The search of substrates for solute carriers (SLCs) constitutes a major issue, owing notably to the role played by some SLCs, such as the renal electrogenic organic cation transporter (OCT) 2 (
), in ...pharmacokinetics, drug-drug interactions and drug toxicity. For this purpose, substrates have been proposed to be identified by their
-inhibition and
-stimulation properties towards transporter activity. To get insights on the sensitivity of this approach for identifying SLC substrates, 15 various exogenous and endogenous OCT2 substrates were analysed in the present study, using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (DiASP) as a fluorescent OCT2 tracer substrate. All OCT2 substrates
-inhibited DiASP uptake in OCT2-overexpressing HEK293 cells, with IC
values ranging from 0.24 µM (for ipratropium) to 2.39 mM (for dopamine). By contrast, only 4/15 substrates, i.e., acetylcholine, agmatine, choline and metformin,
-stimulated DiASP uptake, with a full suppression of the
-stimulating effect of metformin by the reference OCT2 inhibitor amitriptyline. An analysis of molecular descriptors next indicated that
-stimulating OCT2 substrates exhibit lower molecular weight, volume, polarizability and lipophilicity than non-
-stimulating counterparts. Overall, these data indicated a rather low sensitivity (26.7%) of the
-stimulation assay for identifying OCT2 substrates, and caution with respect to the use of such assay may therefore be considered.
Several exposure campaigns of silica–soda–lime window glass have been performed in 30 European sites and 1 in Canada in order to understand, quantify and model the phenomenon of soiling. In this ...purpose samples were exposed sheltered from the rain. Parallel to exposure, several meteorological parameters and pollution concentrations have been monitored. This paper shows first results on the establishment of a dose–response function for glass soiling. Statistical analyses show that PM
10 is not the only parameter, but also SO
2 and NO
2 atmospheric concentrations seem to be responsible for the optical impairment of glass surfaces, expressed as haze.
The air pollution abatement consequences for limestone and window glass during the recent period (1997–2014) were quantified in Paris by a 3-step approach: (1) in-the-field measurement of pollution ...and climatic parameters; (2) weathering calculation by means of dose–response functions in 100 m × 100 m grid cells of the Paris plan; (3) mapping the geographic distribution of the calculated damage. In order to get a global damage estimation of different materials, a set of maps were generated: (1) the total surface of buildings and monuments façades in the part of Paris inscribed on the UNESCO List between the Ile Saint-Louis and the Concorde Square; (2) the surface of limestone and window glass of each façade; (3) the yearly spatial distribution of SO
2
, NO
2
and PM10 concentration; (4) the potential surface damage of materials in response to climatic and pollution doses. The calculated responses are in agreement with those measured in the field during several campaigns of exposure of limestone and window glass in Paris performed during the same period; (5) the effective damage to limestone and window glass. The decreases of the potential and of the effective damage are quantified and mapped. They are driven by the decrease in air pollutant concentrations.
•Intravenous amoxicillin at 6 g/day allowed detectable concentrations in pleural fluid in 90% of cases.•Amoxicillin coefficient of diffusion in pleural fluid was 68%.•Metronidazole achieved excellent ...pleural diffusion, highly correlated with plasma levels.•Considering causative pathogen MICs, an amoxicillin target of Cmin or Css ≥ 5 mg/L in pleural fluid seems appropriate.
The pharmacokinetics of antibiotics in pleural fluid during pleural infections has been poorly described. This study aimed to explore amoxicillin and metronidazole diffusion into the pleural space.
This was an ambispective, single-centre study that included patients with complicated parapneumonic effusion or pleural empyema managed with repeated therapeutic thoracentesis as first-line treatment between 2014 and 2022. Pleural steady-state or trough concentrations of amoxicillin and metronidazole were measured, with a lower limit of quantification of 5 mg/L.
Seventy paired blood and pleural samples were analysed from 40 patients. The median (interquartile range) patient age was 55 years (45–67 years) and 88% were male. The median patient weight was 65.8 kg (57.3–82 kg) and median plasma albumin concentration was 29.7 g/L (23.7–33.9 g/L). Median creatinine clearance was 106 mL/min (95–117 mL/min). Median amoxicillin pleural concentrations in patients treated with oral, bolus and continuous intravenous administrations (6 g/day) were, respectively, 5.2 (<5–6.4), 9.4 (8–13.1) and 10.8 (7.1–13.1) mg/L. Pleural concentrations were <5 mg/L in 5/11 samples (45%) with oral treatment and 6/59 (10%) with intravenous treatment. Median metronidazole pleural concentrations were 18.4 (15.7–22.8) mg/L, with all patients being treated orally (1.5 g/day).
Oral metronidazole (1.5 g/day) and intravenous amoxicillin (6 g/day) achieved therapeutic targets in pleural fluid in most cases, but oral amoxicillin did not.
Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, ...1,4‐alpha‐glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin‐like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.
Even though
has been described in 2002, this species has long been underestimated due to the unreliability of conventional identification methods and only a few cases of infections have been ...reported.
Little is known about clinical significance and antimicrobial susceptibility profile of this uncommon species.
To evaluate the clinical relevance of
and its antimicrobial susceptibility profile.
All
isolates, collected from 2010 to 2019 in 10 French university hospitals, were retrospectively included. Demographic, clinical and microbiological data were collected for all cases. Antimicrobial susceptibility testing was performed according to the 2019 EUCAST guidelines.
Fifty-seven clinical isolates of
were collected in 57 patients (median age, 65.8 years; male/female sex ratio, 1.1), mostly from urine (28 %), blood culture (28 %) and bone/synovial fluid (19 %) samples. Of them, 14 cases of infection were confirmed, mainly bone and joint infections (50 %) followed by urinary tract infections (UTIs) (21 %), bacteremia (14 %), skin and soft-tissue infections (14 %).
was recovered in pure culture in 36 % of cases (UTIs and bacteremia) while mixed cultures were observed for other infections. By testing 52 clinical isolates
, this species appeared to be fully susceptible to linezolid and vancomycin while most isolates (>80 %) were susceptible to amoxicillin (MIC
, 2 µg ml
), gentamicin, tetracycline and rifampicin. Both cefotaxime and ciprofloxacin seemed to have a limited activity (ca. 50 % of susceptible strains). The MIC distribution for ciprofloxacin showed a bimodal profile with a population of highly-resistant strains with MICs >2 µg ml
. Most isolates (>90 %) were categorized as resistant to penicillin G and clindamycin.
should be considered as an actual opportunistic pathogen, and treatment with amoxicillin, vancomycin or linezolid should be preferred.
Bloodstream infections are a leading cause of mortality. Their detection relies on blood cultures (BCs) but time to positivity is often between tens of hours and days. d-lactate is a metabolite ...widely produced by bacteria but very few in human. We aimed to evaluate d-lactate, d-lactate/l-lactate ratio and d-lactate/total lactate ratio in plasma as potential early biomarkers of bacteraemia on a strictly biological standpoint.
A total of 228 plasma specimens were collected from patients who had confirmed bacteraemia (n = 131) and healthy outpatients (n = 97). Specific l-lactate and d-lactate analyses were performed using enzymatic assays and analytical performances of d-lactate, d-lactate/total lactate and d-lactate/l-lactate ratios for the diagnosis of bacteraemia were assessed.
A preliminary in vitro study confirmed that all strains of Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were able to produce d-lactate at significant levels. In patients, plasma d-lactate level was the most specific biomarker predicting a bacteraemia profile with a specificity and predictive positive value of 100% using a cut-off of 131 μmol.L−1. However, sensitivity and negative predictive value were rather low, estimated at 31% and 52%, respectively. d-lactate displayed an Area Under Receiver Operating Characteristic (AUROC) curve of 0.696 with a P value < 0.0001. There was no difference of d-lactate levels between BCs bottles positive for Gram-positive or Gram-negative bacteria (p = 0.55).
d-lactate shows promise as a specific early biomarker of bacterial metabolism. The development of rapid automated assays could raise clinical applications for infectious diseases diagnosis including early bacteraemia prediction.
Primary Carnitine Deficiency (PCD) is a fatty acid oxidation disorder that will be included in the expansion of the French newborn screening (NBS) program at the beginning of 2023. This disease is of ...high complexity to screen, due to its pathophysiology and wide clinical spectrum. To date, few countries screen newborns for PCD and struggle with high false positive rates. Some have even removed PCD from their screening programs. To understand the risks and pitfalls of implementing PCD to the newborn screening program, we reviewed and analyzed the literature to identify hurdles and benefits from the experiences of countries already screening this inborn error of metabolism. In this study, we therefore, present the main pitfalls encountered and a worldwide overview of current practices in PCD newborn screening. In addition, we address the optimized screening algorithm that has been determined in France for the implementation of this new condition.
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