Neurotensin type 1 receptor-mediated activation of krox24, c-fos and Elk-1: preventing effect of the neurotensin antagonists SR 48692 and SR 142948

AbstractStimulation of neurotensin (NT) type 1 receptors (NT1-R) in transfected CHO cells is followed by the activation of mitogen-activated protein kinases and the expression of the early response gene krox24. By making point mutations and internal deletions in the krox24 promoter, we show that proximal serum responsive elements (SRE) are involved in transcriptional activation by NT. In addition, we show that the related early response gene c-fos and the Ets protein Elk-1 are also induced by NT. The involvement of NT1-R in NT-mediated activation of krox24, c-fos and Elk-1 was demonstrated by the preventing effect of the specific antagonists SR 48692 and SR 142948. Finally, we show that the activation of krox24 and Elk-1 on the one hand, and that of c-fos on the other hand, result from independent transduction pathways since the former are pertussis toxin-sensitive whereas the latter is insensitive to pertussis toxin

Toxicity and efficacy of conventional amphotericin B deoxycholate versus escalating doses of amphotericin B deoxycholate—fat emulsion in HIV-infected patients with oral candidosis

BackgroundAmphotericin B deoxycholate remains the treatment of choice for most systemic fungal infections; however, its clinical use can be limited by infusion-related side effects and nephrotoxicity. New formulations of amphotericin in lipid compounds have been shown to decrease toxicity. We previously showed that a lipid emulsion preparation of amphotericin B deoxycholate was better tolerated than the conventional preparation in dextrose. Therefore, we have now studied the clinical tolerance, renal toxicity and efficacy of higher doses of amphotericin B deoxycholate prepared and infused in a fat emulsion (Intralipid 20%). Thus, this report adds information to the previous publication.MethodsForty-two patients infected with HIV and suffering oral candidosis entered the study. The patients received either amphotericin B deoxycholate—glucose 1 mg/kg/day or amphotericin B deoxycholate—lipid emulsion 1 mg/kg/day for 4 days (randomized phase), or amphotericin B deoxycholate—lipid emulsion 2 mg/kg/day or 3 mg/kg/day (escalating-dose phase) for 5 days. Clinical (immediate) side effects and renal (creatinine) tolerance were assessed daily; efficacy against oral candidosis was measured by using a simple clinical score. Serum levels of amphotericin B were also measured.ResultsNone of the patients receiving amphotericin B deoxycholate—lipid emulsion had treatment interrupted, as compared to four (36%) in the amphotericin B deoxycholate—glucose group (p ≤0.01); chills during or after the infusions were significantly less frequent in the amphotericin B deoxycholate—lipid emulsion groups than in the amphotericin B deoxycholate-glucose group (p=0.03). The increase of creatininemia during treatment was significantly higher for patients receiving amphotericin B deoxycholate—glucose than for those receiving amphotericin B deoxycholate—lipid emulsion (p=0.001). The number of patients who had a creatininemia ≥18 mg/L during treatment was significantly higher in both the amphotericin B deoxycholate—glucose group (36%) and in the group receiving the highest dose of amphotericin B deoxycholate—lipid emulsion than in other groups (p≤0.06).The serum concentrations of amphotericin B were lower for the amphotericin B deoxycholate—lipid emulsion regimen than for the amphotericin B deoxycholate—glucose regimen at the same dose of 1 mg/kg/day, but increased with the dose.The change of the oral candidosis score was similar for the same dose of 1 mg/kg/day of amphotericin B deoxycholate infused in either glucose or lipid emulsion; higher doses of amphotericin B deoxycholate—lipid emulsion were more efficacious (p=0.009) and this efficacy seemed to increase with the dose (p=0.06).ConclusionsThe clinical and renal tolerance of amphotericin B deoxycholate are improved when the drug is directly prepared and infused in lipid emulsion (Intralipid) and this preparation allows for greater dosage, up to 3 mg/kg/day, with resultant greater efficacy. This preparation is simple and cost-effective (approximately 7 US $ per 50 mg of amphotercin B) and could be clinically compared to other formulations of amphotericin B

