surgery. In critically ill children, endogenous systemic glucocorticoid availability is elevated already upon ICU admission while ACTH levels are normal. This hormonal constellation suggests the presence of active feedback inhibition of ACTH. In this study, we have documented that intraoperative administration of glucocorticoids accelerates the suppression of ACTH, resulting in low plasma ACTH already upon ICU admission. Pre-operative plasma POMC, the ACTH precursor, but not ACTH, was increased. This is compatible with a centrally activated HPA axis prior to surgery in young children but reduced processing of POMC into ACTH within the pituitary. These findings suggest that glucocorticoid treatment in the context of pediatric cardiac surgery may amplify pre-existing impaired pituitary processing of the prohormone POMC.</p

SMILE: a joint ESA/CAS mission to investigate the interaction between the solar wind and Earth's magnetosphere

The Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) is a collaborative science mission between ESA and the Chinese Academy of Sciences (CAS). SMILE is a novel self-standing mission to observe the coupling of the solar wind and Earth's magnetosphere via X-Ray imaging of the solar wind -- magnetosphere interaction zones, UV imaging of global auroral distributions and simultaneous in-situ solar wind, magnetosheath plasma and magnetic field measurements. The SMILE mission proposal was submitted by a consortium of European, Chinese and Canadian scientists following a joint call for mission by ESA and CAS. It was formally selected by ESA's Science Programme Committee (SPC) as an element of the ESA Science Program in November 2015, with the goal of a launch at the end of 2021. In order to achieve its scientific objectives, the SMILE payload will comprise four instruments: the Soft X-ray Imager (SXI), which will spectrally map the Earth's magnetopause, magnetosheath and magnetospheric cusps; the UltraViolet Imager (UVI), dedicated to imaging the auroral regions; the Light Ion Analyser (LIA) and the MAGnetometer (MAG), which will establish the solar wind properties simultaneously with the imaging instruments. We report on the status of the mission and payload developments and the findings of a design study carried out in parallel at the concurrent design facilities (CDF) of ESA and CAS in October/November 2015

Idarubicin dose escalation during consolidation therapy for adult acute myeloid leukemia

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m daily for 5 days, etoposide 75 mg/m daily for 5 days, and idarubicin 9 mg/m daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P, .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity

A phase II study of liposomal daunorubicin, in combination with cyclophosphamide, vincristine and prednisolone, in elderly patients with previously untreated aggressive non-Hodgkin lymphoma

Liposomal daunorubicin (DaunoXome) was substituted for doxorubicin in the CHOP regimen, aiming to reduce toxicity and maintain or improve efficacy in elderly patients. Eligibility criteria included: age >= 60 years; previously untreated aggressive non-Hodgkin Lymphoma (NHL) and performance status (PS) 0-2. Treatment was cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (maximum 2mg), and DaunoXome 100 mg/m(2) iv on day 1, prednisolone 100mg po on days 1-5 and G-CSF 5 mu g/kg/day sc, for 6-8 cycles. For the 51 patients, median age was 70 years (range 60-88), 94% had diffuse large B-cell lymphoma (DLBCL) and 55% were high-intermediate or high-risk according to the age-adjusted international prognostic index. A mean of 6 cycles was delivered, with dose reductions of DaunoXome in 8.3% of cycles. The combined CR and CRu rate was 65.2%, survival was 566 days and 5-year survival 35%. Three deaths occurred during treatment and may have been related to COP-X. Only 4 (7.8%) of the remaining patients had >= 10% reduction in LVEF. However, 35% of patients were hospitalised during treatment, mostly for febrile neutropenia. The response rate to COP-X was similar to that expected with CHOP, with low cardiac toxicity. The high rate of infectious complications suggests that the DaunoXome dose used may be too high for this patient group. These results support further investigation of this regimen in patients with aggressive NHL

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 μg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662

Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma

Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non-Hodgkin's lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under-represented in NHL (26·2%) vs control subjects (37·2%; P = 0·02), and conferred a 2·4-fold lower risk of follicular (odds ratio = 0·41, 95% confidence interval: 0·19–0·88, p = 0·02) but not diffuse large B-cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects

Quality assessment of QA4ECV Climate Data Records of tropospheric NO2, HCHO and CO OMI, GOME-2 and IASI, and ground-based validation with NDACC DOAS and FTIR observations

International audienc

Comprehensive Quality Assessment of recent Climate Data Records for ECVs NO₂, HCHO and CO

International audienc

Validation of Aura-OMI QA4ECV NO₂ climate data records with ground-based DOAS networks: the role of measurement and comparison uncertainties

International audienceThe QA4ECV version 1.1 stratospheric and tropospheric NO2 vertical column density (VCD) climate data records (CDR) from the satellite sensor OMI are validated, using NDACC zenith scattered light DOAS (ZSL-DOAS) and Multi Axis-DOAS (MAX-DOAS) data as a reference. The QA4ECV OMI stratospheric VCD have a small bias of ~ 0.2 Pmolec cm-2 (5–10 %) and a dispersion of 0.2 to 1 Pmolec cm-2 with respect to the ZSL-DOAS measurements. QA4ECV tropospheric VCD observations from OMI are restricted to near-cloud-free scenes, leading to a negative sampling bias (with respect to the unrestricted scene ensemble) of a few Pmolec cm-2 up to −10 Pmolec cm-2 (−40 %) in one extreme high-pollution case. QA4ECV OMI tropospheric VCD has a negative bias with respect to the MAX-DOAS data (−1 to −4 Pmolec cm-2), a feature also found for the OMI OMNO2 standard data product. The tropospheric VCD discrepancies between satellite and ground-based data exceed by far the combined measurement uncertainties. Depending on the site, part of the discrepancy can be attributed to a combination of comparison errors (notably horizontal smoothing difference error), measurement/retrieval errors related to clouds and aerosols, and to the difference in vertical smoothing and a priori profile assumptions