Delirium detection using relative delta power based on 1 minute single-channel EEG : a multicentre study

Background: Delirium is frequently unrecognised. EEG shows slower frequencies (i.e. below 4 Hz) during delirium, which might be useful in improving delirium recognition. We studied the discriminative performance of a brief single-channel EEG recording for delirium detection in an independent cohort of patients. Methods: In this prospective, multicentre study, postoperative patients aged ≥60 yr were included (n=159). Before operation and during the first 3 postoperative days, patients underwent a 5-min EEG recording, followed by a video-recorded standardised cognitive assessment. Two or, in case of disagreement, three delirium experts classified each postoperative day based on the video and chart review. Relative delta power (1–4 Hz) was based on 1-min artifact-free EEG. The diagnostic value of the relative delta power was evaluated by the area under the receiver operating characteristic curve (AUROC), using the expert classification as the gold standard. Results: Experts classified 84 (23.3%) postoperative days as either delirium or possible delirium, and 276 (76.7%) non-delirium days. The AUROC of the relative EEG delta power was 0.75 [95% confidence interval (CI) 0.69–0.82]. Exploratory analysis showed that relative power from 1 to 6 Hz had significantly higher AUROC (0.78, 95% CI 0.72–0.84, P=0.014). Conclusions: Delirium/possible delirium can be detected in older postoperative patients based on a single-channel EEG recording that can be automatically analysed. This objective detection method with a continuous scale instead of a dichotomised outcome is a promising approach for routine detection of delirium. Clinical trial registration: NCT02404181

Delirium detection using relative delta power based on 1 minute single-channel EEG : a multicentre study

Background: Delirium is frequently unrecognised. EEG shows slower frequencies (i.e. below 4 Hz) during delirium, which might be useful in improving delirium recognition. We studied the discriminative performance of a brief single-channel EEG recording for delirium detection in an independent cohort of patients. Methods: In this prospective, multicentre study, postoperative patients aged ≥60 yr were included (n=159). Before operation and during the first 3 postoperative days, patients underwent a 5-min EEG recording, followed by a video-recorded standardised cognitive assessment. Two or, in case of disagreement, three delirium experts classified each postoperative day based on the video and chart review. Relative delta power (1–4 Hz) was based on 1-min artifact-free EEG. The diagnostic value of the relative delta power was evaluated by the area under the receiver operating characteristic curve (AUROC), using the expert classification as the gold standard. Results: Experts classified 84 (23.3%) postoperative days as either delirium or possible delirium, and 276 (76.7%) non-delirium days. The AUROC of the relative EEG delta power was 0.75 [95% confidence interval (CI) 0.69–0.82]. Exploratory analysis showed that relative power from 1 to 6 Hz had significantly higher AUROC (0.78, 95% CI 0.72–0.84, P=0.014). Conclusions: Delirium/possible delirium can be detected in older postoperative patients based on a single-channel EEG recording that can be automatically analysed. This objective detection method with a continuous scale instead of a dichotomised outcome is a promising approach for routine detection of delirium. Clinical trial registration: NCT02404181

Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients

International audienceObjectives: There is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD.Methods: Individuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderate-severe) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities.Results: Of 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05-1.10), female gender (OR=0.45, 95% CI: 0.25-0.80), body mass index (OR=1.07, 95% CI: 1.02-1.12), hypertension (OR=1.86, 95% CI: 1.01-3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09-3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47-29.62) and rituximab (OR=4.21, 95% CI: 1.61-10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87-2.42) (n=175 each group).Conclusions: In the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD

Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients

International audienceObjectives: There is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD.Methods: Individuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderate-severe) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities.Results: Of 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05-1.10), female gender (OR=0.45, 95% CI: 0.25-0.80), body mass index (OR=1.07, 95% CI: 1.02-1.12), hypertension (OR=1.86, 95% CI: 1.01-3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09-3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47-29.62) and rituximab (OR=4.21, 95% CI: 1.61-10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87-2.42) (n=175 each group).Conclusions: In the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases